Keywords

3.1 Introduction

Cancer is the second most severe lethal disease in the current world and spreading further with continuance and growing incidence in the twenty-first century. According to the estimates from the GLOBOCAN cancer statistics 2018 (International Agency for Research on Cancer, WHO), there are 9.6 million cancer cases deaths in 2018. More than 18.1 million cancer cases are diagnosed, and this rate has been estimated to rise to 29.5 million by the year 2040 (Faisca Phillips 2019; Bray et al. 2018). The condition is so alarming that every fourth person is having a lifetime cancer risk. Is cancer treatable? The short reply to this question is “yes.” Cancer mortality rates can be decreased if cancer cases are detected and treated early with better treatment strategies (Siegel et al. 2019; Wild 2019). Cancer begins from transforming healthy normal tissues into tumor tissues in a multistage development that usually progresses from a precancerous to a malignant tumor. Many types of cancers affect the people, and the cancer cells show no symptoms at an initial stage of development (Papaccio et al. 2017; Kulikov et al. 2017). Cancer cells proliferate and continue to increase unless one of three things occur: (i) The tumor tissues are removed surgically, (ii) using radiation therapy, or (iii) using chemotherapy.

There are different methods of cancer treatment. Current cancer treatment options can be surgical intervention, radiation therapy, chemotherapy, immunotherapy and hormone therapy, or a combination of these options (Miller et al. 2019; Chowdhury et al. 2016). The types of cancer treatment that patients receive depend on the type of cancer patients have and what stage advanced it is. The treatment of cancer by surgery works best for small size solid tumors that are localized in one area (Tyson II et al. 2018; Derks et al. 2017). The surgery to remove the entire tumorous mass should not harm the surrounding normal healthy cells or tissues. Nonsurgical cancer treatment commonly followed is radiation therapy or chemotherapy medication. Radiation therapy practices with high ionizing radiation dose to eradicate cancer cells and slow tumor growth by damaging the DNA (Liu et al. 2016a; Baskar and Itahana 2017). The radiation therapy is commonly used in combination with the surgery to reduce the tumor size, so the tumor can be easily removed by surgical treatment (Bishop et al. 2018a, b). The body can safely receive a limited amount of radiation over the course of the treatment. The radiation dose to be delivered to the cancer site depends upon various factors such as the cancer type, tumor size and location in the body, age of the person, general health and medical history, and possible side effects on the nearby normal tissues (Ghahremani et al. 2018; Cabrera et al. 2016). Immunotherapy is a biological cancer therapy that supports the immune system battle against cancer, and it is not yet as extensively used as surgery, radiation therapy, and chemotherapy (Zaidi and Jaffee 2019; Ishihara et al. 2017). Hormone therapy uses hormones to stop the growth of cancers (Axelrad et al. 2020; Eeles et al. 2016).

Chemotherapy or combined chemotherapy , a very common cancer treatment, uses anticancer drugs to kill or destroy the uncontrolled proliferation of cancerous cells. Conventional chemotherapy works principally by interfering with the synthesis of DNA and mitosis, leading to the death of rapidly proliferating and dividing cancer cells (Senapati et al. 2018; Wang et al. 2016). Unfortunately, due to nonspecific drug targeting by anticancer medicines, conventional chemotherapy fails to target the tumor specifically without interacting with the normal healthy cells (Kumari et al. 2016; Wakaskar 2017; Raza et al. 2019).

This chapter aims to present the limitations of conventional cancer treatment and principal concepts of nanomaterials for cancer treatment, to emphasize the distinguished advantage of nanomaterials-based drug delivery systems (nano DDS) and the mechanism of action underlying their selective targeted drug delivery effects, and to introduce successful recent nano drug delivery system for cancer treatment and diagnosis.

3.2 Limitations of Conventional Cancer Treatment

The conventional cancer treatments effectively destroy the cancer cells, but they are also harmful to the normal healthy cells and tissues (Johnson et al. 2018; Kalyanaraman 2017). Cancer cells cannot be entirely removed by the surgery, and even the existence of a single cancer cell that is unseen can redevelop into a new tumor and metastasize to other parts of the body. The cancer treatment by the surgical procedure is not used for hematological cancers or cancers that have metastasized to other tissues or parts of the body. The radiation therapy administered both internally or externally can also destroy the normal healthy cells and induce the side effects due to the ionizing radiation. The radiation therapy is not used if the tumor is located at extremely vulnerable locations or if the cancer is at the advanced stages. Immunotherapy and hormone therapy cause side effects in the body, and hormone therapy blocks the ability to produce hormones in the body system.

