Nanomedicine for Targeted Drug Delivery in Cancer Chemotherapy

Abstract

Cancer is the uncontrolled proliferation of cells which subsequent spread of other organs of the human body (metastasis). The major therapeutic approaches of cancer chemotherapy are to deliver the correct amount of drug molecule in the desired site (malignant cells) for longer duration of action. Nanomedicine basically by passive as well as active targeting has been implemented for recognition, diagnosis and treatment for cancer and widely accepted in the modern field of oncology. Nanomedicine such as nanoliposomes and polymer based nanoparticles combine with genetic materials administered to the target cells for cancer chemotherapy. The advancement of nanomedicine will improve the therapeutic index of anticancer drug via modulation of pharmacokinetics parameters and tissue distribution to targeted sites. Ligand molecule can be tagged with this nanodevices for recognize the malignant cells via active targeting purposes and drug can be release at the site of specific target area followed by pre-programmed or predictable manner. This novel strategy of drug delivery technology is also applicable for conventional chemotherapy as well as metastatic state of the cancer patients. Targeting of neoplastic cells by nanocarriers play a vital role in novel drug delivery by protecting healthy normal cells from cytotoxicity as well as helpful for preventing the angiogenesis (neovascularization).

1. Introduction

Cancer is one of the serious and devastating illnesses of human beings in all over the world. It is an abnormal growth of cell division where apoptosis is generally disappeared and need very complex for long term treatment [1]. The treatment for cancer in the field of oncology is that surgical removal, radiation, hormone therapy and chemotherapy. Chemotherapy is applied by the use of anticancer drugs loaded formulations at the disease site for recovery of patients. Conventional chemotherapy cannot achieve proper selectively to target the cancerous cells and showed the unwanted or adverse effect for the patient during the chemotherapy [2]. Conventional chemotherapy worked by destroying abnormal proliferated cells and due to its cytotoxic nature it also damages the normal healthy cells. Common side effects are shown alopecia (hair loss), nausea or vomiting, organ dysfunction, anemia, thrombocytopenia, myelosuppression and mucositis [3]. As per therapeutic drug monitory the strategies of modern chemotherapy are preferentially destroying malignant cells without having any harmful toxic effects of the normal healthy cells [4]. Nowadays, in the modern field of oncology anticancer drug loaded nanocarriers or nanomedicine were implemented for detection, diagnosis and recovery of critical illness of the patients. The various nanodevices are designed or fabricated for a major role of treatment of neoplastic diseases via passive or active targeting purposes [5]. Anticancer drug loaded nanodevices can also attack the malignant cells through passive targeting where leaky blood vessels are there due to basement membrane abnormalities [6]. Antibody or ligand conjugated anticancer drug loaded nanodevices are fabricated for active targeting is specially based on molecular recognition [7]. In the modern field of nanotechnology, ligand molecules which are conjugated with the surface of nanocarriers may benefit for active targeting purposes.

Our major focus is to application of nanodevices in the modern field of cancer chemotherapy by avoiding cytotoxicity of normal healthy cells and also discussion of cellular uptake of malignant cells of different organs of the human body by various anticancer drug loaded nanocarriers.

2. Global prevalence of cancer and the side effects of few anticancer drugs

Cancer is the devastating disease which ranked as a leading cause of death in all over world. WHO estimate that cancer is the first or second leading cause of death before the age of 70 years (Figure 1) [8]. The substances that cause abnormal proliferation of cells (malignant cells) known as carcinogens. The change of genetic material in the cells may occur spontaneously as a random event or may be modulation of genetic material [9]. This incident occurs due to an external exposure to a substance (carcinogens) which develops the neoplastic cells as well as promote neovascularization i.e. new blood vessel formation for survive the malignant cells. Carcinogens include radiations, tobacco, chemical or may be viruses also. Few ionizing radiation like X-rays, nuclear power plants and atomic bomb explosions can cause various malignancies particularly sarcomas, leukemia, thyroid, cancer or breast cancer [10].

Figure 1.

Global cancer incidence in present scenario.

Common side effects of chemotherapy include fatigue, hair loss, pain, nerve damage, mouth and throat sores, diarrhea, constipation, nausea & vomiting, blood disorders, loss appetite, heart problem and fertility problem also [11].

