Abstract
Among many nanoparticle-based delivery platforms, liposomes have been particularly successful with many formulations passed into clinical applications. They are well-established and effective gene and/or drug delivery systems, widely used in cancer therapy including breast cancer. In this review we discuss liposome design with the targeting feature and triggering functions. We also summarise the recent progress (since 2014) in liposome-based therapeutics for breast cancer including chemotherapy and gene therapy. We finally identify some challenges on the liposome technology development for the future clinical translation.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Breast cancer is one of the most commonly diagnosed cancers (11.7% of the total cases) and the leading cause of cancer death among women worldwide, according to GLOBOCAN 2020 [1]. The estimated number of new cases of breast carcinomas worldwide is expected to increase to 2.50 million and it is predicted that the breast cancer-related mortality will be 768,646 by 2025. Metastatic progression represents the major risk factor affecting the survival rates [2]. In contrast to the primary tumours that can be surgically operated under standard of care approach, the secondary foci of breast cancer are less approachable, and therefore, chemotherapy and radiotherapy are currently the main treatment methods for metastatic breast cancer [3].
Severe side effects and rapidly developing drug resistance of the tumour cells are the main challenges of the conventional chemotherapy. As most of chemotherapeutic drugs are not selective to cancer cells, one of the most important tasks to improve the effectiveness and tolerability of chemotherapy is selective delivery of the therapeutic agent to cancer tissues with simultaneous minimization of the damage of the healthy organs. Drug resistance of malignant cells is another deficiency of chemotherapy, which is attributed to genetical factors, and first of all, to the heterogeneity of the tumour cellular populations [4], as well as to the effects of the tumour microenvironment and the limited tumour tissue penetrating capability of the drugs [5, 6]. At the same time, molecular studies unveiled that the development and progression of breast cancer is governed by the mutated genes’ expression to a significant extent [7]. In this context, gene therapy is emerging to revolutionize the classic breast cancer treatment paradigm [8]. However, gene therapy is also facing a problem regarding to safe and efficient delivery of therapeutic genes or gene-regulating products into the nucleus of mammalian cells.
To address this challenge, numerous drug and gene delivery systems have been developed including viral vectors [9,10,11] and non-viral vectors, such as liposomes [12], polymers [13,14,15] and inorganic nanomaterials [16]. Viral vectors are the most common gene delivery systems reported in clinical trials, but the safety concerns and limited cargo size are the obstacles hindering their applications [9,10,11]. To overcome these limitations, nanoparticle-based vectors have been explored [17]. Liposomes are well-established nanomaterials for drug/gene delivery [18, 19]. Among the advantages of liposomes are high loading capacity, convenient preparation and excellent biocompatibility [13,14,15]. Liposomes are composed of phospholipid molecules which contain hydrophobic tails and hydrophilic heads, forming the amphiphilic vesicle structures in aqueous solutions. Structurally, liposomes are divided into small unilamellar vesicles (~ 100 nm) and large unilamellar vesicles (200–800 nm) with a single bilayer, and multilamellar vesicles (500–5000 nm) containing multiple bilayers [20]. Due to their amphipathic nature in aqueous media, liposomes have the unique capability of entrapment of both hydrophilic and hydrophobic compounds [21]. The hydrophobic drugs can in principle be encapsulated between each bilayer of liposomes, while water-soluble drugs can be efficient loaded in the middle core. The minimization of side effects of anticancer drugs for the patients can be achieved by targeted liposomes [22]. The surface of liposomes can be modified by appropriate ligands to target the specific receptors of breast cancer or its microenvironment to achieve selective delivery. Triggering is another option that allows to control the local dose of the drug and, for example, initiate the drug release at certain time point after accumulation of a required dose, of when the tumour is sensitive [23]. These superior properties make liposomes promising in cancer therapy including breast cancer, compared with other nanoparticle-based delivery systems. Schematic diagram of liposome-based delivery systems with versatile functionalities is shown in Fig. 1.
Liposomal drug loading can be achieved via passive and active strategies [24, 25]. Passive loading employs the procedure in which liposomes are formed concurrently with drug loading, such as the thin lipid film method [26]. During the bilayer formation in aqueous solution, water-soluble substances are passively encapsulated inside the formed vesicles. Although this method is simple, it only allows a low encapsulation efficiency limited by the aqueous solubility of drugs [26]. In contrast, active loading can result in high drug-loading efficiency by changing medium pH to increase aqueous solubility of drugs [27]. In active loading, the loading drugs typically contains an ionizable amine group and liposomes are first prepared with transmembrane pH gradient (an ammonium sulfate gradient), where the pH value of aqueous phases inside and outside the liposomes is different. The pH outside the liposome allows migration of drug dissolved in the external aqueous phase across the lipid bilayer. Once internalised into the liposomes, the drug becomes protonated and subsequently trapped there due to the differing pH, reaching concentration of 250 mM in liposomes [28,29,30,31]. Then, this selection criterion may exclude a large number of hydrophobic drugs from the list of candidates for liposomal delivery due to the poor aqueous solubility.
Although the liposomes exhibit superior properties compared with other nanocarriers, they still face another major issue, such as the structural instability. Some unsaturated lipid components from natural sources (egg or soybean phosphatidylcholine) form less stable bilayers that undergo oxidation and/or hydrolysis [32, 33]. This disadvantage may cause leakage of encapsulated payloads and fusion of the damaged liposomes. To avoid the oxidation problem, one could adjust the molar ratio between saturated and unsaturated lipids by increasing the lipid saturation level [34]. Another solution is to add small amounts of antioxidants during the liposome manufacturing steps. To keep the hydrolysis to a minimum, liposome formulations are often lyophilized during the fabrication for longer term storage [35, 36].
In this review, we first discuss breast cancer characteristics and the related drug delivery strategies. Next, we summarise recent achievements in liposome-based drug delivery and gene therapies of breast cancer. A special emphasis is placed on the identification of the key challenges that need to be addressed to improve the utility of liposomes in clinical settings. Finally, we provide our perspectives of further clinical translation of the liposome technology.
Breast cancer characteristics
Breast cancer shares the principal cancer hallmarks with many other cancers [37, 38]. However, this complex disease has some features that differentiate it from other malignant neoplasms. First of all, it develops from the mammary gland cells, which are epithelial cells by embryonic origin and morphology forming ducts and lobules in the healthy organ. According to this, the breast cancer tumours stemming from mammary gland ducts develop ductal carcinoma, and the transformed cells of lobuli form lobular carcinomas [39]. Ductal carcinomas tend to appear as solid tumour masses, sometimes having distorted glandular architecture. The cells of lobular breast carcinomas are most commonly distanced from each other and form files or sheets [39, 40].
Next, breast carcinomas may grow within the borders of the original site within the mammary gland or go beyond them. This defines the small, early stage, carcinomas in situ and invasive carcinomas, respectively. The secondary colonies of breast cancer develop following spreading of metastatic cancer cells to distant organs [41]. Different cancers have different patterns of metastatic spreading (organ tropism of metastases) [42]. This as well makes one of the specific features of breast cancer, which most commonly metastasise to the lungs, bones, liver, and brain [43]. The size of the original tumour, the extent of its invasion and metastatic distribution, including the status if regional lymph nodes and distant organs, defines the stage of the breast cancer by tumour (T), node (N), and metastasis (M) classification [44]. The histological grading system, in parallel, defines the degree of malignant transformation of the mammary gland tissue (in terms of loss of differentiation, nuclear polymorphism and mitosis rate).
Finally, the breast cancer is classified by the intensity of expression of certain molecular markers, such as estrogen receptor (ER), progesterone receptor (PR) and HER2-receptor [45]. This classification links the phenotype of cancer cells with a specific origin (luminal vs. basal cells of the mammary ducts). According to this, there are two luminal subtypes of breast cancer (ER+, PR+, HER2−), triple negative (basal-like) breast cancer (ER−, PR−, HER2−), HER2-enriched type (ER−, PR−, HER2+) and normal-like breast cancer (ER+, PR+, HER2−, with low mitotic rates). This classification is very important for the selection of the treatment strategy of breast cancer. In particular, it indicates that certain subtypes of breast cancer are sensitive to hormones and can be treated with hormone-based targeting [45]. The HER2-enriched breast cancer is an indication for the targeted therapy with the ligands to HER2-receptor [46]. The pharmaceutical treatment options for the triple negative breast cancer are limited due to the absence of the established molecular targets. The molecular subtypes of breast cancer demonstrate different biological behaviour. For example, triple negative breast cancer has the highest invasion potential and anomalously high frequency of hepatic metastases compared to the other subtypes [46]. As a result of combination of the biological features and availability/efficiency of the treatment, the molecular subtypes of breast cancer have different prognosis and survival rates.
The idea for the rational design of the nanoparticle-based drug delivery systems for breast cancer treatment may stem from some features of these tumours. The mammary glands, where the breast cancer originally develops naturally undergoes age-related replacement with adipose and fibrous connective tissue [47,48,49]. This creates an additional vulnerability of the mammary cells but also brings into light the effects of the tumour microenvironment on the tumour growth and its response on treatment. For example, pro-angiogenic and pro-fibrotic signalling pathways, such as TGF-β1, which also is a key mechanism of epithelial-to-mesenchymal transition (EMT), are commonly upregulated in advanced breast carcinomas [50]. This may result in excessive accumulation of collagenous connective tissue and scar-like hardening of the affected zone. Enhanced angiogenesis, in turn, stimulates overgrowth of blood vessels with abnormal structure, which can result in a notable enhanced permeability and retention effect (EPR) and increased interstitial pressure in the tumour [51]. These factors may affect biodistribution of the nanoscale drug delivery systems (i.e., stimulate accumulation of the nanodrug in the outer parts of the tumour and prevent penetration of the therapeutic agent to the deep part of it). In addition, the interaction between the nanoparticles and breast cancer cells largely depends on the nanoparticle design and modification. For example, the cationic lipid components can be refined to improve liposomes’ cellular uptake capability, thus, increasing therapeutic efficacy on breast cancer [52]. The morphology of the liposome also played an important role in cell-mediated endocytosis. Soft and disordered liposomes exhibit a lower uptake than those with a rigid and ordered lipid membrane [52]. To optimise the therapeutic outcomes, these factors should be taken into account when designing liposomal nanoparticles.
In contrast to many other cancers, the location of the primary breast carcinoma is surgically approachable, and also can be treated with various local applications of physical factors, such as X-rays, ultrasound, light or magnetic fields which could be combined with drug delivery systems. On the other hand, the main danger of breast cancer is not the primary tumours, but the metastatic secondary tumours [53]. Therefore, for the successful eradication of the metastatic breast cancer, the combination of the molecular subtype properties with the challenges of organ-specific microenvironments (e.g., blood–brain barrier for the metastases to the brain) should be considered in the development of the treatment strategy.
Liposome-based drug delivery
Breast cancer treatment by liposome-formulated drugs
Chemotherapy involves the use of anti-cancer drugs and it is a widely used treatment tool. Common chemotherapeutic drugs used for breast cancer include anthracyclines [doxorubicin (DOX), epirubicin (EPR), daunorubicin (DNR)) and taxanes (paclitaxel (PTX), docetaxel (DTX)] [54, 55]. However, they have major shortfalls including unnecessary cytotoxic exposure, systemic toxicity as well as chemoresistance [56]. These limitations became even worse when combining two or more different drugs simultaneously for breast cancer therapy [57]. For example, the co-administration of DOX and PTX exhibited high response rates; however, a major limitation in its clinical use was high levels of cardiotoxicity induced by combinational chemotherapy. Due to their different pharmacokinetics, free PTX interferes with DOX elimination, resulting in high plasma concentrations of the cardiotoxic DOX as well as its highly cardiotoxic metabolite, doxorubicinol (DOXL) [58].
