Abstract
Biodegradable nanoparticles are highly versatile and adaptable delivery systems for pharmaceutical drugs. The nanoparticles can be targeted to specific cell types and tissues, modified to overcome biological barriers the contained drugs cannot overcome on their own and at the same time mask the undesirable side effects of pharmacological substances. The nanoparticle characteristics can be tailored to specific targets by modifications such as the addition of antibodies to the particle surface or coating them in substances altering their circulation behaviour. Different approaches and examples for targeted drug delivery with biodegradable nanoparticles are discussed, as well as model systems for the advanced evaluation of the used formulations shown.
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1 Introduction
The targeted delivery of drugs within the human organism is an ongoing challenge in pharmaceutical circles. To this day, the administration of drugs by oral or intravenous means leads to a nearly uniform distribution within the body once initial absorption e.g. through the gastrointestinal tract by oral delivery has occurred. This is followed by enrichment in tissues capable of metabolising or storing the substances, specifically liver, kidney and spleen. The only exception in this systemic distribution in many cases is the brain environment. Here, the blood-brain barrier (see Sect. 4.2) due to its highly selective character prevents more than 98% of all pharmaceutical drugs from crossing into the brain environment (Pardridge 2005). The general systemic distribution provides an advantage when tackling systemic illnesses but, in many cases, a targeted approach would be preferable. Modern drugs still carry the potential for both unwanted side effects of a single drug or problematic drug interactions in case of application of multiple substances. The possibility to deliver a drug only to the tissue or organ of interest has been a research target for decades. One of the most promising options to achieve this goal are nanoparticulate delivery systems. Since their first descriptions in the 1970s, nanoparticles have been investigated for a number of potential applications, not limited to targeted drug delivery (Birrenbach and Speiser 1976; Kreuter and Speiser 1976; Scheffel et al. 1972). The use in diagnostic context for example is of particular interest as well. Here, metallic nanoparticles specifically have proven useful (Mody et al. 2010). Yet, for drug delivery approaches, especially in the case of long-term or continuous medication, the nanoparticle systems need to be biocompatible to such a degree as to not build up over time of administration or instigate an immune response for clearing (Mirabello et al. 2015). A base of biodegradable polymers, that can be degraded and metabolised within existing cellular metabolic pathways, have been the solution of choice for some time.
2 Nanoparticulate Drug Delivery Systems
For drug delivery approaches, nanoparticles are classified as structures with a mean size of 1 to 1000 nm. While a colloidal shape is most common, other shapes including cubic or rod-like are possible (Saraiva et al. 2016). The base material, as mentioned above, is usually comprised of biodegradable polymers. This includes both natural macromolecules like human serum albumin (HSA), gelatine, chitosan or alginate, as well as synthetic polymer blocks like polylactic acid (PLA), poly(lactic-co-glycolic) acid (PLGA), polyacrylic acid and its derivatives and others (Kumari et al. 2010). The resulting particles exhibit a natural electric charge, that can range from positive to negative with varying degrees of strength. The drugs are either trapped within the particle matrix itself or bound to the particles surface. Additionally, surface modifications are possible to achieve specific characteristics or target certain cells types, organs or tissues (Fig. 1).
The nanoparticle production itself is largely dependent on the base material. Both chemical polymerisation reactions as well as dispersion-based methods have been described (Kreuter 1983). Chemical polymerisation reactions establish crosslinks between the polymer blocks. Controlling this chemical reaction provides a certain degree of adjustability concerning the appearance and characteristics of the produced nanoparticles. With dispersion methods, the polymer blocks are allowed to form nucleation cores and grow within a solution without establishing chemical links (Fig. 2). In order to influence the produced particle, different parameters, including the dispersion method itself, the complexity and characteristics of the used solvents, the polymer blocks as well as the ratio of potentially more than one base polymer can be adjusted to achieve a certain aim. For both methods, the drugs to be delivered can be trapped within the developing particle structure or linked covalently or chemically to the particle surface (Vauthier and Bouchemal 2009). The nanoparticle surface also provides an area for further development and specific modifications.