Chemotherapy is considered as an effective type of cancer treatment for all types of cancers, but it damages either normal healthy tissues or cells that divide rapidly, such as cells in the macrophages, digestive tract, bone marrow, and hair follicles. The notable drawback of conventional chemotherapy is that it cannot provide specific target action only to the cancer cells. The nonspecific delivery of chemotherapeutic drugs causes severe side effects such as mucositis, myelosuppression, organ dysfunction, alopecia, and thrombocytopenia, and these side effects impose treatment delay, dose reduction, and therapy discontinuation. Furthermore, most of the available chemotherapeutic drugs often cannot penetrate the outer membranes of solid tumors and reach the inside core of solid tumors, failing to destroy the cancer cells. Also, the repeated administration of nonselective chemotherapeutic drugs can influence drug resistance.

Chemotherapeutic drugs are often eliminated from the plasma circulation engulfed by macrophages and P-glycoprotein, acting as the efflux pump, which is overexpressed on the cancer cells surface and prevents the accumulation of drugs inside the tumor. Thus, chemotherapeutic drugs stay in the plasma circulation for a very short and limited time and cannot interact with the cancer cells resulting in the chemotherapy entirely unsuccessful. The low drug solubility, large particle size, low specificity, and high toxicity of chemotherapeutic drugs are also important issues in conventional chemotherapy, making them unable to improve the bioavailability and reach the chemotherapeutic drugs at the tumor sites.

To circumvent the pitfalls as mentioned above and the limitations of conventional cancer treatments, chemotherapeutic drugs need to reformulate with various types of nanomaterials and drug delivery systems.

3.3 Nanomaterials as Drug Delivery System for Cancer Treatment

Since innovative researches and understanding of biological mechanisms of cancer tissues are emerging regularly, novel cancer treatment procedures are being developed to have improved effectiveness of the treatment, thereby enabling the patient’s survivability and improving their quality of life. With the recent technological advances in medical sciences, different types of cancer treatment have been practiced in the past, and many new therapies, such as targeted therapy, are currently being practiced. There have been significant successes in the nanotechnology medical applications (nanomedicine) in recent years, particularly in the drug delivery system (Wolfram and Ferrari 2019; Salvioni et al. 2019; van der Meel et al. 2019; Tran et al. 2017; Prasad et al. 2017).

Treating cancer cells using a nanoparticulate drug delivery system (nano DDS) approach plays a pivotal role in circumventing the limitations of conventional cancer treatment methods by providing simultaneous diagnosis and treatment. The application of nano DDS to cancer treatment could extend beyond the drug delivery system into the making of new therapeutics capable of killing the cancer cells with negligible damage to normal healthy cells and tissues. Various types of organic and inorganic nanomaterials are used to formulate chemotherapeutic drug-loaded nano DDS for cancer diagnosis and treatment. Most of the organic nanomaterials (liposomes, solid lipid nanoparticles, dendrimers, polymeric micelles, polymeric (natural or synthetic) nanoparticles, and polymer-drug conjugates) and inorganic nanomaterials (mesoporous silica nanoparticles, gold nanoparticles, magnetic nanoparticles, carbon nanotubes, and quantum dots) were developed as a vehicle in nano DDS for cancer treatment.

3.4 Unique Advantages of Nano DDS

3.4.1 Particle Size (Kumar et al. 2017; Arms et al. 2018; Ghasemiyeh and Mohammadi-Samani 2018; Tiruwa 2016; Ghasemiyeh and Mohammadi-Samani 2020; Sarcan et al. 2018)

Particle size distribution and small size with high surface area characteristics of nanoparticles are the most important key factors for drug delivery applications. The great advantage of nano DDS is that the particle size and size distributions are tunable. Several types of research have reported that nanoparticulate systems have plenty of advantages over other microparticulate systems. Nanoparticles can improve drug loading, stability, controlled drug release, high cellular uptake, in vivo pharmacokinetics, plasma circulation half-life, biodistribution, targeted drug delivery, tumor accumulation, and ability to cross the blood-brain barrier and transport the drugs to the brain due to their smaller size and flexibility (Prasad et al. 2019). Nanoparticles can also be coated with different types of polymers or surface-functionalized with targeting moieties, peptides, and nucleic acids that bind to specific cancer target sites. The nanoparticles used in a nano DDS should be small size enough to escape or avoid capture by macrophages in the circulation system. Systemically administered nano DDS should have a particle size ranging from 10 to 200 nm, particle size less than 200 nm to avoid sequestration by the liver and spleen, and particle size larger than 10 nm to avoid first-pass metabolism or elimination through the kidneys, benefiting accumulation/clearance and biodistribution behavior. The particle size of nano DDS has been shown to influence the surface functionalization and targeted drug delivery applications for cancer treatment.