Liposomes, as versatile delivery platforms for various drug encapsulation, offer a promising solution to minimise the toxicity issues of chemotherapeutic drugs [59,60,61,62,63]. Franco et al. found that compared to free PTX and DOX, a 1:10 co-encapsulation ratio of PTX and DOX in liposomes was able to improve cardiac toxicity profile by eliminating pharmacokinetic interactions between PTX and both DXR and its metabolite, doxorubicinol in mice bearing the 4T1 breast tumor [58]. A strategy that could possibly stabilise ratiometric drug delivery by encapsulating drug-loaded liposomes in a thermogel matrix was demonstrated elsewhere [64]. It also was observed that the nanohybrid carriers exhibited a sustained local release. This phenomenon could be explained by the diffusion-controlled process, where the encapsulated anthracycline was first released from the liposomes and then diffused through the hydrogel matrix. In vivo studies confirmed that lower cardiotoxicity level from liposome–hydrogel hybrid delivery system was achieved compared to that of liposomal anthracycline without gel encapsulation [64].
The gradually accumulating evidence indicate that the use of liposomal drug delivery systems can help to overcome multidrug resistance (MDR). Liu et al. developed mitochondrial targeting liposomes via the surface modification with dequalinium (DQ), a positively charged chemical that allows to employ negative mitochondrial membrane potential. Two types of drugs, EPR and quinine (QN), were co-loaded in the liposomes [65]. Facilitated by DQ, the unruptured liposomes entered the cells via phagocytosis and were internalized in mitochondria, where QN and EPR upregulated the proapoptotic protein Bax and downregulated the anti-apoptotic protein Mcl-1. This led to the release of cytochrome complex and the activation of caspases 9 and 3, resulting in a cascade of apoptotic reactions in cancer cells. This study minimised the cellular effect on both extrinsic and intrinsic resistance to drugs via the engineered liposome formulations. However, due to the use of multiple drugs within one liposome delivery system, more rigid and comprehensive evaluation procedures are required prior to clinical rollover.
P-glycoprotein (P-gp) that form efflux pumps are particularly responsible for MDR [66]. P-gp is one of the most common ATP binding cassette transporters that overexpressed in breast cancer cells [67]. An interesting nuclear-targeting strategy allowed to minimise MDR in breast cancer using a liposome platform, where aptamer AS1411 (single stranded DNA) was co-encapsulated with DOX. After the cellular internalisation, the aptamer–DOX complex was released from the liposomes and migrated to the nucleus via the aptamer–nucleolin interaction. This nuclear targeting interaction enabled the evasion of DOX efflux by P-gp pumps. As a result, the therapeutic efficacy was enhanced [66]. Although the in vitro results were promising in this study, in vivo evidence needs to be collected for further assessment and validation.
Other strategies to address the P-gp-aided MDR rely on the inhibition of P-gp expression and consequent enhancement of the drug concentration in the cancer cell environment. Liu et al. reported the liposomes co-loaded with tetrandrine (TET) and DNR and functionalised with wheat germ agglutinin (WGA) [68]. WGA promotes cellular uptake via receptor mediated endocytosis by targeting N-acetyl-d-glucosamine and sialic acid on the surface of cells [69]. TET, loaded delivered inside the lipid bilayers, allowed to overcome chemoresistance by suppressing the expression of P-gp. This suppression enabled a greater concentration of DNR in malignant cells. In vitro studies confirmed that the functionalised liposomes effectively accumulated in cancer cells (MCF-7 and MCF-7/ADR), significantly increased the expression of pro-apoptotic proteins (Bax and Bak) and activated caspase 8, 9 and 3 apoptosis pathways. In vivo studies further validated the therapeutic efficacy of such liposomes by comparing their tumour inhibiting capabilities with other treatment conditions, indicating that the liposome-formulated drugs could be a potential strategy in overcoming MDR in MCF-7 breast cancer cells.
Liposomal drug delivery also has the potential to prevent metastatic progression of breast cancer. In the last decade, it has been confirmed that both EMT and vasculogenic mimicry channels (VMC) play a role in the metastasis and chemoresistance of breast cancer [70, 71]. Therefore, the formulation of synergistic liposomes that suppress these mechanisms and induce cancer cell apoptosis is an interesting field of research. EMT is the process, whereby epithelial cells exhibit decreased adhesion and enhanced migration, transforming into mesenchymal cells [72]. To inhibit EMT mechanism in breast cancer, the commonly used drugs for synergistic liposomes include anthracyclines co-delivered with dioscin (DIS) or dihydroartemisin (DHA) [73, 74]. The last two substances are able to suppress EMT by affecting the regulation of key proteins. DIS is responsible for the upregulation of E-cadherin and downregulation of vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9) and vimentin [73]. DHA works in a similar manner, however, is also responsible for downregulation of TGF-β1 and α5β1-integrin [74]. Both liposome-formulated drugs have been tested for metastatic breast cancer in vitro and in vivo, indicating effective anti-tumour capabilities with minimum toxicity [73, 74]. VMC is the formation of vascular channels lacking endothelial cells [75]. Under the hypoxic condition, aggressive breast cancer cells can also form VMC without the involvement of endothelial cells [75]. Synergistic liposomes have been developed to supress VMC process and induce breast cancer cell apoptosis. Drugs used in such liposomes include anthracycline co-encapsulated with celecoxib or honokiol [76, 77]. In vitro studies demonstrated that both liposomal formulations significantly downregulated the expression of key VMC proteins, resulting in a destruction of these channels [76, 77]. In vivo work further exhibited higher anticancer efficacy of the synergistic liposomes on breast cancer metastasis, compared with other treatment conditions [76, 77]. Overall, arming liposomes with synergistic mechanisms could provide a promising strategy in the treatment and prevention of invasive breast cancer.
Breast cancer active targeting by liposomes
Recent research efforts adapted different targeting strategies to reduce nonspecific toxic effects of conventional chemotherapeutic drugs. The term “active targeting liposomes” refers to the liposomes functionalised with targeting reagents that possess a high affinity to molecules overexpressed by the cells of interest. As a result, such delivery systems can selectively deliver therapeutic agents to primary or metastatic tumours, limiting the probability and the potential severity toxic side effects [78]. Furthermore, active targeting strategies are also capable to overcome resistance incurred by conventional drug delivery systems relying on passive cellular uptake of nanocarriers [63]. By utilising targeting ligands, the functionalized liposome undergoes receptor-mediated endocytosis, which results in rapid cellular internalisation. In contrast to passive targeting, where liposomes diffuse through the cell membrane, the targeting feature also enables the complete evasion of P-gp efflux pumps [67].
A wide range of targeting ligands have been explored and tested in in vitro and in vivo breast cancer therapy, including antibodies, aptamers, small molecules, and peptides [74, 77, 79,80,81,82,83,84,85,86]. Antibodies offer sufficient binding affinities and targeting specificity to the antigens overexpressed by the breast cancer cells. However, they encompass high production costs and complex conjugation methodologies [87]. Similarly, nucleic acid strands known as aptamers, demonstrate a relatively high level of binding affinity and target specificity [88]. However, they are susceptible to nucleic degradation over time and may induce potential immunogenicity [89]. Small molecules are inexpensive in scale-up manufacturing and involve simple conjugation with nanocarriers. They also exhibit minimal cytotoxicity and immunogenicity [90]. Some receptors overexpressed by cancer cells, such as the folate receptor utilise small molecules as their targeting ligand [91]. Peptides, with their relatively small molecular size and weight, also offer high binding affinity and specificity, economic cost of production and low immunogenicity [89]. Table 1 presented a list of receptors and corresponding ligands used in targeted liposomes for breast cancer therapy.
Breast cancer treatment by triggerable liposome-based drug delivery
On-demand release of encapsulated drugs from liposomes emerged as a recent advancement. Optimisation of this technology via engineering of triggerable liposomes attracts great attention [93,94,95,96,97]. Various triggering modalities were explored for stimulating an immediate drug release from liposomes and classified into internal and external triggers [93, 96, 98]. Internal triggers correspond to the unique physiological characteristics of tumour microenvironment and include pH variation [99,100,101,102] and enzyme effects [103]. Heat [15, 104,105,106,107,108], light [109,110,111,112,113], ultrasound [107] and magnetic fields [108] are among the external triggering sources. These triggering modalities have been widely applied to the liposome technology for breast cancer treatment in preclinical applications. While very important, the triggering mechanisms are not the primary focus of this article as they were comprehensively reviewed, discussed and interpreted recently [109,110,111,112,113].
pH-sensitive liposomes
The pH of extracellular space of the tumour tissues is lower relative to normal cells [114], due to lactate production and increased hydrolysis of ATP by cancer cells. Considering this condition, the pH-sensitive liposomes that can maintain stability in normal physiological conditions, while disassemble and release the drugs in an acidic microenvironment were engineered [115]. These liposomes responded to the variation of pH values between normal and cancerous tissues by releasing the therapeutic payload. Jiang et al. reported a pH-sensitive liposome called Trojan horse liposome encapsulating PTX for breast cancer therapy [99]. The liposome introduced a pH-responsive dimethylmaleic amide (DMA) bond into 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE) with a linker of lysine to form DLD/PTX-Lips. In weak acidic pH microenvironment, the cleavage of DMA amide transferred the zeta-potential of liposome from negative to positive, which facilitated intercellular uptake and endosomal escape. As a result, more PTX were released from liposome and drug accumulation in tumour sites was subsequently enhanced. In vitro results showed that the DLD/PTX-Lips exhibited much higher cytotoxicity to 4T1 murine breast cancer cells than free PTX with concentrations from 0.01 to 5 μg/mL and conventional liposomes. In vivo anticancer efficacy was assessed in a mouse model bearing with 4T1cells. The tumour inhibition rate of the DLD/PTX-Lips was 57.4%, significantly higher than that of free PTX (25.1%) and conventional liposome (30.4%).
In addition, certain ligands may promote receptor-mediated endocytosis when bounded with pH-sensitive liposomes for targeted delivery [116]. Silva et al. developed a folate-coated and DOX-loaded pH-sensitive liposomes (SpHL-DOX-Fol), where folate ligand was conjugated to the liposome surface [116]. The release of DOX was increased from 21.5% ± 3.9% to 53.6% ± 5.7% when pH decreased from 7.4 to 5.0. The results in 4T1 cell viability showed that liposomes with low concentration of 0.15 μM had higher cytotoxicity than free drug, but no statistical differences were observed. The in vivo antitumour activities of the thermo-sensitive liposomes were conducted in BALB/c mice bearing 4T1 cells, with the better therapeutic outcomes (68% tumour growth reduction) being observed compared to free DOX and liposome-formulated DOX.
Thermo-sensitive liposomes (TSL)
Under normal physiological temperature, the lipid membrane structure of TSL was tightly arranged at the gelatinous state, which protects the encapsulated drug from the diffusion through the membrane. However, when these liposomes were heated to transition temperature (Tm), such as, for example, the Tm of dipalmitoylphosphatidylcholine (DPPC) is 41.5 °C, the lipids underwent a gel-to-liquid phase transition, leading to structure destabilisation and drug release [109, 117, 118]. Various TSL encapsulating anticancer drugs were developed and used for breast cancer treatments [119,120,121,122]. Zhang et al. developed a novel thermo-sensitive liposome incorporating DTX (DTX-TL) to improve antitumour effects of the drug [123]. In vitro release studies showed that the drug release at 42 °C was significantly higher than that at 37 °C, indicating the temperature control on drug release (Fig. 2a). For in vivo drug release, the tumour of a mouse model bearing with MCF-7 cells was heated to 42 °C for 30 min using a homemade hyperthermia device connected with a thermostatic circulator. The work displayed that mice treated with TSL exhibited the maximal tumour size reduction compared with the mouse groups treated by other conditions (Fig. 2b, c). TSL can also be engineered to deliver dual drugs via the one platform for enhanced therapeutic efficacy. The co-delivery of tamoxifen and imatinib using TSL was developed by Jose et al. for synergistic breast cancer treatment [119]. More than 80% drugs were released from TSL in 30 min after the temperature was above transition temperature of 39.4 °C. At 40 °C, the growth inhibition of MCF-7 cells treated with this liposome formulation co-encapsulating 5 μM tamoxifen and 3.75 μM imatinib was observed to increase to 86.3 ± 1.5%, compared with the liposomes loaded with the singlet drug at the same concentration (70.6 ± 2.4% for tamoxifen and 43.0 ± 3.3% for imatinib). The enhanced in vitro therapeutic efficacy of the same liposomes in MDA-MB-231 cells was also reported, with the growth inhibition of 66.5 ± 3.9%.