Historically, the first pharmaceutically developed nanoparticles were “bare” on the surface, but already Akasaka et al. (1988) published an albumin-based nanoparticle modified with cell-specific antibodies for targeted delivery. In 2001, the first albumin-based nanoparticles for tumour therapy advanced to clinical studies (Damascelli et al. 2001) and in 2005, the first albumin-nanoparticles were approved by the “Food and Drug Administration” (FDA) as medicinal product, followed by approval through the European Medicines Agency (EMA) in 2008. This drug is called Abraxane, a formulation of HSA nanoparticles containing the cytostatic agent paclitaxel, and is used in cancer treatment (Miele et al. 2009).
Surface modifications can encompass any number of substances, including peptides, proteins, antibodies, small molecules and even polymers different from the base polymers. They can be attached through covalent bonds or simple adsorption and will have different effects, allowing either passive or active targeting approaches, but also increasing the circulation time of the nanoparticles in the blood stream (Gref et al. 1994). This is necessary to allow sufficient absorption of the nanoparticles in the targeted tissues (Zara et al. 2002) and is achieved by masking the nanoparticles from being recognised as foreign by the immune system (Storm et al. 1995). Potential ways to mask them include hydrophilic surfaces modifications (van Vlerken et al. 2007; Kaul and Amiji 2002) as well as addition of surfactants (Troster and Kreuter 1992) or serum components (Wagner et al. 2012), forming so called “stealth”-particles with increased retention time in circulation (Moghimi and Hunter 2001). Combining this effect with further targeting, either passive or active, provides a highly specific delivery system for drugs.
2.1 Passive Targeting
The passive targeting approach is most common in tumour targeting. Tumour growth is usually accompanied by increased angiogenesis and decreased lymphatic drainage (Maeda et al. 2000). The formed blood vessels tend to be imperfect in as far as the endothelial cells lining the vessels do not form a continuous, unbroken structure. The normal tight endothelial configuration prevents nanoparticles circulating in the blood stream from simply being taken up into the surrounding tissue. When the endothelial barrier is thus riddled with imperfections, the particles can simply penetrate through these into the surrounding tissue. The vessels found in tumours show holes between endothelial cells with a diameter of 200 to 600 nm, thus allowing nanoparticles to be taken up into the tumour tissue and accumulate there (Noguchi et al. 1998). This effect is known as the “Enhanced Permeability and Retention” (EPR) effect and forms the basis for passive targeting. This effect is especially useful when combined with the above-mentioned “stealth”-particles.
2.2 Active Targeting
Active targeting makes use of cellular structures of the target cells and uses established cellular uptake mechanisms for the nanoparticle transport into the cells. Ligands like polysaccharides, proteins or antibodies are bound to the nanoparticle surface and will interact with their specific receptors present on the cellular surface (Nobs et al. 2004). This enables the active uptake of the nanoparticles in the cells of interest. Based on the specific ligand selected for the particle modification, specific cells and tissues can be targeted as destination of the nanoparticles.
3 Nanoparticles for Specific Tumour Therapy
Therapeutic intervention for cancer treatment and tumour targeting is a major area of interest in nanoparticle development. Due to the nature of tumour growths as highly proliferating and adaptable tissues, successful drugs often have a general cytotoxic affect and a wide variety of negative side effects. Encapsulating these drugs in nanoparticles has the potential of masking undesirable side effects while still delivering them to the areas where their effects are of use, namely the tumours themselves. This masking has been shown for the chemotherapeutic doxorubicin, whose cytotoxic side effects on heart tissue and testes were significantly lowered when encapsulated in HSA nanoparticles (Pereverzeva et al. 2007). Examples for tumour specific targeting are the targeting of breast cancer or melanoma cells based on receptor expression and making photosensitisers a viable treatment option despite their challenging side effects.