3.4.2 High Drug Payload (Ghasemiyeh and Mohammadi-Samani 2018; Meunier et al. 2017; Liu et al. 2020; Qu et al. 2016; Huang et al. 2016)

An effective nanoparticulate system should load and hold a higher amount of drugs, thereby decreasing the frequent dose of uptake and increasing drug plasma concentration after administration in the body. Drug loading in the nano DDS can be done by adsorption/absorption and incorporation techniques. A high drug loading capacity and encapsulation efficiency mainly depend on the classification of drugs (e.g., biopharmaceutical classification systems (BCS) Class I–IV) and drug solubility in the nano DDS, which is related to the drug-polymer interactions, compositions of excipients, and the presence of active functional groups from drug and excipients. For instance, the solid lipid core of solid lipid nanoparticles can accommodate a higher amount of hydrophobic chemotherapeutic drugs, and liposomes can load and hold both hydrophobic and hydrophilic chemotherapeutic drugs due to their unique characteristics.

3.4.3 Controlled Drug Release (Li et al. 2016a; Kamaly et al. 2016; Deodhar et al. 2017; Liu et al. 2019a; Paris et al. 2018)

It is crucial to take consideration of both polymer biodegradation and drug release kinetics in simulated body conditions when formulating a nano DDS. The drug release behavior from nano DDS mainly depends on (i) solubility of active pharmaceutical ingredient, (ii) nano DDS degradation or erosion, (iii) desorption from the surface-attached drug or incorporated drug from the inside polymer core, (iv) drug diffusion through the nano DDS, and (v) the combination of diffusion and erosion processes. For example, the drug release of uniformly drug distributed nanospheres occurs by diffusion or matric erosion. If the active drug diffusion is more rapid than matrix erosion, then the drug release mechanism is mostly maintained by diffusion. The burst drug release from nanoparticles at the early stage is primarily attributed to surface-attached drug molecules to the large surface of nano DDS. It is indicated that the method of drug loading has a pivotal role in the drug release profile from nanoparticles. If the active pharmaceutical ingredient is entrapped in the nano DDS by the incorporation technique, then the nano DDS has a negligible amount of burst drug release and controlled drug release profile. If the nano DDS is surface-modified or coated by other synthetic or natural polymers, the drug release profile is then controlled by drug diffusion from the surface polymeric membrane.

3.4.4 Surface Modification (Ahmad et al. 2018a; Choi and Meghani 2016; Ahmad et al. 2018b; Ganesan et al. 2018; Ramalingam and Ko 2016; Ramalingam and Ko 2015; Ramalingam et al. 2016)

Surface modification or coating on the nano DDS can improve drug biodistribution, pharmacokinetics, and oral and brain drug delivery. To enhance drug targeting, it is crucial to prolong the nanoparticle circulation and minimize the opsonization in vivo, and it can be accomplished by coating or surface modification of nano DDS with biodegradable hydrophilic polymers, e.g., natural polymers such as chitosan and their derivatives, PEG, polysorbate 80, poloxamer, and polyethylene oxide. Several researches publish that PEG surface modification on nano DDS avoids opsonization and reduces phagocytosis.

3.5 Physiology of Tumor and Tumor Targeting Using Nano DDS

3.5.1 Angiogenesis and Tumor Vasculatures

A well understanding and knowledge of the angiogenesis and tumor vasculature characteristics have facilitated effective cancer treatment against various types of cancers. To develop the nano DDS, it is essential to find the biomarkers of the tumor microenvironment and the important differences in normal healthy cells (Liu et al. 2021). The process of angiogenesis in tumor sites promotes new blood vessels with discontinuous epithelium from preexisting vascular systems. The irregular blood vessels present in tumor regions have unusual morphological and physiological conditions dissimilar from normal vasculatures. The discontinuities between epithelial cells or vascular gap openings of tumors are remarkably 10 and 100 times larger in tumor models than in normal tissues. Lack of lymphatic drainage with leakiness favors the passive accumulation of long-circulating macromolecules and into the tumor (Li et al. 2016b; Park et al. 2016; Yang and Gao 2017; Wong et al. 2016). These findings suggest that the nano DDS of certain sizes can penetrate leaky tumor vasculatures and selectively carry the chemotherapeutic drugs to the tumor regions.