When TSL were used in combination with chemotherapy and thermotherapy, these liposomes demonstrated the dual advantages of temperature-triggered drug release and hyperthermia effect. In addition to chemotherapeutic drug release upon heating, hyperthermia effect is directly cytotoxic to cancer cells at the exposed area, resulting in the improved therapeutic efficacy [124]. Ou et al. developed TSL by utilising gold nanoantennas to generate mild hyperthermia and release DOX from TSL upon illumination by near-infrared laser at 808 nm wavelength. The unique geometry of multibranched gold coated on the surface of the liposomes was utilised to enable the energy transfer from the light to heat, activating the hyperthermia and drug release from TLS simultaneously [120]. In vitro studies revealed the higher toxicity of such TSL towards MDA-MB-231 cells compared to free DOX even at low drug concentration of 0.5 μg/mL (33% vs. 17%). However, this work did not demonstrate the in vivo therapeutic efficacy of the combined treatment via the TSL. To the best of our knowledge, ThermoDOX® was only one thermo-sensitive liposome formulation under Phase I/II clinical trials for cancer therapy [125]. In ThermoDOX®, lysolipids were incorporated into the formulation to lower the liposome phase transition at room temperature, facilitating rapid drug release upon heating. This lysolipid-based liposome formulation containing DOX was developed by Needham et al. and has been invested by Celsion Corp [126]. It was utilised to combine hyperthermia and chemotherapy for treatment of breast patients with chest wall recurrence [127].
Light-sensitive liposomes
External light source is a convenient stimulus employed in the activation of the on-demand release from the liposomes due to its tuneable spectral properties, illumination intensities and times. What’s more, spatial and temporal control of light sources provides an extra flexibility to precisely tune the release of cargo. The mechanism of light-sensitive liposomes can be classified into photophysical effect via molecular absorbers, plasmonic nanoparticles and inorganic nanomaterials and photochemical activation effect including photoisomerization, photocleavage, and photosensitization-induced oxidation [113]. Photosensitization-induced oxidation strategies involves reactive oxygen species (ROS) generation from photosensitisers (PSs) when activated by light illumination at specific wavelengths [128,129,130]. Singlet oxygen is one type of ROS generated via photosensitiser, which has unpaired electrons and unstable bonds [113]. The unsaturated carbon–carbon bond in lipid chains can be oxidised by singlet oxygen to form hydroperoxides that in turn undergoes decomposition of the lipid bilayers [131].
Based on the triggering mechanism mentioned above, the light-sensitive liposomes could be engineered by incorporating PS into the liposome formulation. Under light illumination, PS was activated to generate singlet oxygen or other ROS, oxidising the lipid components, and causing the destabilisation of the liposome structure.
Verteporfin is a well-known PS that has already been clinically approved for the photodynamic therapy (PDT) of macular degeneration and used for treatment of cancers, such as ophthalmic, small cell lung, dermatological, head and neck, brain, gastroenterological and gynaecological cancers [132]. Sneider et al. designed liposomes loaded with verteporfin for the treatment of triple negative breast cancer (TNBC) [91]. Liposomes were modified with DSPE-PEG2000-folic acid to help the liposomes with cancer targeting capability and enhanced cellular uptake. In vitro studies demonstrated that MDA-MB-231 cells treated with the light-sensitive liposomes at 690 nm light exhibited 33% cell viability. Although this work applied PDT effect to the cancer cells via light-sensitive liposomes, drug release could also be achieved using this triggering mechanism. The light source used in this work has some disadvantages limiting the utility of visible light (380–740 nm) in in vivo therapies. First, limited tissue penetration depth of the visible light does not allow it to sufficiently treat deep tissues; second, light energy in the range of 200–650 nm can be absorbed by many endogenous fluorophores, including epidermis pigments, hemoglobins, and chlorophylls [133]. Compared to shorter wavelengths, the near infrared (NIR, 750–1870 nm) light has the relatively lower absorption of hemoglobin and water, resulting in deeper tissue penetration and making it advantageous for in vivo applications [134]. Yang et al. designed a liposome delivery system that can be triggered by near-infrared light at 808 nm [135]. Lipophilic IR780 was incorporated into the lipid bilayer and hydrophilic chemotherapeutic TPZ was co-loaded into the liposomal core (Lip(IR780&TPZ)). Cell apoptosis analysis showed that the proportion of apoptotic 4T1 cells was about 36.2% after the treatment with Lip(IR780&TPZ) at 808 nm laser irradiation. In vivo studies further demonstrated the tumour size in BALB/c mice bearing 4T1 cellular xenografts treated with Lip(IR780&TPZ) was significantly smaller than that of mouse groups treated with other conditions including free drug, empty liposomes and Lip(IR780&TPZ) without laser irradiation, indicating the enhanced antitumour therapeutic efficacy of light-triggered liposomes for breast cancer.
Ultrasound- and magnetic-sensitive liposomes
Ultrasound waves and magnetic fields were widely explored as an external triggering modality in combination with TSL discussed above [136, 137]. Due to the physical properties of acoustic waves and magnetic fields, local heat can be generated from these two external sources with high intensities, which are more tumour site-specific and non-invasive in practice. In addition, they both exhibited excellent tissue penetration capability [109]. In addition to triggering drug release from TSL, high-intensity focused ultrasound (HIFU) or magnetic fields can kill cancer cells via hyperthermia process. Magnetic resonance guided HIFU combining with ThermoDox® was under phase I clinical study on stage IV HER2-negative breast cancer patients [138].
Another triggering mechanism of ultrasound-sensitive liposomes is based on mechanical cavitation by incorporating the liposomes with microbubbles [139, 140]. Depending on the amplitude and frequency of ultrasound waves as well as the size and properties of microbubbles, stable cavitation or internal cavitation will occur upon the ultrasound triggering. At lower intensities, the microbubbles undergo oscillation (stable cavitation), resulting in local swirling and fluid convection. The corresponding shear stresses in the surrounding fluid can rupture and deform liposomes, leading to the drug release [141]. Low-intensity ultrasound has slight influence on chemical properties and anti-tumour activities of encapsulated drugs [142]. Unlike stable cavitation, internal cavitation under high intensities ultrasound will cause collapses of microbubbles and generate shockwaves which can increase the permeability of membrane [109, 143]. This effect not only induces the drug release from liposomes but also facilitates the cellular uptake of liposomes.
Magnetic-sensitive liposomes can also be used for magnetic resonance imaging (MRI) guided cancer therapy [144]. In general, magnetic nanoparticles (MNPs), such as iron oxides, are encapsulated in liposomes to achieve MRI and drug release simultaneously. The movements of MNPs aligned to external magnetic fields can induce mechanical forces to rupture the liposomes. Furthermore, liposome accumulation at tumour site can also be enhanced by external magnetic field guidance [145]. For examples, Song et al. designed the liposomes co-loaded with magnetic nanocubes and emodin to enhance the chemotherapeutic effect in breast cancers [144]. The in vitro results demonstrated that MCF-7 cell killing effect was increased by 24.1% with the liposome–emodin treatment alone and MRI-mediate tumour target further enhanced the effect of the liposomal chemotherapy by 8.67%. In vivo study confirmed that MRI-guided liposome accumulation within the tumour site in mice bearing 4T1 breast cancer cells was observed and the tumour weight of the treated group was 12 times less than control.
Liposome-based gene therapy for breast cancer
Each breast cancer subtype was associated with gene mutations, causing certain cells in the breast become abnormal. Gene therapy is a promising strategy for treatment of breast cancer subtypes bearing distinct genetic alterations, especially for triple negative breast cancers which cannot be treated by effective targeted therapies due to the loss of receptors [146]. Cationic liposomes are potential gene delivery systems able to naturally complex with the negatively charged DNA [147]. The liposome bilayers can protect complexed nucleic acids against degradation by cell and neutralization by antibodies [148]. In addition, the positive charge of cationic liposomes can facilitate their interaction with the negatively charged cell membrane by endocytosis, resulting in efficient cellular uptake and content release into the cytoplasm [13, 149]. The approach for cancer gene therapy is by encapsulating plasmids [150] and oligonucleotides [151] in cationic liposomes [152]. Notably CRISPR/Cas9 system as the most promising gene-editing technology used for cancer gene therapy will be discussed independently.
Liposome-formulated oligonucleotide therapeutics
Oligonucleotides are short synthetic nucleic acids with the potential to treat or manage a wide range of diseases [153]. These gene agents are capable to modulate expression levels of protein-coding genes by binding to specified sequences within a genome or RNA [154]. Among the various oligonucleotide-based therapies, antisense oligonucleotides (ASOs) and small interfering ribonucleic acids (siRNAs) were the most widely explored and used in research and clinical applications for breast cancer therapy [155,156,157]. Comprised of a singular RNA strand, ASOs are complementary to messenger RNAs (mRNA) that are responsible for the coding of proteins. As ASOs carry a non-coding RNA (ncRNA) segment, they effectively silence genes of interest by hybridizing to a specific section within mRNA, inhibiting the production of respective proteins. siRNA are artificially synthesized double-stranded RNA molecules. They are widely used for transient silencing of gene of interest, which involves the design and production of a sequence specific to the target mRNA [158]. siRNA cleaves the mRNA through RNA induced silencing protein-complex (RISC)-mediated process [159]. The performance of ASO and siRNA-based therapeutics will pave the way for more clinical trials on cancer therapy. However, there were some challenges for using these agents including their rapid degradation, poor cellular uptake and rapid renal clearance following systemic administration [159, 160]. To overcome these limits and enhance the therapeutic outcomes, many efforts have been made to develop the nanocarriers delivering ASO and siRNA, such as liposomes that have the potential to be an effective vehicle with improved efficacy and safety profiles [161,162,163,164,165,166,167].
Sharma et al. developed a cationic liposomal delivery system loaded with ASO to inhibit miRNA-191, an oncogenic miRNA overexpressed on breast cancer tissue attributable to malignant transformation progression [164]. After encapsulating the corresponding antisense oligonucleotide anti-miRNA-191, the in vitro inhibiting efficacy of the liposome delivery platform was tested in MCF-7 and ZR-75-1 breast cancer cell lines. The authors found the liposome-mediated anti-miR-191 delivery exhibited better transfection efficiency of anti-miR-191 in breast cancer cells. Another interesting result obtained from this work indicated that the engineered liposomes alone could inhibit growth of breast cancer cells. Thus, the synergistic effect of stearylamine–liposome in combination with anti-miR-191 displayed elevated levels of cell apoptosis and migration suppression, in addition to elevating chemosensitivity of breast cancer cells to anti-cancer drugs [164].
Another recent work reported synergistic anti-tumour activity of PTX and Polo-like kinase 1 (PLK-1)-targeting siRNA in breast cancer via cationic liposome delivery systems [166]. These liposomes were engineered to co-load PTX and siPLK-1, followed by surface modification with targeting aptamer (AS1411) to further enhance tumour targeting capability. PLK1 mRNA expression level of breast cancer cells (MCF-7) was obviously reduced, with approximately 79% knockdown after the treatment with the liposomes. In addition, tumour growth was significantly inhibited and survival rate of tumour-bearing mice was prolonged after the treatment with such liposomes. Collectively, co-delivery of chemotherapeutic drugs and siRNA via this liposome system may have synergistic anti-breast cancer effect.