3.1 HER2-Overexpressing Breast Cancer
The human epidermal growth factor receptor-2 (HER2) is one of three important receptors that can be found in breast cancer and is an important prognostic factor. A humanised monoclonal antibody targeting HER2 called trastuzumab was approved by the FDA in 2008 and improved prognosis of patients with this type of cancer significantly. Modifying nanoparticles with this agent allows for making use of the effect trastuzumab can achieve on its own while simultaneously delivering a second drug to combat the tumour. Incorporating doxorubicin as chemotherapeutic agent into HSA nanoparticles and modifying them on the surface with covalently bound trastuzumab has allowed for specific targeting of HER2-overexpressing breast cancer cells, improved internalisation (Fig. 3) and prolonged the effect of doxorubicin in these cells (Anhorn et al. 2008).
The nanoparticle base of HSA is rapidly degraded after cellular uptake allowing the encapsulated doxorubicin to be released and therefore significantly increasing its intracellular concentration and effectiveness. The uptake into the target cells is insured through the monoclonal antibody trastuzumab. When bound on the nanoparticle surface, the antibodies are still capable of binding to their target receptor HER2 on the tumour cells and are quickly internalised. Due to the covalent bond with the nanoparticles, these are internalised in the same process and thus become accessible for the intracellular degradation and doxorubicin release (Fig. 4).
3.2 Melanomas
The same principles as described above can be used to target any number of different cancers based on the expression of specific receptors. A second example is the targeting of melanoma cells based on their overexpression of integrin αVβ3 (Wagner et al. 2010b). This integrin is involved in angiogenesis and is overexpressed in a number of cancers including melanomas. A monoclonal antibody called DI17E6 has been described, that can inhibit the growth of melanomas both in vitro and in vivo. When this antibody is covalently bound to doxorubicin-loaded HSA nanoparticles, its own effect can be enhanced through the cytotoxic effect of the doxorubicin when delivered directly to the melanoma cells (Fig. 5). This leads to an increased cytotoxicity in the target cells (αVβ3-high expressing melanoma cells) when compared to either free doxorubicin or the DI17E6 antibody alone, while not showing cytotoxicity in cells low in expressing integrin αVβ3, as shown in Table 1:
3.3 Nanoparticulate Photosensitisers for Tumour Therapy
Photosensitisers are compounds capable of producing highly reactive oxygen species and inducing cellular death when exposed to light of a certain wavelength. The second generation photosensitiser mTHPC (trade name Foscan) was approved for the treatment of advanced head and neck cancer by the EMA in 2001 and has shown a significant phototoxicity in many cancer cells in vitro. Yet, due to its poor water solubility and dark toxicity the applicability to a wider variety of cancer in vivo has proven difficult. Therefore nanoparticles were developed encapsulating mTHPC in order to decrease its dark toxicity and improve water solubility. PLGA nanoparticles loaded with mTHPC were shown to accumulate mTHPC in colon carcinoma cells in an amount comparable to the free substance (Löw et al. 2011). While the phototoxic effect after light exposure was similar in cells treated with either the encapsulated or free mTHPC, the dark toxicity was significantly reduced in cells exposed to nanoparticular mTHPC (Fig. 6). Therefore encapsulating mTHPC ameliorates the negative side effects of the drug while maintaining its intended effect. Combining the encapsulation of mTHPC with targeting approaches as discussed above could open up a number of avenues where mTHPC can be used in cancer treatments without the significant side effects that prevent the wider use of the free substance.
4 Nanoparticles for Crossing Biological Barriers
Nanoparticular development for improved drug delivery does not only have to take the ultimate target of the particle delivery into account, but also needs to consider the route the particles have to take to reach that target. The initial application of nanoparticles is theoretically possible through all routes also used for non-encapsulated drugs. The main routes used are topical, oral or intravenous delivery. Especially in the case of topical and oral delivery, additional barriers have to be overcome for the nanoparticles to reach the blood stream. Next to topical administration, oral delivery has high patient compliance and is therefore the preferred mode of administration when it comes to a wide variety of drugs. The absorption occurs in the gastrointestinal tract, mainly the duodenum and small intestine, as long as the nanoparticles are capable of interacting with this gastrointestinal barrier (Ensign et al. 2012).