3.5.2 Mechanisms of Tumor Targeting by Nano DDS

Tumor-targeted drug delivery can be attained by inherent passive targeting and adopted active targeting strategies. Active drug targeting of chemotherapeutic drugs can be accomplished by conjugating the targeting moiety on the nano DDS. Passive drug targeting is achieved by loading chemotherapeutic drugs into a nano DDS that passively reaches the cancer target site or tissue through the EPR effect. For example, several studies reported that liposomes surface-modified with targeting moiety influenced the drug targeting and it can work as a drug reservoir exhibiting controlled drug release profile and drug accumulation at the tumor site (Kanamala et al. 2016; Masood 2016; Anarjan 2019; Derakhshandeh and Azandaryani 2016; Dai et al. 2016).

3.5.2.1 Passive Tumor Targeting

The EPR effect-mediated chemotherapeutic drug deliveries of nano DDS have been considered one of the strategies to accumulate the drug at the tumor sites. Compared to blood vessels in normal tissues, angiogenic blood vessels at the tumor sites have bigger size openings between nearby vascular endothelial cells. This can help the nano DDS to accumulate at the tumor tissues and then release a higher concentration of the drugs specifically into the tumor cells, thus permitting effective cancer treatment with least systemic side effects. Various studies have demonstrated that EPR plays a pivotal part in passive drug targeting. The EPR effect mainly depends on many factors, such as the nano DDS surface properties, tumor types, and immunogenicity. Passive drug targeting is due to the faulty leaky tumor vasculature with irregular epithelium, reduced level of lymphatic drainage, and lowered uptake of the interstitial fluid, supporting passive targeting of nano DDS in tumors (Kumari et al. 2016; Wakaskar 2017; Masood 2016; Mahato 2017).

3.5.2.2 Active Tumor Targeting

Passive tumor targeting can help the localization of nano DDS at the tumor sites, but it is not able to encourage cellular uptake by tumor cells. This can be accomplished by active tumor targeting. Compared to passive tumor targeting, active tumor targeting strategy relies on a biological communication between targeting ligand on the surface of nano DDS and the receptor on the target tumor cell surface. Active tumor targeting strategy can easily differentiate the normal healthy cells and tumor cells. A large number of targeting ligands and targets have been identified and evaluated for facilitating active drug targeting of nano DDS for various types of cancers (Table 3.1). Such ligands on the surface of nano DDS often actively attach to specific receptors on the tumor cell surface, increasing the drug-containing nano DDS internalization by receptor-mediated endocytosis, improving the therapeutic efficacy, controlling the delivery of chemotherapeutic drugs to healthy tissues, and also decreasing the systemic adverse effects. Hence, active tumor targeting has displayed promising outcomes in circumventing different pitfalls, such as multidrug resistance in tumors and bypassing the blood-brain barrier (Anarjan 2019; He et al. 2020; Lin et al. 2016; Nag and Delehanty 2019).

Table 3.1 Targeting moiety and targets for active targeting of nano DDS
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3.6 Nano DDS for Cancer Treatment

3.6.1 Organic Nanomaterials for Cancer Treatment

Most of the organic nanomaterials (liposomes, solid lipid nanoparticles, polymeric micelles, dendrimers, polymeric nanoparticles, and polymer-drug conjugates) are used as a carrier and targeting system for cancer treatment (Fig. 3.1).

Fig. 3.1
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Different types of organic nanomaterials for cancer treatment

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3.6.1.1 Liposomes

Liposomes are described as phospholipid vesicles comprising of one or more concentric bilayer vesicles surrounding the discrete aqueous phase. Because liposome composition is identical to that of cellular membranes, liposomes are safer and biocompatible than other synthetic polymers. Because of the unique structure of liposomes, both hydrophobic and hydrophilic drugs can be incorporated in liposomes. Liposomes can load and hold hydrophobic drugs in the lipid bilayers and hydrophilic drugs in the aqueous core. Liposomes have several advantages than other drug delivery systems, and it is administrated as a potential nanocarrier for drug delivery of chemotherapeutic drugs (Mishra et al. 2018; Ahmed et al. 2019). Currently, there are many liposomal products in the market (Table 3.2) and clinical development (Table 3.3) for cancer treatment.