Although cationic liposomes were the most common and well-investigated nanocarriers for ASO and siRNA delivery, they may cause some changes to cells, such as cell shrinking, reduced number of mitoses and vacuolization of the cytoplasm [168]. Therefore, the potential of non-cationic liposomes as gene delivery systems was investigated. Alshaer et al. developed a non-cationic liposomal delivery system loaded with siRNA–protamine (siRNA/prot) complex. Its surface was further modified with the anti-CD44 aptamer (Apt1) to actively target CD44 expressing TNBC cells (Fig. 3a) [167]. CD44, the cell surface glycoprotein, is an appropriate targeting receptor for targeted therapeutics due to its superficial overexpression on tumours. The luciferase (luc2) gene silencing efficacy of this targeted liposomal system was tested in both in vitro (MDA-MB-231-Luc2-eGFP cells) and in vivo settings (TNBC mouse model). The maximal in vitro gene silencing activity was observed in the cells treated with the Apt1 functionalised liposomes (gene expression level of 25.7 ± 15.1%), compared with non-targeted liposomes (47.2 ± 10.6%) (Fig. 3b). The in vivo work further demonstrated the Luc2 mRNA expression level was significantly inhibited by Apt1 functionalised liposomes, compared with PBS control group (Fig. 3c). Furthermore, the observed bioluminescence signal emitted from the tumours exemplifies the tumour inhibiting capability of the siRNA-loaded liposome systems (Fig. 3d).
Alternative gene therapy for breast cancer is using microRNA (miRNA). A miRNA is a short non-coding RNA molecule containing about 20 nucleotides. It was found in plants, animals and some viral cells with the function of regulating gene expression post-transcriptionally [169]. miRNA act as a guide by base-pairing with complementary sequences within mRNA molecules to negatively regulate its expression. This feature is used for silencing specific oncogene by engineered extrinsic miRNA. A number of miRNA formulations have been studied for cancer gene therapy [170, 171]. A functional miRNA liposome was constructed by Yan et al. to treat TNBC by silencing the Slug gene. The 25-nucleotide sense strand of miRNA was encapsulated into DSPE-PEG2000-tLyp-1 peptide-modified functional liposomes. In vitro results showed that Slug gene was silenced and the TGF-β1/Smad pathway was inhibited in TNBC cells, leading to inhibition of invasiveness and growth of TNBC cells. A stronger anticancer effect than functional vinorelbine liposomes was observed in TNBC cancer-bearing mice and nearly complete inhibition of tumour growth was achieved by combining functional miRNA liposomes and functional vinorelbine liposomes [172].
Liposome-formulated CRISPR therapeutics
Over recent years, new genetic editing techniques including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR) have established themselves as a prominent therapeutic option for various cancers including breast cancer [173,174,175,176,177,178]. Among these genome editing technologies, CRISPR has emerged as a potential alternative to ZFNs and TALENs due to its preparatory simplicity, high gene editing efficiency and simultaneous multiple loci editing [179, 180]. It became more suitable for preclinical and clinical applications compared to other gene editing technologies. In this approach, a nuclease protein (Cas9) introduces a double-stranded break (DSB) in the target sequence of a DNA molecule, enabling the incorporation of a new sequence into the genome as directed by the guide RNA (gRNA) repair template [181]. So far, CRISPR has been successful in cancer CAR-T immunotherapy to treat primary defects of the immune system, hemoglobinopathies, hemophilia, metabolic disorders, and muscular dystrophy [182,183,184]. Major advances have recently been made in the clinical applications of CRISPR through the development of therapeutics that can specifically disrupt the expression of disease-relevant genes [185,186,187]. However, this technology remains at relatively early stages of development and has not been clinically tested for breast cancer yet. This is due to the lack of efficient delivery systems, inadequate transfection efficiency, quick rate of biodegradability and potential off-target effect [188,189,190]. Viral-based delivery systems have largely been used for CRISPR transfection. However, the major challenge was associated with CRISPR/Cas9-specific immunogenicity induced by viral vectors [191]. As a promising delivery alternative, various non-viral delivery strategies have been explored and developed, including liposome delivery systems [192,193,194,195]. Liposome-based CRISPR therapeutics, while few articles were currently reported for breast cancer, appears to have promise in the field of cancer gene therapy [196,197,198].
Zhang et al. employed a cationic liposomal system to overcome the CRISPR’s inadequate transfection efficiency [199]. The authors constructed a polyethylene–glycol–phospholipid-modified (PLNP) liposome system encapsulating a Cas9/single-guide RNA (sgRNA) plasmid (DNA). To demonstrate the transfection efficiency of such engineered liposomes, the authors selected to knock down polo-like kinase 1 (PLK-1) gene, a master regulator of cancer cell division, using these nanocarriers. In vitro transfection results exhibited higher transfection efficiency of 37.8% in breast cancer cells (MCF-7) treated with PLNP containing CRISPR/sgRNA plasmid, compared to the Lipofectamine2000 (a commercial liposome transfection agent) which demonstrated 3.15% only. This work did not show the in vivo therapeutic effect of this liposome-formulated CRISPR technology in breast cancer. However, the authors claimed the in vivo efficacy of these liposomes in a mouse model bearing melanoma cells (A375).
Guo et al. applied a noncationic, tumour-targeting liposome–hydrogel hybrid system to knock out Lipocalin 2 (Lcn2), a breast cancer-promoting gene, through CRISPR-based genome editing [200]. This system encapsulated three CRISPR plasmids encoding a Cas9 nuclease and a guide RNA sequence for identification and disruption of the Lcn2 gene in the genome of targeted human TNBC cells (Fig. 4a). The in vitro genome editing efficiency demonstrated that Lcn2 mRNA expression levels in TNBC cells were largely reduced, with ~ 80% of Lcn2 loss observed in both MDA-MB-231 and MDA-MB-436 cell lines (Fig. 4b, c). In vivo therapeutic efficacy of this liposome system was tested in a mouse model bearing MDA-MB-231 cells. The nanocarrier treated mouse group displayed significant inhibition of tumour growth by 77% in volume, compared with other treatment conditions (Fig. 4d). The results obtained from these two studies indicated liposomes may be considered as a promising delivery formulation for enhanced transfection of CRISPR and subsequently therapeutic effect in breast cancer. It is notable that in these two studies the authors used CRISPR plasmid DNA to achieve gene knockdown effect. However, the major issue associated with plasmid DNA was high levels of unintended gene edits due to the relatively long period that plasmids persist inside cells, which would hamper the clinical translation of CRISPR technology [201].
Conclusions
The experimental development of liposome delivery systems is progressing at a fast pace, following the demand for the new strategies for breast cancer treatment. However, there is no well-developed understanding or road map on the design of the new liposome formulation for breast cancer. Selection of the targeting and triggering modalities in most publications largely depends on the molecular subtypes of the tumour and the ongoing conventional treatments. Despite the traditional liposome-formulated chemotherapeutic drugs have been widely used in the clinical practice in breast cancer treatment, there are some barriers for the clinical implementation of these new liposome formulations. In the case of the triggerable liposomes, the triggering mechanisms need to be further investigated when designing such liposome formulations. For example, the choice of the phospholipid component for light-triggered liposomes needs to be based on the desired photo-induced mechanisms. If a photochemical pathway, such as photo-oxidative reaction, is applied, unsaturated phospholipids would be used in the formulation. In addition, active ingredients used in the triggerable liposome formulation also need to be optimized to weight up their benefits and risks to the healthy tissues.
From the perspective of the clinical applications, we envision that far-reaching development of the liposome technology will eventually benefit the breast cancer patients. Many studies confirmed that various liposome constructs loaded with drugs can lower the levels of cardiotoxicity, address drug resistance and improve the overall drug release profile. By modifying the liposome surface with targeting ligands, these liposomes additionally offer opportunities for designing site-specific therapy, minimising non-specific effect of traditional chemotherapeutic drugs. The new generation liposomes with triggering features even allows exquisite control of payload release, largely enhancing the therapeutic outcomes for breast cancer patients. We believe that these liposome formulations would expand the range of drug/gene delivery options for the treatments of breast cancer, addressing the critical problems of drug toxicity and limited therapeutic effects.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. https://doi.org/10.3322/caac.21660
Martin TA, Ye L, Sanders AJ, Lane J, Jiang WG (2013) Cancer invasion and metastasis: molecular and cellular perspective. Madame Curie bioscience database. Landes Bioscience, Austin
Al-Mahmood S, Sapiezynski J, Garbuzenko OB, Minko T (2018) Metastatic and triple-negative breast cancer: challenges and treatment options. Drug Deliv Transl Res 8(5):1483–1507. https://doi.org/10.1007/s13346-018-0551-3
Lim ZF, Ma PC (2019) Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy. J Hematol Oncol 12(1):134. https://doi.org/10.1186/s13045-019-0818-2
Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99(19):1441–1454. https://doi.org/10.1093/jnci/djm135
Tannock IF, Lee CM, Tunggal JK, Cowan DS, Egorin MJ (2002) Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy. Clin Cancer Res 8(3):878–884
Yang HT, Jaeger M, Walker A, Wei D, Leiker K, Tao WT (2018) Break breast cancer addiction by CRISPR/Cas9 genome editing. J Cancer 9(2):219–231