4.1 The Gastrointestinal Barrier
The gastrointestinal tract provides a significant barrier for the absorption of drugs and nanoparticles. Different areas have different pH values, which affect the chemical properties and thus absorption rates of substances based on their structure and properties. Additionally, the intestinal tract is covered by a mucus layer of varying thickness depending on the area of intestine. To either overcome or utilise this mucus barrier, administered nanoparticles need to be specifically modified to either attach to or cross the mucus layer (Ensign et al. 2012). Successful mucus penetration or permeation has been shown with PLGA nanoparticles loaded with mTHPC as a model drug and duodenal cancer as target (unpublished data). The nanoparticles were modified with specific surfactants to change their surface properties in such a way, that they were preferentially bound to the intestinal mucus. Their size in combination with physical characteristics then allowed them to either penetrate the mucus layer and reach the underlying duodenal cells, or caused them to be stuck in the mucus layer and degraded there, releasing the contained drugs at this specific side. The produced nanoparticles showed increased accumulation in cellular models of duodenal cells with a mucus layer in contrast to intestinal cells without this layer.
Excursion: The Mucus Chip—An Initial Advanced Testing Module
Considering both the complexity of the gastrointestinal system in general and the challenging nature of the intestinal mucus layer specifically, advanced testing system are necessary to investigate the properties and behaviour of orally administered nanoparticles (Elberskirch et al. 2019). As the first hurdle to either encountering intestinal cells or absorption into the general circulation is the mucus layer itself, a specific test system for mucus penetration and retention was devised. The mucus chip contains a defined layer of intestinal mucus suspended between permeable membranes (Fig. 7). To simulate the intestinal situation, substances are applied from the apical side in a static system, while a peristaltic flow of buffer solution is maintained on the basolateral side to simulate natural peristalsis. Based on the amount of nanoparticles found in the basolateral compartment at different time points, the mucus permeation can be measured and further optimisation steps considered.
4.2 The Blood-Brain Barrier
Another region of the human body, that poses a significant challenge for drug delivery, is the brain. Any drugs, substances or nanoparticles, that want to reach brain tissue, have to pass the blood-brain barrier (Pardridge 2005). This barrier is comprised of the endothelial cells forming the brain capillaries, the surrounding basement membrane with embedded pericytes and the end feet of associated astrocytes (Keaney and Campbell 2015; Fig. 8). What makes the capillaries within the brain unique in contrast to the rest of the body is the fact that the endothelial cells are connected by tight junctions all around, leaving no gaps at all and restricting even small molecular diffusion in the intracellular space (Daneman and Prat 2015). The main options to overcome this barrier are active or passive transport processes. Only a small number of either water- or lipid-soluble molecules can cross the blood-brain barrier independently. The transport processes used for uptake are adsorptive transcytosis, receptor-mediated transcytosis or the use of transport proteins (Saunders et al. 2013; Tuma and Hubbard 2003). Nanoparticles, due to their size, are restricted to making use of one of these processes. The exact route nanoparticles take in order to reach neuronal cells has been extensively discussed and investigated (Wohlfart et al. 2012; Wagner et al. 2012). It has been shown that nanoparticles modified to present apolipoprotein E (ApoE) on their surface are internalised into brain capillary endothelial cells through receptor-mediated endocytosis by the LRP1 receptor, as shown through mechanism studies (Wagner et al. 2012), followed by transcytosis to neighbouring cells, specifically astrocytes (Begley 2012), and can be found in different regions of the brain as soon as 30 min after intravenous injection (Fig. 9) in a mouse model (Zensi et al. 2009). ApoE or other ligands like ApoA1 (Zensi et al. 2010), transferrin (Ulbrich et al. 2009) or insulin (Ulbrich et al. 2011) have dedicated receptors expressed in the brain capillaries. These receptors can be targeted for nanoparticle transport using specific antibodies for these receptors similar to tumour targeting (Ulbrich et al. 2009) or by presenting the receptor-specific proteins on the nanoparticle surface. To achieve this, the proteins can be covalently bound or non-covalently recruited to the nanoparticles. Specific modifications are necessary to achieve this and examples are shown in the following paragraphs.