Table 3.2 Approved and marketed liposome-based drugs for cancer treatment
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Table 3.3 Liposome-based drugs in clinical development for cancer treatment
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The types of phospholipids, targeting ligand, PEGylation, and stimuli-sensitive materials determined the charge of the surface of the liposomes . In addition, liposomes with surface modification protect the incorporated drug from degradation, increase the targeting, improve the pharmacokinetic and pharmacodynamics properties, and reduce the toxic side effect of the chemotherapeutic drugs (Patel 2020; Mohamed et al. 2019). PEG conjugation has been identified as a unique strategy for the evasion of RES uptake. The targeting ligands, peptides, and nucleic acid-functionalized liposomes can specifically deliver the chemotherapeutic drugs to the tumor sites. The use of liposome targeted delivery systems in combination therapies of chemotherapy and phototherapy to transport anticancer drugs and photosensitizer can reduce the side effects, significantly enhance the drug accumulation at the target site, and improve the effectiveness of chemotherapy and photodynamic therapy (Cao et al. 2018). Different types of liposomes for targeted anticancer drug delivery are summarized in Table 3.4.

Table 3.4 Liposome-based targeted drug delivery systems for cancer treatment
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3.6.1.2 Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLNs) are made from biological and safe grade lipids, and it is biocompatible and less toxic compared to polymeric or inorganic nanomaterials. SLNs promote the high drug upload of multiple hydrophobic and hydrophilic drugs. SLNs are a versatile drug delivery system that has been applied to enhance the therapeutic effect of chemotherapeutic drugs. Targeted delivery of chemotherapeutic drugs from SLNs reduces the systemic side effects and improves the therapeutic action. SLNs can enhance the chemotherapeutic drug delivery applications for cancer treatment by tumor targeting mechanisms of actions such as passive, active, and codelivery mechanisms (Ganesan et al. 2018; Ramalingam and Ko 2016; Lingayat et al. 2017; Patel et al. 2018). Several studies have reported that SLNs are used as a targeted drug delivery vehicle for different types of tumors. The outcomes of SLNs as carriers of chemotherapeutic drugs are summarized in Table 3.5.

Table 3.5 Application of SLNs against different types of cancers
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3.6.1.3 Polymeric Micelles

Polymeric micelles composed of amphiphilic block copolymers with a hydrophilic corona and hydrophobic core are colloidal nanoparticulate drug delivery systems for chemotherapeutic drugs. Polymeric micelles form a self-assembled structure spontaneously in an aqueous environment. The hydrophobic core of the polymeric micelles possesses a high drug loading of water insoluble chemotherapeutic drugs, and hydrophilic corona provides steric stability to avoid rapid uptake by the RES, resulting in extended drug circulation in the body. In addition to passive drug targeting, polymeric micelles can be surface-modified with targeting ligands for active tumor targeting to enhance the selectivity for cancer cells and improve intracellular delivery of anticancer drugs by receptor-mediated endocytosis while reducing systemic toxicity and severe side effects compared to systemic chemotherapy (Marzbali and Khosroushahi 2017; Gothwal et al. 2016; Biswas et al. 2016). Currently, many chemotherapeutic drug-loaded polymeric micelles are evaluated for effective cancer treatment (Table 3.6).

Table 3.6 Application of polymeric micelles against different types of cancers
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3.6.1.4 Dendrimers

Dendrimers are highly branched globular macromolecules with their 3D nonpolymeric architectures: a central core, a corona with functional groups, and a hyperbranched mantle. Dendrimers’ unique properties like polyvalency, well-defined molecular weight, nanosize, the high degree of branching, water solubility, and simple synthesis procedure make them promising drug carrier systems for anticancer drugs. The dendrimers’ biological effect is initiated by terminal moieties, and the dendrimers seem to be excellent candidates for carriers of anticancer drugs. A variety of dendrimers, including PAMAM, PEG, PPI, and PLL, have been successfully developed for drug delivery applications, and the PAMAM is most widely employed for targeted cancer therapy. Surface modification or conjugation of dendrimers with PEG and other ligands can help reduce the cytotoxicity of dendrimers and enhance plasma circulation time and accumulation of tumor through the EPR effect (Kaur et al. 2016; Augustus et al. 2017; Munir et al. 2016; Parajapati et al. 2016; Abedi-Gaballu et al. 2018; Sherje et al. 2018). Numerous researches that have been conducted to study the application of dendrimers in cancer treatment are presented in Table 3.7.