Cardoso F, Harbeck N, Fallowfield L, Kyriakides S, Senkus E, Group EGW (2012) Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 23(Suppl 7):vii11–vii19. https://doi.org/10.1093/annonc/mds232
Huo WY, Zhao GN, Yin JG, Ouyang X, Wang YN, Yang CH, Wang BJ, Dong PX, Wang ZX, Watari H, Chaum E, Pfeffer LM, Yue JM (2017) Lentiviral CRISPR/Cas9 vector mediated miR-21 gene editing inhibits the epithelial to mesenchymal transition in ovarian cancer cells. J Cancer 8(1):57–64
Li A, Lee CM, Hurley AE, Jarrett KE, De Giorgi M, Lu WQ, Balderrama KS, Doerfler AM, Deshmukh H, Ray A, Bao G, Lagor WR (2019) A self-deleting AAV-CRISPR system for in vivo genome editing. Mol Ther-Meth Clin D 12:111–122
Maggio I, Zittersteijn HA, Wang Q, Liu J, Janssen JM, Ojeda IT, van der Maarel SM, Lankester AC, Hoeben RC, Goncalves MAFV (2020) Integrating gene delivery and gene-editing technologies by adenoviral vector transfer of optimized CRISPR-Cas9 components. Gene Ther 27:209–225
Zununi Vahed S, Salehi R, Davaran S, Sharifi S (2017) Liposome-based drug co-delivery systems in cancer cells. Mater Sci Eng C Mater Biol Appl 71:1327–1341. https://doi.org/10.1016/j.msec.2016.11.073
Zuris JA, Thompson DB, Shu Y, Guilinger JP, Bessen JL, Hu JH, Maeder ML, Joung JK, Chen ZY, Liu DR (2015) Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat Biotechnol 33(1):73–80
Wang M, Zuris JA, Meng FT, Rees H, Sun S, Deng P, Han Y, Gao X, Pouli D, Wu Q, Georgakoudi I, Liu DR, Xu QB (2016) Efficient delivery of genome-editing proteins using bioreducible lipid nanoparticles. Proc Natl Acad Sci USA 113(11):2868–2873
Chen WJ, Deng W, Goldys EM (2017) Light-triggerable liposomes for enhanced endolysosomal escape and gene silencing in PC12 cells. Mol Ther-Nucl Acids 7:366–377
Ma PA, Xiao HH, Li CX, Dai YL, Cheng ZY, Hou ZY, Lin J (2015) Inorganic nanocarriers for platinum drug delivery. Mater Today 18(10):554–564
Wang HX, Li M, Lee CM, Chakraborty S, Kim HW, Bao G, Leong KW (2017) CRISPR/Cas9-based genome editing for disease modeling and therapy: challenges and opportunities for nonviral delivery. Chem Rev 117(15):9874–9906
Pattni BS, Chupin VV, Torchilin VP (2015) New developments in liposomal drug delivery. Chem Rev 115(19):10938–10966. https://doi.org/10.1021/acs.chemrev.5b00046
Zylberberg C, Gaskill K, Pasley S, Matosevic S (2017) Engineering liposomal nanoparticles for targeted gene therapy. Gene Ther 24(8):441–452. https://doi.org/10.1038/gt.2017.41
Chinnagounder Periyasamy P, Leijten JC, Dijkstra PJ, Karperien M, Post JN (2012) Nanomaterials for the local and targeted delivery of osteoarthritis drugs. J Nanomater 2012:1–13
Olusanya TOB, Ahmad RRH, Ibegbu DM, Smith JR, Elkordy AA (2018) Liposomal drug delivery systems and anticancer drugs. Molecules 23(4):907
Federman N, Denny CT (2010) Targeting liposomes toward novel pediatric anticancer therapeutics. Pediatr Res 67(5):514–519
Moussa HG, Martins AM, Husseini GA (2015) Review on triggered liposomal drug delivery with a focus on ultrasound. Curr Cancer Drug Tar 15(4):282–313
Pauli G, Tang WL, Li SD (2019) Development and characterization of the solvent-assisted active loading technology (SALT) for liposomal loading of poorly water-soluble compounds. Pharmaceutics. https://doi.org/10.3390/pharmaceutics11090465
Malam Y, Loizidou M, Seifalian AM (2009) Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol Sci 30(11):592–599. https://doi.org/10.1016/j.tips.2009.08.004
Barenholz Y (2003) Relevancy of drug loading to liposomal formulation therapeutic efficacy. J Liposome Res 13(1):1–8. https://doi.org/10.1081/lpr-120017482
Gubernator J (2011) Active methods of drug loading into liposomes: recent strategies for stable drug entrapment and increased in vivo activity. Expert Opin Drug Deliv 8(5):565–580. https://doi.org/10.1517/17425247.2011.566552
Lee C, Na K (2020) Anthocyanin-loaded liposomes prepared by the pH-gradient loading method to enhance the anthocyanin stability, antioxidation effect and skin permeability. Macromol Res 28(3):289–297
Abraham SA, Edwards K, Karlsson G, Hudon N, Mayer LD, Bally MB (2004) An evaluation of transmembrane ion gradient-mediated encapsulation of topotecan within liposomes. J Control Release 96(3):449–461. https://doi.org/10.1016/j.jconrel.2004.02.017
Fritze A, Hens F, Kimpfler A, Schubert R, Peschka-Suss R (2006) Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradient. Biochim Biophys Acta 1758(10):1633–1640. https://doi.org/10.1016/j.bbamem.2006.05.028
Haran G, Cohen R, Bar LK, Barenholz Y (1993) Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta 1151(2):201–215. https://doi.org/10.1016/0005-2736(93)90105-9
Samuni AM, Lipman A, Barenholz Y (2000) Damage to liposomal lipids: protection by antioxidants and cholesterol-mediated dehydration. Chem Phys Lipids 105(2):121–134. https://doi.org/10.1016/s0009-3084(99)00136-x
Anchordoquy TJ, Koe GS (2000) Physical stability of nonviral plasmid-based therapeutics. J Pharm Sci 89(3):289–296. https://doi.org/10.1002/(SICI)1520-6017(200003)89:3%3c289::AID-JPS1%3e3.0.CO;2-N
Rudolphi-Skorska E, Filek M, Zembala M (2017) The effects of the structure and composition of the hydrophobic parts of phosphatidylcholine-containing systems on phosphatidylcholine oxidation by ozone. J Membr Biol 250(5):493–505. https://doi.org/10.1007/s00232-017-9976-8
Payton NM, Wempe MF, Xu Y, Anchordoquy TJ (2014) Long-term storage of lyophilized liposomal formulations. J Pharm Sci 103(12):3869–3878. https://doi.org/10.1002/jps.24171
Crowe LM, Womersley C, Crowe JH, Reid D, Appel L, Rudolph A (1986) Prevention of fusion and leakage in freeze-dried liposomes by carbohydrates. Biochimica et Biophysica Acta (BBA)-Biomembranes 861:131–140
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013
Makki J (2015) Diversity of breast carcinoma: histological subtypes and clinical relevance. Clin Med Insights Pathol 8:23–31. https://doi.org/10.4137/CPath.S31563
McCart Reed AE, Kutasovic JR, Lakhani SR, Simpson PT (2015) Invasive lobular carcinoma of the breast: morphology, biomarkers and ’omics. Breast Cancer Res 17:12. https://doi.org/10.1186/s13058-015-0519-x
Sainsbury JR, Anderson TJ, Morgan DA (2000) ABC of breast diseases: breast cancer. BMJ 321(7263):745–750. https://doi.org/10.1136/bmj.321.7263.745
Chen WJ, Hoffmann AD, Liu HP, Liu X (2018) Organotropism: new insights into molecular mechanisms of breast cancer metastasis. Npj Precis Oncol 2:1–2
Lu X, Kang Y (2007) Organotropism of breast cancer metastasis. J Mammary Gland Biol Neoplasia 12(2–3):153–162. https://doi.org/10.1007/s10911-007-9047-3
Singletary SE, Connolly JL (2006) Breast cancer staging: working with the sixth edition of the AJCC Cancer Staging Manual. CA Cancer J Clin 56(1):37–47. https://doi.org/10.3322/canjclin.56.1.37(quiz 50–31)
Higgins MJ, Baselga J (2011) Targeted therapies for breast cancer. J Clin Invest 121(10):3797–3803. https://doi.org/10.1172/JCI57152
Jamdade VS, Sethi N, Mundhe NA, Kumar P, Lahkar M, Sinha N (2015) Therapeutic targets of triple-negative breast cancer: a review. Br J Pharmacol 172(17):4228–4237. https://doi.org/10.1111/bph.13211
Mancuso P, Bouchard B (2019) The impact of aging on adipose function and adipokine synthesis. Front Endocrinol (Lausanne) 10:137. https://doi.org/10.3389/fendo.2019.00137
Sims AH, Howell A, Howell SJ, Clarke RB (2007) Origins of breast cancer subtypes and therapeutic implications. Nat Clin Pract Oncol 4(9):516–525
Nie K, Su MY, Chau MK, Chan S, Nguyen H, Tseng T, Huang Y, McLaren CE, Nalcioglu O, Chen JH (2010) Age- and race-dependence of the fibroglandular breast density analyzed on 3D MRI. Med Phys 37(6):2770–2776. https://doi.org/10.1118/1.3426317
de Kruijf EM, Dekker TJA, Hawinkels L, Putter H, Smit V, Kroep JR, Kuppen PJK, van de Velde CJH, Ten Dijke P, Tollenaar R, Mesker WE (2013) The prognostic role of TGF-beta signaling pathway in breast cancer patients. Ann Oncol 24(2):384–390. https://doi.org/10.1093/annonc/mds333
Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65(1–2):271–284
Abumanhal-Masarweh H, da Silva D, Poley M, Zinger A, Goldman E, Krinsky N, Kleiner R, Shenbach G, Schroeder JE, Shklover J, Shainsky-Roitman J, Schroeder A (2019) Tailoring the lipid composition of nanoparticles modulates their cellular uptake and affects the viability of triple negative breast cancer cells. J Control Release 307:331–341. https://doi.org/10.1016/j.jconrel.2019.06.025
Chen MT, Sun HF, Zhao Y, Fu WY, Yang LP, Gao SP, Li LD, Jiang HL, Jin W (2017) Comparison of patterns and prognosis among distant metastatic breast cancer patients by age groups: a SEER population-based analysis. Sci Rep 7(1):9254. https://doi.org/10.1038/s41598-017-10166-8
McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM (2017) Anthracycline chemotherapy and cardiotoxicity. Cardiovasc Drugs Ther 31(1):63–75. https://doi.org/10.1007/s10557-016-6711-0
Willson ML, Burke L, Ferguson T, Ghersi D, Nowak AK, Wilcken N (2019) Taxanes for adjuvant treatment of early breast cancer. Cochrane Database Syst Rev 9(9):Cd004421. https://doi.org/10.1002/14651858.CD004421.pub3
Bazak R, Houri M, El Achy S, Kamel S, Refaat T (2015) Cancer active targeting by nanoparticles: a comprehensive review of literature. J Cancer Res Clin Oncol 141(5):769–784. https://doi.org/10.1007/s00432-014-1767-3
Mayer LD, Janoff AS (2007) Optimizing combination chemotherapy by controlling drug ratios. Mol Interv 7(4):216–223. https://doi.org/10.1124/mi.7.4.8
Franco MS, Roque MC, de Barros ALB, de Oliveira SJ, Cassali GD, Oliveira MC (2019) Investigation of the antitumor activity and toxicity of long-circulating and fusogenic liposomes co-encapsulating paclitaxel and doxorubicin in a murine breast cancer animal model. Biomed Pharmacother 109:1728–1739. https://doi.org/10.1016/j.biopha.2018.11.011
Zhao M, Ding XF, Shen JY, Zhang XP, Ding XW, Xu B (2017) Use of liposomal doxorubicin for adjuvant chemotherapy of breast cancer in clinical practice. J Zhejiang Univ Sci B 18(1):15–26. https://doi.org/10.1631/jzus.B1600303
Din FU, Aman W, Ullah I, Qureshi OS, Mustapha O, Shafique S, Zeb A (2017) Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int J Nanomed 12:7291–7309. https://doi.org/10.2147/ijn.S146315
Dong M, Luo L, Ying X, Lu X, Shen J, Jiang Z, Wang L (2018) Comparable efficacy and less toxicity of pegylated liposomal doxorubicin versus epirubicin for neoadjuvant chemotherapy of breast cancer: a case-control study. Onco Targets Ther 11:4247–4252. https://doi.org/10.2147/ott.S162003