3. Application of nanomedicine

Cancer is a complicated biological disorder in the human body where abnormal proliferation occurs in malignant cells. The main focus of modern treatment of cancer chemotherapy is to damage the neoplastic cells or control of growth rate and also avoiding cytotoxicity i.e. not to produce any harmful effect in normal healthy cells. Malignant cells are able to proliferate in the human body through new blood vessels generation for neoplastic cell growth formation (neovascularization) known as angiogenesis and lymphatic streams, causing metastasis by forming a secondary tumor [12]. Anticancer drugs work in different ways: by killing the neoplastic cells through direct exposure of chemical agent, by inducing apoptosis (suicide of malignant cells) and arrest neovascularization i.e. (angiogenesis) [3]. The design of nanocarriers revealed a new avenue in the field of oncology such as solid lipid nanoparticles, nanolipid vesicles such as nanoliposomes, carbon nanotubes, dendrimer, micelles, quantum dots, mesoporous silica and protein based nanoparticles etc. which are loaded with anticancer drugs. These nanodevices show potential activity and may utilize for both active and passive targeting during chemotherapy.

4. Dendrimers

Dendrimers are hyper branched nanodevices macromolecules which are three-dimensional structure made up of polymer branching units by covalently attaching with central core for organizing concentric layers [13]. These types of devices have the ability to improve bioavailability as well as the solubility of hydrophobic drugs which can be incorporated in to the intramolecular core of these nanodevices or tagged to their surface of functional groups. By employing biocompatible components with antineoplastic drugs, loaded dendrimers will modify therapeutic index and dosage regimen also (Figure 2) [14].

Figure 2.

Structure of dendrimer and its application.

5. Carbon nanotubes

Carbon nanotubes are built of single or more graphene sheets which are rolled up into a cylindrical tube like single-walled (SW-CNT) or multiwalled (MW-CNT) carbon nanotube structure. These carbon nanotubes are involved fullerenes group (a third allotropic form of carbon) [15]. These nanodevices may assume the hollow sphere, ellipsoid shape and also exists many other forms where the outer diameters are typically in the range of 0.4–2 nm for SW-CNT and 2–100 nm for the MW-CNT [16]. Water insoluble anticancer drugs can easily be incorporated into the hydrophobic hollow interior of carbon nanotubes [17]. Anti-neoplastic drug can be loaded into carbon nanotube for passive as well as active targeting (Figure 3).

Figure 3.

Schematic diagram of carbon nanotube and its application.

6. Quantum dots

Quantum dots are fluorescent semiconducting inorganic nanocarriers. These nanocarriers are applying for several biomedical applications such as cellular imaging and drug delivery [18]. For the synthesis of quantum dots, two common methods are there; one is a bottom-up approach (by self-assembly processes in solution following chemical reduction) and another one is by a top-down method (by means of molecular beam epitaxy ion implantation, e-beam or X-ray lithography) [19, 20]. Most quantum dots are constructed of three parts, an extremely small core (2–10 nm in diameter) of a semiconductor component (e.g. CdSe) surrounded by another semiconductor material, such as ZnS [21]. Finally, a cap made of different components encapsulates the double layer structures of the QDs [22]. The inner semiconductor of CdSe coated with the outer shell of ZnS for QDs revealed most important nanodevices for drug delivery (Figure 4) [23].

Figure 4.

Internal structure of quantum dots and it’s fluorescence property.

7. Nanoliposome or nanolipid vesicles

Liposomes are artificial microscopic bilayer of phospholipids vesicles. These vesicles consist of natural or synthetic lipids represent as nanocarriers in the field of modern drug delivery as well as applications for cancer chemotherapy [24]. Natural phospholipid or synthetic i.e. conventional phospholipids are constructed with one or more hydrophilic tails and hydrophilic head. The lipid bilayer vesicles i.e. liposomes in aqueous solution depends on the different condition such as the method of preparation i.e. stirring, hydration, sonication, extrusion, and they microfluidification, or electroformation (Figure 5) [25, 26]. This nanodevices size ranges between 50 and 500 nm and are available as unilamellar vesicles (<100 nm), large unilamellar vesicles (100–1000 nm) or giant unilamellar vesicles (>1 μm) [27].

Figure 5.

Internal structure of nanoliposome and its preparation.