Table 3.7 Dendrimer-based nano DDS for cancer treatment
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3.6.1.5 Polymeric Nanoparticles

The polymeric nanoparticulate system from natural and synthetic biodegradable polymers has earned more attention due to their biodegradability, biocompatibility, tailorability and stability, ease of coating or surface modification, and low cost. Polymeric nanoparticles, in general, can be used to improve solubility, controlled release, and bioavailability for systemic delivery of anticancer drugs. Drug-loaded polymeric nanoparticles can be developed to actively or passively accumulate in sites of the tumor by controlling their particle size or surface functionalizing with targeting moieties. Polymers like hyaluronic acid and pullulan are used to activate nanoparticles for active targeted drug delivery. These polymers degrade in physiological body conditions, and by-products of the polymers are not harmful to the body. Various natural and synthetic polymers-based nanoparticles were developed and reported for cancer treatment and diagnosis (Masood 2016; Prasad et al. 2017; Conte et al. 2016; Wong et al. 2020; Espinosa-Cano et al. 2018; Taghipour-Sabzevar et al. 2019). Natural and synthetic polymers-based nano DDS for cancer treatment are summarized in Tables 3.8 and 3.9.

Table 3.8 Natural polymers-based nano DDS for cancer treatment
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Table 3.9 Synthetic polymers-based nano DDS for cancer treatment
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3.6.1.6 Polymer-Drug Conjugates

Polymer-drug conjugates (PDCs) can be prepared as nano DDS by covalently conjugating one or more drugs to a polymer backbone before the synthesis of nanoparticles. PDCs are identified as the most examined type of nano DDS, and currently, many PDs in clinical trials and several polymer-drug conjugates are successfully transformed into clinical practice. For example, N-(2-hydroxypropyl) methacrylamide-DOX was the first chemotherapeutic PDC to reach clinical trial studies about 22 years ago. The conjugation of therapeutic drugs to polymers provides many benefits, including improved drug solubilization, stability, controlled drug delivery, enhanced efficacy and improved pharmacokinetics, biodistribution, as well as reduced toxicity and immunogenicity. The main advantage of using PDCs is that the physical and chemical characteristics of polymers can be modified to reduce the toxicity and improve the therapeutic efficacy of the loaded chemotherapeutics . In addition, PDCs have displayed increased accumulation of tumors, improved therapeutic index, prolonged circulation, controlled release of the anticancer drugs, and active tumor uptake by active targeting (Ekladious et al. 2019; Thanou and Duncan 2003; Vicent and Duncan 2006; Li and Wallace 2008) (Table 3.10).

Table 3.10 Polymer-drug conjugates for cancer treatment
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3.6.2 Inorganic Nanomaterials for Cancer Treatment

Inorganic nanomaterials have been intensively studied for cancer therapy and diagnostic imaging due to their great advantages, such as high drug loading, large surface area, improved bioavailability, reduced toxic side effects and controlled release of anticancer drugs, and their tolerance to most organic solvents. Mesoporous silica nanoparticles , gold nanoparticles, magnetic nanoparticles, carbon nanotubes, and quantum dots are commonly used in cancer treatment and diagnosis in various ways (Fig. 3.2) (Khafaji et al. 2019; Veeranarayanan and Maekawa 2019; Liu et al. 2017b).

Fig. 3.2
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Different types of inorganic nanomaterials for cancer treatment

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3.6.2.1 Mesoporous Silica Nanoparticles (Senapati et al. 2018; Ahmadi Nasab et al. 2018; Moreira et al. 2016; de Oliveira Freitas et al. 2017; Yang and Yu 2016; Saini and Bandyopadhyaya 2019)

Silica nanoparticles are extensively used nanoparticle systems in cancer treatment due to its various benefits such as easy synthesis, well-controlled diameter, adjustable pore volume, and potential surface modification. There are two types of silica nanoparticles (core or shell silica nanoparticles and mesoporous silica nanoparticles (MSNs)) established for cancer treatment. Of the two types, MSNs are mostly used as a nano DDS in cancer treatment. One study demonstrated that gemcitabine-loaded MSNs are used to treat pancreatic cancer. One research group developed the rod-shaped magnetic MSNs for suicide gene therapy. The shapes of the MSNs also play a vital role in drug delivery applications. Compared to spherical MSNs, rod shape-like MSNs displayed higher drug loading, better drug release, and gene delivery.