Chang HI, Yeh MK (2012) Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy. Int J Nanomed 7:49–60. https://doi.org/10.2147/ijn.S26766
Moosavian SA, Bianconi V, Pirro M, Sahebkar A (2019) Challenges and pitfalls in the development of liposomal delivery systems for cancer therapy. Semin Cancer Biol. https://doi.org/10.1016/j.semcancer.2019.09.025
Cao D, Zhang X, Akabar MD, Luo Y, Wu H, Ke X, Ci T (2019) Liposomal doxorubicin loaded PLGA-PEG-PLGA based thermogel for sustained local drug delivery for the treatment of breast cancer. Artif Cells Nanomed Biotechnol 47(1):181–191. https://doi.org/10.1080/21691401.2018.1548470
Liu L, Mu LM, Yan Y, Wu JS, Hu YJ, Bu YZ, Zhang JY, Liu R, Li XQ, Lu WL (2017) The use of functional epirubicin liposomes to induce programmed death in refractory breast cancer. Int J Nanomed 12:4163–4176. https://doi.org/10.2147/IJN.S133194
Li X, Wu X, Yang H, Li L, Ye Z, Rao Y (2019) A nuclear targeted Dox-aptamer loaded liposome delivery platform for the circumvention of drug resistance in breast cancer. Biomed Pharmacother 117:109072. https://doi.org/10.1016/j.biopha.2019.109072
Muley H, Fado R, Rodriguez-Rodriguez R, Casals N (2020) Drug uptake-based chemoresistance in breast cancer treatment. Biochem Pharmacol 177:113959. https://doi.org/10.1016/j.bcp.2020.113959
Liu S, Song XL, Wang YH, Wang XM, Xiao Y, Wang X, Cheng L, Li XT (2017) The efficacy of WGA modified daunorubicin anti-resistant liposomes in treatment of drug-resistant MCF-7 breast cancer. J Drug Target 25(6):541–553. https://doi.org/10.1080/1061186X.2017.1298602
Liu Y, Xie X, Hou X, Shen J, Shi J, Chen H, He Y, Wang Z, Feng N (2020) Functional oral nanoparticles for delivering silibinin and cryptotanshinone against breast cancer lung metastasis. J Nanobiotechnology 18(1):83. https://doi.org/10.1186/s12951-020-00638-x
Elzamly S, Badri N, Padilla O, Dwivedi AK, Alvarado LA, Hamilton M, Diab N, Rock C, Elfar A, Teleb M, Sanchez L, Nahleh Z (2018) Epithelial-mesenchymal transition markers in breast cancer and pathological responseafter neoadjuvant chemotherapy. Breast Cancer (Auckl) 12:1178223418788074. https://doi.org/10.1177/1178223418788074
Shen Y, Quan J, Wang M, Li S, Yang J, Lv M, Chen Z, Zhang L, Zhao X, Yang J (2017) Tumor vasculogenic mimicry formation as an unfavorable prognostic indicator in patients with breast cancer. Oncotarget 8(34):56408–56416. https://doi.org/10.18632/oncotarget.16919
Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15(3):178–196. https://doi.org/10.1038/nrm3758
Yao XM, Niu FJ, Kong L, Cai FY, Jing M, Fu M, Liu JJ, He SY, Zhang L, Liu XZ, Ju RJ, Li XT (2020) GGP modified daunorubicin plus dioscin liposomes inhibit breast cancer by suppressing epithelial-mesenchymal transition. Drug Dev Ind Pharm 46(6):916–930. https://doi.org/10.1080/03639045.2020.1763397
Ju RJ, Cheng L, Peng XM, Wang T, Li CQ, Song XL, Liu S, Chao JP, Li XT (2018) Octreotide-modified liposomes containing daunorubicin and dihydroartemisinin for treatment of invasive breast cancer. Artif Cells Nanomed Biotechnol 46(sup1):616–628. https://doi.org/10.1080/21691401.2018.1433187
Andonegui-Elguera MA, Alfaro-Mora Y, Caceres-Gutierrez R, Caro-Sanchez CHS, Herrera LA, Diaz-Chavez J (2020) An overview of vasculogenic mimicry in breast cancer. Front Oncol 10:220. https://doi.org/10.3389/fonc.2020.00220
Ju RJ, Li XT, Shi JF, Li XY, Sun MG, Zeng F, Zhou J, Liu L, Zhang CX, Zhao WY, Lu WL (2014) Liposomes, modified with PTD(HIV-1) peptide, containing epirubicin and celecoxib, to target vasculogenic mimicry channels in invasive breast cancer. Biomaterials 35(26):7610–7621. https://doi.org/10.1016/j.biomaterials.2014.05.040
Ju RJ, Cheng L, Qiu X, Liu S, Song XL, Peng XM, Wang T, Li CQ, Li XT (2018) Hyaluronic acid modified daunorubicin plus honokiol cationic liposomes for the treatment of breast cancer along with the elimination vasculogenic mimicry channels. J Drug Target 26(9):793–805. https://doi.org/10.1080/1061186X.2018.1428809
Olusanya TOB, Haj Ahmad RR, Ibegbu DM, Smith JR, Elkordy AA (2018) Liposomal drug delivery systems and anticancer drugs. Molecules. https://doi.org/10.3390/molecules23040907
Bharti R, Dey G, Banerjee I, Dey KK, Parida S, Kumar BN, Das CK, Pal I, Mukherjee M, Misra M, Pradhan AK, Emdad L, Das SK, Fisher PB, Mandal M (2017) Somatostatin receptor targeted liposomes with Diacerein inhibit IL-6 for breast cancer therapy. Cancer Lett 388:292–302. https://doi.org/10.1016/j.canlet.2016.12.021
Zevon M, Ganapathy V, Kantamneni H, Mingozzi M, Kim P, Adler D, Sheng Y, Tan MC, Pierce M, Riman RE, Roth CM, Moghe PV (2015) CXCR-4 targeted, short wave infrared (SWIR) emitting nanoprobes for enhanced deep tissue imaging and micrometastatic cancer lesion detection. Small 11(47):6347–6357. https://doi.org/10.1002/smll.201502202
Walenkamp AME, Lapa C, Herrmann K, Wester HJ (2017) CXCR4 ligands: the next big hit? J Nucl Med 58(Suppl 2):77S-82S. https://doi.org/10.2967/jnumed.116.186874
Kim D-M, Kim M, Park H-B, Kim K-S, Kim D-E (2019) Anti-MUC1/CD44 dual-aptamer-conjugated liposomes for cotargeting breast cancer cells and cancer stem cells. ACS Appl Biol Mater 2(10):4622–4633
Fu M, Tang W, Liu JJ, Gong XQ, Kong L, Yao XM, Jing M, Cai FY, Li XT, Ju RJ (2020) Combination of targeted daunorubicin liposomes and targeted emodin liposomes for treatment of invasive breast cancer. J Drug Target 28(3):245–258. https://doi.org/10.1080/1061186X.2019.1656725
Belfiore L, Saunders DN, Ranson M, Vine KL (2020) N-alkylisatin-loaded liposomes target the urokinase plasminogen activator system in breast cancer. Pharmaceutics. https://doi.org/10.3390/pharmaceutics12070641
Nguyen VD, Min HK, Kim CS, Han J, Park JO, Choi E (2019) Folate receptor-targeted liposomal nanocomplex for effective synergistic photothermal-chemotherapy of breast cancer in vivo. Colloids Surf B Biointerfaces 173:539–548. https://doi.org/10.1016/j.colsurfb.2018.10.013
Thomas E, Menon JU, Owen J, Skaripa-Koukelli I, Wallington S, Gray M, Mannaris C, Kersemans V, Allen D, Kinchesh P, Smart S, Carlisle R, Vallis KA (2019) Ultrasound-mediated cavitation enhances the delivery of an EGFR-targeting liposomal formulation designed for chemo-radionuclide therapy. Theranostics 9(19):5595–5609. https://doi.org/10.7150/thno.34669
Chapman AP (2002) PEGylated antibodies and antibody fragments for improved therapy: a review. Adv Drug Deliv Rev 54(4):531–545. https://doi.org/10.1016/s0169-409x(02)00026-1
Vandghanooni S, Eskandani M, Barar J, Omidi Y (2018) Bispecific therapeutic aptamers for targeted therapy of cancer: a review on cellular perspective. J Mol Med (Berl) 96(9):885–902. https://doi.org/10.1007/s00109-018-1669-y
Mendes TF, Kluskens LD, Rodrigues LR (2015) Triple negative breast cancer: nanosolutions for a big challenge. Adv Sci (Weinh) 2(11):1500053. https://doi.org/10.1002/advs.201500053
Yoo J, Park C, Yi G, Lee D, Koo H (2019) Active targeting strategies using biological ligands for nanoparticle drug delivery systems. Cancers (Basel). https://doi.org/10.3390/cancers11050640
Sneider A, Jadia R, Piel B, VanDyke D, Tsiros C, Rai P (2017) Engineering remotely triggered liposomes to target triple negative breast cancer. Oncomedicine 2:1–13. https://doi.org/10.7150/oncm.17406
Kangarlou S, Ramezanpour S, Balalaie S, Roudbar Mohammadi S, Haririan I (2017) Curcumin-loaded nanoliposomes linked to homing peptides for integrin targeting and neuropilin-1-mediated internalization. Pharm Biol 55(1):277–285. https://doi.org/10.1080/13880209.2016.1261301
Puri A (2013) Phototriggerable liposomes: current research and future perspectives. Pharmaceutics 6(1):1–25. https://doi.org/10.3390/pharmaceutics6010001
Huynh E, Zheng G (2014) Porphysome nanotechnology: a paradigm shift in lipid-based supramolecular structures. Nano Today 9(2):212–222
Alvarez-Lorenzo C, Concheiro A (2014) Smart drug delivery systems: from fundamentals to the clinic. Chem Commun (Camb) 50(58):7743–7765. https://doi.org/10.1039/c4cc01429d
Mura S, Nicolas J, Couvreur P (2013) Stimuli-responsive nanocarriers for drug delivery. Nat Mater 12(11):991–1003. https://doi.org/10.1038/nmat3776
Torchilin VP (2014) Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat Rev Drug Discov 13(11):813–827. https://doi.org/10.1038/nrd4333
Massiot J, Rosilio V, Makky A (2019) Photo-triggerable liposomal drug delivery systems: from simple porphyrin insertion in the lipid bilayer towards supramolecular assemblies of lipid-porphyrin conjugates. J Mater Chem B 7(11):1805–1823. https://doi.org/10.1039/c9tb00015a
Jiang L, He B, Pan D, Luo K, Yi Q, Gu Z (2016) Anti-cancer efficacy of paclitaxel loaded in pH triggered liposomes. J Biomed Nanotechnol 12(1):79–90. https://doi.org/10.1166/jbn.2016.2123
Yoshizaki Y, Yuba E, Sakaguchi N, Koiwai K, Harada A, Kono K (2017) pH-sensitive polymer-modified liposome-based immunity-inducing system: effects of inclusion of cationic lipid and CpG-DNA. Biomaterials 141:272–283
Almurshedi AS, Radwan M, Omar S, Alaiya AA, Badran MM, Elsaghire H, Saleem IY, Hutcheon GA (2018) A novel pH-sensitive liposome to trigger delivery of afatinib to cancer cells: impact on lung cancer therapy. J Mol Liq 259:154–166
Zhen S, Liu Y, Lu JJ, Tuo XQ, Yang XL, Chen H, Chen W, Li X (2020) Human papillomavirus oncogene manipulation using clustered regularly interspersed short palindromic repeats/Cas9 delivered by pH-sensitive cationic liposomes. Hum Gene Ther 31:309–324
Meers P (2001) Enzyme-activated targeting of liposomes. Adv Drug Deliv Rev 53(3):265–272. https://doi.org/10.1016/s0169-409x(01)00205-8
Chen WJ, Deng W, Xu X, Zhao X, Vo JN, Anwer AG, Williams TC, Cui HX, Goldys EM (2018) Photoresponsive endosomal escape enhances gene delivery using liposome-polycation-DNA (LPD) nanovectors. J Mater Chem B 6(32):5269–5281
Fologea D, Salamo G, Henry R, Borrelli MJ, Corry P (2016) X-ray controlled drug release from liposomes. Biophys J 110(3):200a–200a
de Matos MBC, Beztsinna N, Heyder C, Fens M, Mastrobattista E, Schiffelers RM, Leneweit G, Kok RJ (2018) Thermosensitive liposomes for triggered release of cytotoxic proteins. Eur J Pharm Biopharm 132:211–221. https://doi.org/10.1016/j.ejpb.2018.09.010
Zhang J, Wang S, Deng Z, Li L, Tan G, Liu X, Zheng H, Yan F (2018) Ultrasound-triggered drug delivery for breast tumor therapy through iRGD-targeted paclitaxel-loaded liposome-microbubble complexes. J Biomed Nanotechnol 14(8):1384–1395. https://doi.org/10.1166/jbn.2018.2594