4.2.1 Covalently Bound ApoE
ApoE can be bound to the surface of different base nanoparticles and used for a variety of treatments.
In one study, HSA nanoparticles with covalently bound ApoE have been developed and used to transport oximes across an in vitro blood-brain barrier model (Wagner et al. 2010a). Oximes are used in the treatment of organophosphate poisoning by reactivating the blocked acetylcholine esterase in cells, but cannot cross the blood-brain barrier in therapeutically relevant doses. Thus, they are unable to ameliorate the neurological effects caused by an imbalance in acetylcholine as neurotransmitter. Therefore, they were adsorbed to HSA nanoparticles. These particles had ApoE bound to their surface and were then applied to an in vitro blood-brain barrier model. It was shown that only particles with the ApoE modification were taken up into the capillary endothelial cells in a significant amount. These nanoparticles were also capable of transporting oximes across the in vitro barrier model while maintaining their functionality in combating organophosphate poisoning (Dadparvar et al. 2011).
In a second study, the base particle consisted of PLA (Stab et al. 2016). Here, the ApoE-modified nanoparticles showed as well higher accumulation in brain capillary endothelial cells than unmodified nanoparticles (Fig. 10).
4.2.2 Non-covalent ApoE Recruitment
The protein ApoE cannot only be bound to nanoparticles before they are administered, it is also present in human serum and circulates freely in the blood stream. Thus, if a reliable way to attract it to the surface of circulating nanoparticles is identified, the natural reservoir of this apolipoprotein can be used for targeting the nanoparticles. Meister et al. (2013) have shown that PLA nanoparticles produced in the presence of polyvinyl alcohol (PVA) are capable of attracting and maintaining a so-called protein corona of plasma proteins. This corona contained both ApoE and ApoA1 among other proteins. Flurbiprofen-loaded PLA-PVA nanoparticles were successfully taken up into brain capillary endothelial cells, capable of crossing an in vitro blood-brain barrier model and could reduce the γ-secretase activity though in vitro release of the contained flurbiprofen (Meister et al. 2013). They were also capable of decreasing the amount of Aβ42 produced by an in vitro cellular model of Alzheimer’s disease (Stab et al. 2016, Fig. 11).
Excursion: Blood-Brain Barrier Model Systems
The decision, whether a covalent or non-covalent binding of targeting modifications is necessary or advisable needs to be made on a case by case basis. Every particle system is unique in its properties and behaviour dependent on particle material, contained substance and targeted application. To analyse and evaluate this, reliable, advanced model systems for the targeted areas are vital. This is especially true in the case of the blood-brain barrier. Reliable, reproducible model systems closely mimicking the in vivo situation and reactions are essential for evaluating nanoparticles developed for BBB crossing (Helms et al. 2016). Initial model systems were based on immortalised cell lines and maintained the receptor and transporter status of the in vivo BBB, but the characteristic barrier tightness could not be replicated. This barrier tightness is characterised by the transendothelial electrical resistance (TER) value, which can be determined and monitored in model systems. Immortalised cell lines achieved at most values of 40 Ωcm2. As achieving a certain tightness or TER value is one basis for the selectivity, these lines were useful for binding and uptake but not transport studies. A step towards replicating the barrier transport behaviour was taken with the development of in vitro BBB models based on isolated primary cells (Nakhlband and Omidi 2011; Stab et al. 2016). These capillary endothelial cells were isolated from animal sources like bovine, porcine or rodent material. But these models, due to their non-human origin, do not express the identical receptors and transporters as found in humans. A model system presenting all relevant characteristics, both in protein expression and transport behaviour of an intact, sufficiently selective barrier has been published in recent years (Lippmann et al. 2012). The specifically necessary brain capillary endothelial cells are differentiated from human induced pluripotent stem cells (Fig. 12). This human origin ensures a high transferability of the results obtained in this model system based on transporter status and the barrier tightness obtained is comparable or superior to that achieved in primary cell models (Lippmann et al. 2014). The source material of human induced pluripotent stem cells also presents the opportunity to develop specific models for neurological diseases and investigate whether the uptake and transport processes are altered in a diseased state and if so, how this impacts therapeutic options.