The development of nanolipid vesicles or nanoliposomes is applicable for chemotherapy during treatment of cancer for their property having both controlled release and targeted drug delivery at the disease site specific action [27]. Encapsulation of chemotherapeutic agents or anticancer drugs within the lipid vesicles can enhance the cellular uptake as well as improve the therapeutic index by systemic administration during chemotherapy [28, 29]. The circulation-time of liposomes can be enhanced and by conjugating stealth-imparting polymers to their surfaces poly-ethylene glycol (PEG) their detection by the reticuloendothelial system (RES) can be reduced [30]. Nanolipid vesicles can penetrate preferentially on the malignant cells (due to the leaky vasculature of tumor cells) by means of a passive targeting process via the enhanced permeability and retention (EPR) effect [31, 32]. Ligand molecules may be attached to the liposomal surface or vesicles for actively target to the cancer cells. Ligands such as antibody or aptamer, proteins, peptides which are conjugated or tagged with the lipid vesicles covalently or non-covalently can easily recognize the neoplastic cells which are specific to the cancer cells or to the endothelial cells of the tumor vasculature (Figure 6 and Table 1) [33].

Figure 6.

Entrapment of anticancer drug loaded nanoliposome by active and passive targeting.

Clinical products	Formulation	Indication	Company	Year
Nanolipid vesicles
Onivyde	Liposomal irinotecan	Pancreatic cancer	Merrimack	2015
Visudyne	Liposomal verteporfin	Macular degeneration, wet age-related, myopia, and ocular histoplasmosis	Bausch and Lomb	2000
DaunoXome	Liposomal daunorubicin	AIDS-related Kaposi’s sarcoma	Galen	1996
AmBisome	Liposomal amphotericin B	Fungal/protozoal infections	Gilead Sciences	—
Myocet	Liposomal doxorubicin	Combination therapy with cyclophosphamide in metastatic breast cancer	Elan Pharmaceuticals	2000
Doxil/Caelyx	Liposomal doxorubicin	Ovarian, breast cancer, Kaposi’s sarcoma, and multiple myeloma	Janssen	1995–2008
Marqibo	Liposomal vincristine	Acute lymphoblastic leukemia	Talon Therapeutics Inc.	2012
Inorganic and metallic nanoparticles
GastroMARKumirem	SPION coated with silicone	Imaging agent	AMAG Pharmaceuticals	2001–2004
INFed	Iron dextran (low MW)	Iron deficiency in chronic kidney disease (CKD)	Sanofi Aventis	1957
Feridex/endorem	SPION coated with dextran	Imaging agent	AMAG Pharmaceuticals
Venofer	Iron sucrose	Iron deficiency in chronic kidney disease (CKD)	Luitpold Pharmaceuticals	2000
NanoTherm	Iron oxide	Glioblastoma	MagForce	2010

Table 1.

List of lipid-based nanolipid vesicles, and inorganic (metallic) nanoparticles approved by the FDA.

8. Polymeric nanoparticles

Polymeric nanoparticles (PNPs) are colloidal nature with submicron range of 10–1000 nm in size. Drugs are incorporated within the nanoparticles or attached to the surface of them to forma nanosphere or nanocapsule achieves sustained release to malignant cells for targeted action (Figure 7 and Table 1) [31, 34]. Generally biodegradable polymers are poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), poly(amino acids), poly(q-caprolactone) (PCL) and herbal polymers consist albumin, alginate, chitosan, and gelatin are used. Cytotoxic drugs such as doxorubicin, cisplatin or other anticancer can be loaded drug in polymeric nanoparticles for cancer chemotherapy which prevent toxic or unwanted effects [35]. Due to leaky blood vessels anticancer drug loaded nanoparticles easily penetrate the malignant cells at the targeted sites and accumulate via passive targeting [36]. Monoclonal antibodies are used for specific targeting ability. To further modify the therapeutic efficacy of anticancer drugs (mAbs) is conjugated or tagged with the surface of polymeric nanoparticles used for active targeting of malignant cells in cancer chemotherapy. For the treatment of breast cancer cells with positive expression of human epidermal growth factor receptor 2 Trastuzumab (Herceptin i.e. HER2) is may be used [37].

Figure 7.

Internal structure of polymeric nanoparticle include nanocapsule and nanosphere.