The research carried out by Lee et al. showed how MSNs decorated with doxorubicin-loaded multiple magnetite nanocrystals promoted effective cell death in a melanoma model, confirming passive targeting and nanoparticle accumulation in the tumor site. Huan et al. used MSNs modified with polyethyleneimine/PEG to deliver doxorubicin jointly with P-glycoprotein siRNA. This research explained that nanoparticles were efficiently biodistributed, resulting in 8% of the EPR effect at the tumor site. MSNs can also be surface-functionalized with various types of ligand molecules such as aptamers, growth factors, peptides, and vitamins to actively target tumors via receptor-mediated endocytosis. In the study carried out by Kayuan et al., DOX-loaded HB5 aptamer-functionalized MSNs were used for combined chemo-photothermal therapies. This study verified that combination therapies promote cancer cell killing compared to chemo-photothermal therapy alone. MSNs achieve a satisfactory level of active targeting and reduce toxic side effects in the healthy normal cells.

3.6.2.2 Gold Nanoparticles (Sztandera et al. 2018; Peng and Liang 2019; Kumar et al. 2012; Singh et al. 2018)

Gold nanoparticles (GNPs) have been investigated for its potential application in cancer treatment, diagnostics, and targeted drug delivery. Current researches confirm numerous advantages of GNPs for cancer treatment, primarily due to enabling the control of preparation of GNPs with multiple sizes and shapes and the possibility of surface functionalization on GNPs with various functional and targeting agents. Many features of GNPs are related to their shape and size. The size of spherical GNPs influenced plasma concentration, circulation time, and cellular uptake. It was also reported that the smaller particles of GNPs permeated into the blood-brain barrier, deep layers of skin, and placental barrier. Surface functionalization of GNPs provides significant effects on plasma half-life, protection against aggregation, biocompatibility, preventing the removal by the MPS and RES, targeted transport and drug accumulation at the desired site. For the GNP-based drug delivery system, passive targeting, active targeting, or a combination of both strategies can improve tumor accumulation. A remarkable approach confirming the intracellular delivery of chemotherapeutic drugs involves their conjugation to the surface of GNPs through thiol functional groups. The examples of chemotherapeutic drugs conjugated with GNPs are listed in Table 3.11.

Table 3.11 Gold nanoparticles for cancer treatment
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Due to their exceptional properties of absorption and scattering of electromagnetic radiation, GNPs are of specific interest for the PTT in cancer treatment. This PTT treatment procedure involves the utilization of electromagnetic radiation or laser radiation to generate local heating and hyperthermia for the thermal destruction of cancerous cells. The PTT efficacy may be additionally improved by the application of photothermal compounds such as transition metal oxide/sulfide nanomaterials and nanocarbons, enabling an improved transformation of light into heat.

3.6.2.3 Magnetic Nanoparticles (Zhang et al. 2018d; Kolosnjaj-Tabi and Wilhelm 2017; Fathi Karkan et al. 2017; Fathi et al. 2020; Lungu et al. 2016)

Magnetic nanoparticles (MNPs) have been discovered as a potential carrier system to modify the pharmacokinetics of loaded drugs, decrease the cytotoxicity, improve the controlled release, and increase the half-life. Due to the unique properties of higher magnetic moments and surface to volume ratios, it can be used for hyperthermia therapy of cancer treatment and targeted delivery. MNPs are in magnetic resonance imaging to enhance the image contrast of targeted tumor tissues. MNPs can be functionalized with high affinity ligands such as peptides and antibodies to enhance the selectivity further and localize MNPs at the tumor sites. Recently, the MNP application in biosensors has been extensively studied for rapid cancer diagnosis and prevention of cancer metastasis. Various types of MNPs employed in cancer treatment and diagnosis are summarized in Table 3.12.