5 Final Remarks
Overall, it is clear that nanoparticles are a highly adaptable option for drug formulations capable of masking undesirable side effects of drugs while allowing them to maintain their therapeutic effect upon release in the target cells or tissue. Especially when it comes to at present unsolved issues, like the dark toxicity and hydrophobic characteristics of mTHPC or the selectivity of the blood-brain barrier preventing most drugs from crossing into the brain, nanoparticles open up new avenues for the application of existing substances or advancing the development of new therapeutic treatments. Based on the possibilities to modify just about every characteristic of a nanoparticle, they can be tailored to achieve specific effects and present targeted properties. But nanoparticles are not limited to applications in drug delivery. Depending on what is incorporated, nanoparticles can be used in theragnostics (Fang and Zhang 2010), diagnostic applications (Mirabello et al. 2015), for gene therapy (Cullis and Hope 2017) or to improve stem cell differentiation (Dayem et al. 2016).
Abbreviations
- ApoE:
-
Apolipoprotein E
- BBB:
-
Blood-brain barrier
- EGFR:
-
Epidermal growth factor receptor
- EPR:
-
Enhanced Permeability and Retention
- EMA:
-
European Medicines Agency
- FDA:
-
Food and Drug Administration
- HSA:
-
Human serum albumin
- HER2:
-
Human epidermal growth factor receptor-2
- PLA:
-
Polylactic acid
- PLGA:
-
Poly(lactic-co-glycolic) acid
- PVA:
-
Polyvinyl alcohol
- TER:
-
Transendothelial electrical resistance
References
Akasaka Y, Ueda H, Takayama K et al (1988) Preparation and evaluation of bovine serum albumin nanospheres coated with monoclonal antibodies. Drug Des Deliv 3(1):85–97
Anhorn MG, Wagner S, Kreuter J et al (2008) Specific targeting of HER2 overexpressing breast cancer cells with doxorubicin loaded trastuzumab modified human serum albumin nanoparticles. Bioconjugate Chem 19(12):2321–2331
Begley D (2012) Brain superhighways. Sci Transl Med 4(147):147fs29
Birrenbach G, Speiser PP (1976) Polymerized micelles and their use as adjuvants in immunology. J Pharm Sci 65(12):1763–1766
Cullis PR, Hope MJ (2017) Lipid nanoparticle systems for enabling gene therapies. Mol Ther 25(7):1467–1475
Dadparvar M, Wagner S, Wien SL et al (2011) HI 6 human serum albumin nanoparticles – development and transport over an in vitro blood-brain barrier model. Toxicol Lett 206(1):60–66
Damascelli B, Cantu G, Mattavelli F et al (2001) Intraarterial chemotherapy with polyoxyethylated castor oil free paclitaxel, incorporated in albumin nanoparticles (ABI-007): phase II study of patients with squamous cell carcinoma of the head and neck and anal canal: preliminary evidence of clinical activity. Cancer 92(10):2592–2602
Daneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harb Perspect Biol 7(1):
Dayem AA, Choi HY, Yang GM et al (2016) The potential of nanoparticles in stem cell differentiation and further therapeutic applications. Biotechnol J 11(12):1550–1560
Elberskirch L, Knoll T, Moosmann A et al (2019) A novel microfluidic mucus-chip for studying the permeation of compounds over the mucus barrier. J Drug Deliv Sci Tech 54:
Ensign LM, Cone R, Hanes J (2012) Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barrier. Adv Drug Deliv Rev 64(5):557–570
Fang C, Zhang M (2010) Nanoparticle-based theragnostics: integrating diagnostic and therapeutic potentials in nanomedicine. J Control Release 146(1):2–5