Vlasova KY, Piroyan A, Le-Deygen IM, Vishwasrao HM, Ramsey JD, Klyachko NL, Golovin YI, Rudakovskaya PG, Kireev II, Kabanov AV, Sokolsky-Papkov M (2019) Magnetic liposome design for drug release systems responsive to super-low frequency alternating current magnetic field (AC MF). J Colloid Interface Sci 552:689–700. https://doi.org/10.1016/j.jcis.2019.05.071
van Ballegooie C, Man A, Win M, Yapp DT (2019) Spatially specific liposomal cancer therapy triggered by clinical external sources of energy. Pharmaceutics. https://doi.org/10.3390/pharmaceutics11030125
Zangabad PS, Mirkiani S, Shahsavari S, Masoudi B, Masroor M, Hamed H, Jafari Z, Taghipour YD, Hashemi H, Karimi M, Hamblin MR (2018) Stimulus-responsive liposomes as smart nanoplatforms for drug delivery applications. Nanotechnol Rev 7(1):95–122. https://doi.org/10.1515/ntrev-2017-0154
Lee Y, Thompson DH (2017) Stimuli-responsive liposomes for drug delivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol. https://doi.org/10.1002/wnan.1450
Miranda D, Lovell JF (2016) Mechanisms of light-induced liposome permeabilization. Bioeng Transl Med 1(3):267–276. https://doi.org/10.1002/btm2.10032
Chen W, Goldys EM, Deng W (2020) Light-induced liposomes for cancer therapeutics. Prog Lipid Res 79:101052. https://doi.org/10.1016/j.plipres.2020.101052
Gerweck LE, Seetharaman K (1996) Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res 56(6):1194–1198
Karanth H, Murthy RS (2007) pH-sensitive liposomes–principle and application in cancer therapy. J Pharm Pharmacol 59(4):469–483. https://doi.org/10.1211/jpp.59.4.0001
de Oliveira SJ, Fernandes RS, Ramos Oda CM, Ferreira TH, Machado Botelho AF, Martins Melo M, de Miranda MC, Assis Gomes D, Dantas Cassali G, Townsend DM, Rubello D, Oliveira MC, de Barros ALB (2019) Folate-coated, long-circulating and pH-sensitive liposomes enhance doxorubicin antitumor effect in a breast cancer animal model. Biomed Pharmacother 118:109323. https://doi.org/10.1016/j.biopha.2019.109323
Ruocco MJ, Siminovitch DJ, Griffin RG (1985) Comparative study of the gel phases of ether- and ester-linked phosphatidylcholines. Biochemistry 24(10):2406–2411. https://doi.org/10.1021/bi00331a003
Yatvin MB, Weinstein JN, Dennis WH, Blumenthal R (1978) Design of liposomes for enhanced local release of drugs by hyperthermia. Science 202(4374):1290–1293. https://doi.org/10.1126/science.364652
Jose A, Ninave KM, Karnam S, Venuganti VVK (2019) Temperature-sensitive liposomes for co-delivery of tamoxifen and imatinib for synergistic breast cancer treatment. J Liposome Res 29(2):153–162. https://doi.org/10.1080/08982104.2018.1502315
Ou YC, Webb JA, Faley S, Shae D, Talbert EM, Lin S, Cutright CC, Wilson JT, Bellan LM, Bardhan R (2016) Gold nanoantenna-mediated photothermal drug delivery from thermosensitive liposomes in breast cancer. ACS Omega 1(2):234–243. https://doi.org/10.1021/acsomega.6b00079
Rengan AK, Jagtap M, De A, Banerjee R, Srivastava R (2014) Multifunctional gold coated thermo-sensitive liposomes for multimodal imaging and photo-thermal therapy of breast cancer cells. Nanoscale 6(2):916–923. https://doi.org/10.1039/c3nr04448c
Kheirolomoom A, Lai CY, Tam SM, Mahakian LM, Ingham ES, Watson KD, Ferrara KW (2013) Complete regression of local cancer using temperature-sensitive liposomes combined with ultrasound-mediated hyperthermia. J Control Release 172(1):266–273. https://doi.org/10.1016/j.jconrel.2013.08.019
Zhang H, Gong W, Wang ZY, Yuan SJ, Xie XY, Yang YF, Yang Y, Wang SS, Yang DX, Xuan ZX, Mei XG (2014) Preparation, characterization, and pharmacodynamics of thermosensitive liposomes containing docetaxel. J Pharm Sci 103(7):2177–2183. https://doi.org/10.1002/jps.24019
Ta T, Porter TM (2013) Thermosensitive liposomes for localized delivery and triggered release of chemotherapy. J Control Release 169(1–2):112–125. https://doi.org/10.1016/j.jconrel.2013.03.036
Borys N (2000) Phase 1/2 study of thermodox with approved hyperthermia in treatment of breast cancer recurrence at the chest wall (DIGNITY). ClinicalTrials gov Identifier: NCT00826085
Needham D, Anyarambhatla G, Kong G, Dewhirst MW (2000) A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model. Cancer Res 60(5):1197–1201
Rugo H, Zagar T, Formenti S, Vujaskovic Z, Muggia F, O’Connor B, Myerson R, Hsu I-C, Borys N, Blackwell K (2013) Abstract P4–15-05: novel targeted therapy for breast cancer chest wall recurrence: Low temperature liposomal doxorubicin and mild local hyperthermia. AACR, Philadelphia
Pooler JP (1989) Photooxidation of cell membranes using eosin derivatives that locate in lipid or protein to study the role of diffusible intermediates. Photochem Photobiol 50(1):55–68. https://doi.org/10.1111/j.1751-1097.1989.tb04129.x
Girotti AW (1990) Photodynamic lipid peroxidation in biological systems. Photochem Photobiol 51(4):497–509. https://doi.org/10.1111/j.1751-1097.1990.tb01744.x
Robertson CA, Evans DH, Abrahamse H (2009) Photodynamic therapy (PDT): a short review on cellular mechanisms and cancer research applications for PDT. J Photochem Photobiol B 96(1):1–8. https://doi.org/10.1016/j.jphotobiol.2009.04.001
Tejero I, Gonzalez-Lafont A, Lluch JM, Eriksson LA (2004) Photo-oxidation of lipids by singlet oxygen: a theoretical study. Chem Phys Lett 398(4–6):336–342
Huang Z (2005) A review of progress in clinical photodynamic therapy. Technol Cancer Res Treat 4(3):283–293. https://doi.org/10.1177/153303460500400308
Son J, Yi G, Yoo J, Park C, Koo H, Choi HS (2019) Light-responsive nanomedicine for biophotonic imaging and targeted therapy. Adv Drug Deliv Rev 138:133–147
Hemmer E, Acosta-Mora P, Méndez-Ramos J, Fischer S (2017) Optical nanoprobes for biomedical applications: shining a light on upconverting and near-infrared emitting nanoparticles for imaging, thermal sensing, and photodynamic therapy. J Mater Chem B 5(23):4365–4392
Yang Y, Yang X, Li H, Li C, Ding H, Zhang M, Guo Y, Sun M (2019) Near-infrared light triggered liposomes combining photodynamic and chemotherapy for synergistic breast tumor therapy. Colloids Surf B Biointerfaces 173:564–570. https://doi.org/10.1016/j.colsurfb.2018.10.019
Alawak M, Abu Dayyih A, Mahmoud G, Tariq I, Duse L, Goergen N, Engelhardt K, Reddy Pinnapireddy S, Jedelska J, Awak M, Konig AM, Brussler J, Bartsch JW, Bakowsky U (2021) ADAM 8 as a novel target for doxorubicin delivery to TNBC cells using magnetic thermosensitive liposomes. Eur J Pharm Biopharm 158:390–400. https://doi.org/10.1016/j.ejpb.2020.12.012
Amrahli M, Centelles M, Cressey P, Prusevicius M, Gedroyc W, Xu XY, So PW, Wright M, Thanou M (2021) MR-labelled liposomes and focused ultrasound for spatiotemporally controlled drug release in triple negative breast cancers in mice. Nanotheranostics 5(2):125–142. https://doi.org/10.7150/ntno.52168
de Maar JS, Suelmann BBM, Braat M, van Diest PJ, Vaessen HHB, Witkamp AJ, Linn SC, Moonen CTW, van der Wall E, Deckers R (2020) Phase I feasibility study of Magnetic Resonance guided High Intensity Focused Ultrasound-induced hyperthermia, Lyso-Thermosensitive Liposomal Doxorubicin and cyclophosphamide in de novo stage IV breast cancer patients: study protocol of the i-GO study. BMJ Open 10(11):e040162. https://doi.org/10.1136/bmjopen-2020-040162
Li Y, An H, Wang X, Wang P, Qu F, Jiao Y, Zhang K, Liu Q (2018) Ultrasound-triggered release of sinoporphyrin sodium from liposome-microbubble complexes and its enhanced sonodynamic toxicity in breast cancer. Nano Res 11(2):1038–1056
Prabhakar A, Banerjee R (2019) Nanobubble liposome complexes for diagnostic imaging and ultrasound-triggered drug delivery in cancers: a theranostic approach. ACS Omega 4(13):15567–15580. https://doi.org/10.1021/acsomega.9b01924
Marmottant P, Hilgenfeldt S (2003) Controlled vesicle deformation and lysis by single oscillating bubbles. Nature 423(6936):153–156. https://doi.org/10.1038/nature01613
Schroeder A, Avnir Y, Weisman S, Najajreh Y, Gabizon A, Talmon Y, Kost J, Barenholz Y (2007) Controlling liposomal drug release with low frequency ultrasound: mechanism and feasibility. Langmuir 23(7):4019–4025. https://doi.org/10.1021/la0631668
Pecha R, Gompf B (2000) Microimplosions: cavitation collapse and shock wave emission on a nanosecond time scale. Phys Rev Lett 84(6):1328–1330. https://doi.org/10.1103/PhysRevLett.84.1328
Song Y, Sheng Z, Xu Y, Dong L, Xu W, Li F, Wang J, Wu Z, Yang Y, Su Y, Sun X, Ling D, Lu Y (2019) Magnetic liposomal emodin composite with enhanced killing efficiency against breast cancer. Biomater Sci 7(3):867–875. https://doi.org/10.1039/c8bm01530a
Wang Y, Kohane DS (2017) External triggering and triggered targeting strategies for drug delivery. Nat Rev Mater 2(6):1–14
Bottai G, Truffi M, Corsi F, Santarpia L (2017) Progress in nonviral gene therapy for breast cancer and what comes next? Expert Opin Biol Ther 17(5):595–611. https://doi.org/10.1080/14712598.2017.1305351
Simoes S, Filipe A, Faneca H, Mano M, Penacho N, Duzgunes N, de Lima MP (2005) Cationic liposomes for gene delivery. Expert Opin Drug Deliv 2(2):237–254. https://doi.org/10.1517/17425247.2.2.237
Judge AD, Bola G, Lee AC, MacLachlan I (2006) Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther 13(3):494–505. https://doi.org/10.1016/j.ymthe.2005.11.002
Miller AD (1998) Cationic liposomes for gene therapy. Angew Chem Int Ed 37(13–14):1768–1785
Kaneda Y, Iwai K, Uchida T (1989) Increased expression of DNA cointroduced with nuclear protein in adult rat liver. Science 243(4889):375–378. https://doi.org/10.1126/science.2911748
Thierry AR, Dritschilo A (1992) Intracellular availability of unmodified, phosphorothioated and liposomally encapsulated oligodeoxynucleotides for antisense activity. Nucleic Acids Res 20(21):5691–5698. https://doi.org/10.1093/nar/20.21.5691
Paliwal SR, Paliwal R, Agrawal GP, Vyas SP (2011) Liposomal nanomedicine for breast cancer therapy. Nanomedicine (Lond) 6(6):1085–1100. https://doi.org/10.2217/nnm.11.72
Roberts TC, Langer R, Wood MJA (2020) Advances in oligonucleotide drug delivery. Nat Rev Drug Discov 19(10):673–694. https://doi.org/10.1038/s41573-020-0075-7
Wan J, Bauman JA, Graziewicz MA, Sazani P, Kole R (2013) Oligonucleotide therapeutics in cancer. Cancer Treat Res 158:213–233. https://doi.org/10.1007/978-3-642-31659-3_9
Zuo J, Jiang Y, Zhang E, Chen Y, Liang Z, Zhu J, Zhao Y, Xu H, Liu G, Liu J, Wang W, Zhang S, Zhen Y (2019) Synergistic effects of 7-O-geranylquercetin and siRNAs on the treatment of human breast cancer. Life Sci 227:145–152. https://doi.org/10.1016/j.lfs.2019.04.047