Table 3.12 Magnetic nanoparticles for cancer treatment
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3.6.2.4 Carbon Nanotubes (Chen et al. 2017; Son et al. 2016; Pardo et al. 2018)

Carbon nanotubes (CNTs) are very popular systems for cancer treatment and diagnosis due to their many unique properties such as structure and high specific surface area to volume. CNTs are classified into single-walled carbon nanotubes and multi-walled carbon nanotubes based on the number of graphene sheets used for the preparation. CNTs have been investigated in all the cancer treatment modalities, including thermal, photodynamic, and gene therapy, drug delivery, lymphatic targeted chemotherapy, and diagnostic techniques. Recently developed single-walled carbon nanotube-based drug delivery systems for cancer treatment are summarized in Table 3.13. CNTs may help the attached chemotherapeutic drugs to penetrate through the target cell to treat cancer.

Table 3.13 Carbon nanotube-based systems for cancer treatment
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The CNTs are used as a photosensitizer for photodynamic therapy. CNTs are used as a contrast medium for diagnostic imaging techniques, and it can be used in ultrasonography, photoacoustic imaging, PET, and MRM for cancer diagnostic applications.

3.6.2.5 Quantum Dots (Zhao et al. 2016; Fang et al. 2017; Lee et al. 2017)

Quantum dots (QDs) are nanosized crystals comprised of a semiconductor core within a shell composed of second semiconductor material. QDs have outstanding optical properties, such as high brightness, tunable emission spectra, and resistance to photo-bleaching. Quantum dots have been used in targeting and localizing tumors and sentinel lymph node mapping in vivo. New imaging techniques like quantum dots resolve the limitations of sensitivity and specificity from current imaging techniques like X-ray, ultrasound, radionuclide imaging, computed tomography, and MRI. Recent studies in surface functionalization of QDs improve their potential application in imaging of cancer. Bioconjugation of QDs with peptides and antibodies can be used for tumor-targeted drug delivery, nanodiagnostics, imaging, and photodynamic therapy. The application of quantum dot conjugates is listed in Table 3.14.

Table 3.14 Quantum dots for cancer treatment and diagnosis
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3.7 Challenges and Future Perspectives

Despite numerous advanced technologies in the production of safe biopolymers and nanomaterials, there remain controversies regarding the safety of nanoformulations. Although the benefits of some biopolymers, dendrimers, and metal-based inorganic nanomaterials are remarkable, toxicity remains a serious problem. It has been proven, for example, that PEI and excessive positive charges of dendrimers destabilize the cell membrane. Thus, advancements in biopolymer synthesis and purification techniques promise to reduce side effects and enhance treatment efficacy. The instability, immune response, potential toxicity, and chronic inflammation challenges for micelles and inorganic nanomaterials need to be focused so that more effective cancer treatment strategies can be developed. Combination therapy with nanomaterials for different types of cancers remains a challenge because of the distinct cancer development mechanisms. For targeted drug therapy, inorganic nanomaterials and micelles can be surface-functionalized with target agents such as magnetic, light, and pH imaging contrast agents; the major limitation of these clinical treatment methods is the poor tissue penetration. All the nanomaterials are not biodegradable so that it can be retained and circulated in the body system for a more extended period after administration. Various research and strategies aimed at overcoming all these challenges will facilitate nanomaterial usage as a drug delivery system and eventually enhance patient survival.

The future perspective of stimuli-responsive nanomaterials can be obtained by various strategies, including enzymatic activation, pH variants, magnetic fields, ultrasound, light, redox potential, and thermal gradients for efficient cancer treatment and diagnosis. Further advancements in the nanomaterials system can improve their application in localizing metastasis, quantitative measurement of molecular targets, and monitoring the efficacy and tracking of drug delivery.

3.8 Conclusion

This chapter has summarized a variety of nanomaterials that are either being used or have the potential to be used as nano drug delivery systems for cancer treatment. Nanomaterials-based cancer treatment has shown significant advantages and new strategies over conventional cancer treatment. Passive or active targeting can significantly remove the systemic side effects of conventional chemotherapies. Targeted drug delivery has made a considerable impact on selective recognizing of the tumor tissues, controlled drug delivery, and overcoming limitations of the conventional chemotherapies. Numerous nanomedicines have been approved by the FDA and indicated satisfactory performance in clinical practice. Although some nanomaterials have not been approved upon their clinical translation, new strategies and promising nanomaterials that are under progress show great assurance, thus providing hope for innovative cancer treatment choices in the near future.