Gref R, Minamitake Y, Peracchia MT et al (1994) Biodegradable long-circulating polymeric nanospheres. Science 263(5153):1600–1603
Helms HC, Abbott NJ, Burk M et al (2016) In vitro models of the blood-brain barrier: an overview of commonly used brain endothelial cell culture models and guidelines for their use. J Cereb Blood Flow Metab 36(5):862–890
Kaul G, Amiji M (2002) Long-circulating poly(ethylene glycol)-modified gelatin nanoparticles for intracellular delivery. Pharm Res 19(7):1061–1067
Keaney J, Campbell M (2015) The dynamic blood-brain barrier. FEBS J 282:4067–4079
Kreuter J (1983) Evaluation of nanoparticles as drug-delivery systems I: preparation methods. Pharm Acta Helv 58:196–209
Kreuter J, Speiser PP (1976) New adjuvants on a polymethylmethacrylate base. Infect Immun 13(1):204–210
Kumari A, Yadav SK, Yadav SC (2010) Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointer. 75(1):1–18
Lippmann ES, Azarin SM, Kay JE et al (2012) Human blood-brain barrier endothelial cells derived from pluripotent stem cells. Nat Biotechnol 30(8):783–791
Lippmann ES, Al-Ahmad A, Azarin SM et al (2014) A retinoic acid-enhance, multicellular human blood-brain barrier model derived from stem cell sources. Sci Rep 4:4160
Löw K, Knobloch T, Wagner S et al (2011) Comparison of intracellular accumulation and cytotoxicity of free mTHPC and mTHPC-loaded PLGA nanoparticles in human colon carcinoma cells. Nanotech 22:
Maeda H, Wu J, Sawa T et al (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65(1–2):271–284
Meister S, Zlatev I, Stab J et al (2013) Nanoparticulate flurbiprofen reduces amyloid-β42 generation in an in vitro blood-brain barrier model. Alzheimers Res Ther 5(6):91
Miele E, Spinelli GP, Miele E et al (2009) Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer. Int J Nanomed 4:99–105
Mirabello V, Calatayud DG, Arrowsmith RL et al (2015) Metallic nanoparticles as synthetic building blocks for cancer diagnostics: from materials design to molecular imaging applications. J Mater Chem B 3(28):5657–5672
Mody VV, Siwale R, Singh A et al (2010) Introduction to metallic nanoparticles. J Pharm Bioallied Sci 2(4):282–289
Moghimi SM, Hunter AC (2001) Capture of stealth nanoparticles by the body’s defences. Crit Rev Ther Drug Carrier Syst 18(6):527–550
Nakhlband A, Omidi Y (2011) Barrier functionality of porcine and bovine brain capillary endothelial cells. Bioimpacts 1(3):153–159
Nobs L, Buchegger F, Gumy R et al (2004) Current methods for attaching targeting ligands to liposomes and nanoparticles. J Pharm Sci 93(8):1980–1992
Noguchi Y, Wu J, Duncan R et al (1998) Early phase tumor accumulation of macromolecules: a great difference in clearance rate between tumor and normal tissues. Jpn J Cancer Res 89(3):307–314
Pardridge WM (2005) The blood-brain barrier: bottleneck in brain drug development. NeuroRX 2:3–14
Pereverzeva E, Treschalin I, Bodyagin D et al (2007) Influence of the formulation on the tolerance profile of nanoparticle-bound doxorubicin in healthy rats: focus in cardio- and testicular toxicity. Int J Pharm 337(1–2):346–356
Saraiva C, Praca C, Ferreira R et al (2016) Nanoparticle-mediated brain drug delivery: overcoming blood-brain barrier to treat neurodegenerative diseases. J Control Release 235:34–47
Saunders NR, Daneman R, Dziegielewska KM et al (2013) Transporters of the blood-brain and blood-CSF interfaces in development and in the adult. Mol Aspects Med 34(2–3):742–752