Crooke ST (2017) Molecular mechanisms of antisense oligonucleotides. Nucleic Acid Ther 27(2):70–77. https://doi.org/10.1089/nat.2016.0656
Le BT, Raguraman P, Kosbar TR, Fletcher S, Wilton SD, Veedu RN (2019) Antisense oligonucleotides targeting angiogenic factors as potential cancer therapeutics. Mol Ther Nucleic Acids 14:142–157. https://doi.org/10.1016/j.omtn.2018.11.007
Wang J, Lu Z, Wientjes MG, Au JL (2010) Delivery of siRNA therapeutics: barriers and carriers. AAPS J 12(4):492–503. https://doi.org/10.1208/s12248-010-9210-4
Ahmadzada T, Reid G, McKenzie DR (2018) Fundamentals of siRNA and miRNA therapeutics and a review of targeted nanoparticle delivery systems in breast cancer. Biophys Rev 10(1):69–86. https://doi.org/10.1007/s12551-017-0392-1
Eloy JO, Petrilli R, Raspantini GL, Lee RJ (2018) Targeted liposomes for siRNA delivery to cancer. Curr Pharm Des 24(23):2664–2672. https://doi.org/10.2174/1381612824666180807121935
Sakurai Y, Hada T, Kato A, Hagino Y, Mizumura W, Harashima H (2018) Effective therapy using a liposomal siRNA that targets the tumor vasculature in a model murine breast cancer with lung metastasis. Mol Ther Oncolytics 11:102–108. https://doi.org/10.1016/j.omto.2018.10.004
Wan Y, Dai W, Nevagi RJ, Toth I, Moyle PM (2017) Multifunctional peptide-lipid nanocomplexes for efficient targeted delivery of DNA and siRNA into breast cancer cells. Acta Biomater 59:257–268. https://doi.org/10.1016/j.actbio.2017.06.032
Gujrati M, Vaidya AM, Mack M, Snyder D, Malamas A, Lu ZR (2016) Targeted dual pH-sensitive lipid ECO/siRNA self-assembly nanoparticles facilitate in vivo cytosolic sieIF4E delivery and overcome paclitaxel resistance in breast cancer therapy. Adv Healthc Mater 5(22):2882–2895. https://doi.org/10.1002/adhm.201600677
Sharma S, Rajendran V, Kulshreshtha R, Ghosh PC (2017) Enhanced efficacy of anti-miR-191 delivery through stearylamine liposome formulation for the treatment of breast cancer cells. Int J Pharm 530(1–2):387–400. https://doi.org/10.1016/j.ijpharm.2017.07.079
Tang J, Howard CB, Mahler SM, Thurecht KJ, Huang L, Xu ZP (2018) Enhanced delivery of siRNA to triple negative breast cancer cells in vitro and in vivo through functionalizing lipid-coated calcium phosphate nanoparticles with dual target ligands. Nanoscale 10(9):4258–4266. https://doi.org/10.1039/c7nr08644j
Yu S, Bi X, Yang L, Wu S, Yu Y, Jiang B, Zhang A, Lan K, Duan S (2019) Co-delivery of paclitaxel and PLK1-targeted siRNA using aptamer-functionalized cationic liposome for synergistic anti-breast cancer effects in vivo. J Biomed Nanotechnol 15(6):1135–1148. https://doi.org/10.1166/jbn.2019.2751
Alshaer W, Hillaireau H, Vergnaud J, Mura S, Delomenie C, Sauvage F, Ismail S, Fattal E (2018) Aptamer-guided siRNA-loaded nanomedicines for systemic gene silencing in CD-44 expressing murine triple-negative breast cancer model. J Control Release 271:98–106. https://doi.org/10.1016/j.jconrel.2017.12.022
Kedmi R, Ben-Arie N, Peer D (2010) The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation. Biomaterials 31(26):6867–6875. https://doi.org/10.1016/j.biomaterials.2010.05.027
Cannell IG, Kong YW, Bushell M (2008) How do microRNAs regulate gene expression? Biochem Soc Trans 36(Pt 6):1224–1231. https://doi.org/10.1042/BST0361224
Rupaimoole R, Slack FJ (2017) MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 16(3):203–222. https://doi.org/10.1038/nrd.2016.246
Mathiyalagan P, Sahoo S (2017) Exosomes-based gene therapy for MicroRNA delivery. Methods Mol Biol 1521:139–152. https://doi.org/10.1007/978-1-4939-6588-5_9
Yan Y, Li XQ, Duan JL, Bao CJ, Cui YN, Su ZB, Xu JR, Luo Q, Chen M, Xie Y, Lu WL (2019) Nanosized functional miRNA liposomes and application in the treatment of TNBC by silencing Slug gene. Int J Nanomed 14:3645–3667. https://doi.org/10.2147/IJN.S207837
Chen Y, Zhang Y (2018) Application of the CRISPR/Cas9 system to drug resistance in breast cancer. Adv Sci (Weinh) 5(6):1700964. https://doi.org/10.1002/advs.201700964
Huang N, Huang Z, Gao M, Luo Z, Zhou F, Liu L, Xiao Q, Wang X, Feng W (2018) Induction of apoptosis in imatinib sensitive and resistant chronic myeloid leukemia cells by efficient disruption of bcr-abl oncogene with zinc finger nucleases. J Exp Clin Cancer Res 37(1):62. https://doi.org/10.1186/s13046-018-0732-4
Puria R, Sahi S, Nain V (2012) HER2+ breast cancer therapy: by CPP-ZFN mediated targeting of mTOR? Technol Cancer Res Treat 11(2):175–180. https://doi.org/10.7785/tcrt.2012.500247
Wang J, Li T, Zhou M, Hu Z, Zhou X, Zhou S, Wang N, Huang L, Zhao L, Cao Y, Xiao M, Ma D, Zhou P, Shang Z, Zhou J (2015) TALENs-mediated gene disruption of FLT3 in leukemia cells: using genome-editing approach for exploring the molecular basis of gene abnormality. Sci Rep 5:18454. https://doi.org/10.1038/srep18454
Nyquist MD, Li Y, Hwang TH, Manlove LS, Vessella RL, Silverstein KA, Voytas DF, Dehm SM (2013) TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer. Proc Natl Acad Sci USA 110(43):17492–17497. https://doi.org/10.1073/pnas.1308587110
Zhan T, Rindtorff N, Betge J, Ebert MP, Boutros M (2019) CRISPR/Cas9 for cancer research and therapy. Semin Cancer Biol 55:106–119. https://doi.org/10.1016/j.semcancer.2018.04.001
Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339(6121):819–823. https://doi.org/10.1126/science.1231143
Savic N, Schwank G (2016) Advances in therapeutic CRISPR/Cas9 genome editing. Transl Res 168:15–21. https://doi.org/10.1016/j.trsl.2015.09.008
Lino CA, Harper JC, Carney JP, Timlin JA (2018) Delivering CRISPR: a review of the challenges and approaches. Drug Deliv 25(1):1234–1257
Maeder ML, Gersbach CA (2016) Genome-editing technologies for gene and cell therapy. Mol Ther 24(3):430–446. https://doi.org/10.1038/mt.2016.10
Cornu TI, Mussolino C, Cathomen T (2017) Refining strategies to translate genome editing to the clinic. Nat Med 23(4):415–423. https://doi.org/10.1038/nm.4313
Xia AL, He QF, Wang JC, Zhu J, Sha YQ, Sun B, Lu XJ (2019) Applications and advances of CRISPR-Cas9 in cancer immunotherapy. J Med Genet 56(1):4–9. https://doi.org/10.1136/jmedgenet-2018-105422
Mullard A (2015) Novartis secures first CRISPR pharma collaborations. Nat Rev Drug Discov 14(2):82–82
Cyranoski D (2016) First trial of CRISPR in people. Nature 535(7613):476–477
Le Page M (2020) CRISPR shows promise in cancer First trial of this form of gene editing for people with tumours passes safety test. New Sci 245(3269):12–12
Guo P, Liu D, Subramanyam K, Wang B, Yang J, Huang J, Auguste DT, Moses MA (2018) Nanoparticle elasticity directs tumor uptake. Nat Commun 9(1):130. https://doi.org/10.1038/s41467-017-02588-9
Yin H, Song CQ, Dorkin JR, Zhu LJ, Li Y, Wu Q, Park A, Yang J, Suresh S, Bizhanova A, Gupta A, Bolukbasi MF, Walsh S, Bogorad RL, Gao G, Weng Z, Dong Y, Koteliansky V, Wolfe SA, Langer R, Xue W, Anderson DG (2016) Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat Biotechnol 34(3):328–333. https://doi.org/10.1038/nbt.3471
Tao Y, Hou X, Zuo F, Li X, Pang Y, Jiang G (2019) Application of nanoparticle-based siRNA and CRISPR/Cas9 delivery systems in gene-targeted therapy. Nanomedicine (Lond) 14(5):511–514. https://doi.org/10.2217/nnm-2018-0522
Mintz RL, Gao MA, Lo K, Lao YH, Li M, Leong KW (2018) CRISPR technology for breast cancer: diagnostics, modeling, and therapy. Adv Biosyst. https://doi.org/10.1002/adbi.201800132
Li L, Hu S, Chen X (2018) Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities. Biomaterials 171:207–218. https://doi.org/10.1016/j.biomaterials.2018.04.031
Jain V, Kumar H, Anod HV, Chand P, Gupta NV, Dey S, Kesharwani SS (2020) A review of nanotechnology-based approaches for breast cancer and triple-negative breast cancer. J Control Release 326:628–647. https://doi.org/10.1016/j.jconrel.2020.07.003
Pahle J, Walther W (2016) Vectors and strategies for nonviral cancer gene therapy. Expert Opin Biol Ther 16(4):443–461. https://doi.org/10.1517/14712598.2016.1134480
Chen F, Alphonse M, Liu Q (2020) Strategies for nonviral nanoparticle-based delivery of CRISPR/Cas9 therapeutics. Wiley Interdiscip Rev Nanomed Nanobiotechnol 12(3):e1609. https://doi.org/10.1002/wnan.1609
Lin Y, Wu J, Gu W, Huang Y, Tong Z, Huang L, Tan J (2018) Exosome-liposome hybrid nanoparticles deliver CRISPR/Cas9 system in MSCs. Adv Sci (Weinh) 5(4):1700611. https://doi.org/10.1002/advs.201700611
Chen Z, Liu F, Chen Y, Liu J, Wang X, Chen AT, Deng G, Zhang H, Liu J, Hong Z, Zhou J (2017) Targeted delivery of CRISPR/Cas9-mediated cancer gene therapy via liposome-templated hydrogel nanoparticles. Adv Funct Mater. https://doi.org/10.1002/adfm.201703036
Eoh J, Gu L (2019) Biomaterials as vectors for the delivery of CRISPR-Cas9. Biomater Sci 7(4):1240–1261. https://doi.org/10.1039/c8bm01310a
Zhang LM, Wang P, Feng Q, Wang NX, Chen ZT, Huang YY, Zheng WF, Jiang XY (2017) Lipid nanoparticle-mediated efficient delivery of CRISPR/Cas9 for tumor therapy. Npg Asia Mater 9:e441
Guo P, Yang J, Huang J, Auguste DT, Moses MA (2019) Therapeutic genome editing of triple-negative breast tumors using a noncationic and deformable nanolipogel. Proc Natl Acad Sci USA 116(37):18295–18303. https://doi.org/10.1073/pnas.1904697116
Peng R, Lin G, Li J (2016) Potential pitfalls of CRISPR/Cas9-mediated genome editing. FEBS J 283(7):1218–1231. https://doi.org/10.1111/febs.13586
Acknowledgements
This project was supported by the Sydney Vital, Translational Cancer Research, Sydney, NSW, Australia, through a Cancer Institute NSW competitive grant. The views expressed herein are those of the authors and are not necessarily those of the Cancer Institute NSW.
Funding
This project was supported by the Sydney Vital, Translational Cancer Research, through a Cancer Institute NSW competitive grant.
Author information
Authors and Affiliations
Contributions
BY had the idea for the article, performed the literature search and drafted the manuscript, BS and SS performed the literature search and drafted some parts of the manuscript, AG contributed to breast cancer characterisation part, and WD supervised the work and revised the entire manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Yang, B., Song, Bp., Shankar, S. et al. Recent advances in liposome formulations for breast cancer therapeutics. Cell. Mol. Life Sci. 78, 5225–5243 (2021). https://doi.org/10.1007/s00018-021-03850-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-021-03850-6