Scheffel U, Rhodes BA, Natarajan TK et al (1972) Albumin microspheres for study of the reticuloendothelial system. J Nucl Med 13(7):498–503
Stab J, Zlatev I, Raudszus B et al (2016) Flurbiprofen-loaded nanoparticles can cross a primary porcine in vitro blood-brain barrier model to reduce Amyloid-β42 burden. J Nanomed Biother Discov 6:140
Storm G, Belliot SO, Daemen T et al (1995) Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system. Adv Drug Deliv Rev 17:31–48
Troster SD, Kreuter J (1992) Influence or the surface properties of low contact angle surfactants on the body distribution of 14C-poly(mthyl methacrylate) nanoparticles. J Microencapsul 9(1):19–28
Tuma PL, Hubbard AL (2003) Transcytosis: crossing cellular barriers. Physol Rev 83(3):871–932
Ulbrich K, Hekmatara T, Herbet E et al (2009) Transferrin- and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood-brain barrier. Eur J Pharm Biopharm 71(2):251–256
Ulbrich K, Knoblich R, Kreuter J (2011) Targeting the insulin receptor: nanoparticles for drug delivery across the blood-brain barrier (BBB). J Drug Target 19(2):125–132
van Vlerken LE, VyasTK AM (2007) Poly(ethylene glycol)-modified nanocarriers for tumor-targeted and intracellular delivery. Pharm Res 24(8):1405–1414
Vauthier C, Bouchemal K (2009) Methods for the preparation and manufacture of polymeric nanoparticles. Pharm Res 26(5):1025–1058
Wagner S, Kufleitner J, Wien SL et al (2010a) Nanoparticulate transport of oximes over an in vitro blood-brain barrier model. PLoS One 5(12):e14213
Wagner S, Rothweiler F, Anhorn MG et al (2010b) Enhanced drug targeting by attachment of an anti αv-integrin antibody on doxorubicin loaded human serum albumin nanoparticles. Biomat 31:2388–2398
Wagner S, Zensi A, Wien SL et al (2012) Uptake mechanism of ApoE-modified nanoparticles on brain capillary endothelial cells as a blood-brain barrier model. PLoS ONE 7(3):
Wohlfart S, Gelperina S, Kreuter J (2012) Transport of drugs across the blood-brain barrier by nanoparticles. J Control Release 161(2):264–273
Zara GP, Cavalli R, Bargoni A et al (2002) Intravenous administration to rabbits of non-stealth and stealth doxorubicin-loaded solid lipid nanoparticles at increasing concentrations of stealth agent: pharmacokinetics and distribution of doxorubicin in brain and other tissues. J Drug Target 10(4):327–335
Zensi A, Begley D, Pontikis C et al (2009) Albumin nanoparticles targeted with ApoE to enter the CNS by transcytosis and are delivered to neurones. J Control Release 137(1):78–86
Zensi A, Begley D, Pontikis C et al (2010) Human serum albumin nanoparticles modified with apolipoprotein A-I cross the blood-brain barrier and enter the rodent brain. J Drug Target 18(10):842–848
Acknowledgements
The authors would like to thank the European Commission, BMBF and BMVg for funding several parts of this work. The authors thank the Faerber GmbH (Zweibruecken, Germany) for the supply of the porcine intestine and skull/brain.
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Danz, K., von Briesen, H., Wagner, S. (2021). Biodegradable Nanoparticles for Specific Drug Transport. In: J.M. Abadie, M., Pinteala, M., Rotaru, A. (eds) New Trends in Macromolecular and Supramolecular Chemistry for Biological Applications. Springer, Cham. https://doi.org/10.1007/978-3-030-57456-7_13
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