9. Protein-based nanoparticles

In the field of nanomedicine for cancer treatment, protein has been constructed as nanocarriers for chemotherapy. They are three-dimensional structure and have several advantages such as good biocompatibility, biodegradability and low toxicity. Proteins designed as nanodevices mainly include albumin, transferrin, ferritin, low-density lipoprotein, high density lipoprotein etc. [38]. Protein based nanoparticle delivers anticancer drugs has been widely studied and shown good clinical application prospects [39]. Albumin-bound paclitaxel are the most classic compound for protein-based nanoparticles. Paclitaxel was incorporated into albumin via hydrophobic interaction and then formation of albumin bound paclitaxel nanoparticles with a diameter range of 130 nm, which is traded as Abraxane (celgene) [40]. Nowadays Abraxane has become one of the best-selling protein-based nanoparticles for cancer chemotherapy. Amine, thiol and carboxyl groups which are the binding sites of albumin can be combined with anticancer drugs by non-covalent interactions such as hydrophobic and electrostatic interactions [41]. Protein-based nanoparticles specifically respond to stimuli in the malignant cells and deliver the drug to the tumor region, enabling targeted therapy (Figure 8) [42].

Figure 8.

Protein based nanoparticle and its application.

Iron homeostasis-related proteins such as transferrin and ferritin, are another class of proteins are commonly used as protein based nanoparticles shown excellent performance in receptor-mediated active targeted delivery [43]. Transferrin is the main iron-containing hydrophilic transporter in plasma mainly formed by hepatocytes in the human body, and also responsible for transporting iron in hepatocytes to cells in other tissues [44]. Transferrin are constructed of single chain glycoprotein and is divided into two evolutionary lobes, namely C-lobe (343 amino acids) and N-lobe (336 amino acids) which are connected to each other by a short spacer [45].

Transferrin mediates iron uptake by binding with the transferrin receptor (TfR) which is glycoprotein including TfR₁ and TfR₂ are the major protein receptor for iron metabolism in vivo. TfR is expressed in both in normal as well as cancer tissues. Research studies have confirmed that the expression rate of TfR in cancer cells is nearly 100 times higher than that of normal cells. Neoplastic cells rapidly grow and iron demand is greatly enhanced during DNA synthesis, differentiation and for regeneration also [44]. TfR expression is therefore enhanced in malignant cells in order to adapt to the increased iron requirement and maintain rapid cell division. Transferrin nanoparticles can be widely applicable for tumor diagnosis for its active transport capability and beneficial for targeted delivery of therapeutic agents.

Transferrin-templated copper nanoclusters-doxorubicin NPs were fabricatedfor targeted drug delivery and bioimaging. Transferrin can also be used alone as ligand to provide active tumor targeting capabilities of drug delivery systems.

10. Viral nanoparticles

In the field of nanoparticles and biomedicine viruses may be used to develop technologies particularly in tissue targeting and drug delivery. Viral nanoparticles are significant in their protection of nucleic acids due to the stability of capsid [46]. This physical feature enhances the resistance of VNPs to both temperature and pH levels while allowing the VNPs to remain stable in different types of solvents [47]. Various VNP platforms have been constructed, such as bacteriophages and icosahedral plant viruses as well as rod-shaped plant viruses and filamentous phages [48]. The adaptability of this binding drug moiety can occur via adsorption, encapsulation and covalent attachment (Figure 9) [49]. Cargo molecules may be incorporated through interactions with the interior architecture of the capsid and their highly systemic and repetitive surfaces provide multiple sites for the covalent attachment of site specific residues [50]. Imaging agents and therapeutic drugs can chemically linked to reactive functional groups such as thiol for specific delivery. This method has been validated through the use of virus-like protein cage architecture used to attach and release the anticancer drugs such as doxorubicin [51].

Figure 9.

Viral nanoparticle and its application.

11. Mesoporous silica nanoparticles

Large amount of anticancer drugs can be incorporated mesoporous silica nanoparticles (MSN) and their accumulation in tumor tissues has been observed via passive targeting [52]. Silica nanoparticles having a porous architecture, in their physical structure and they are beneficial for biomedical and nanomedicine applications. Prolongation of circulation, drug availability and biodistribution of therapeutic drugs may modify after PEGylation processes which can promote escape from the reticuloendothelial system (RES) [53]. Mesoporous silica nanoparticles (MSNs) are preferably studied for targeted drug delivery, diagnosis, bio sensing and cellular uptake in the field of biomedical application. Mon disperse spherical nanoparticles (SNP) with diameter ranges of 20–200 nm were employed to study size, dose and cell type-dependent cytotoxicity in A549 and Hep G2 epithelial cells and NIH/3T3fibroblastasca nanoparticles having pore diameters ranging from 2 to 50 nm with narrow pore size distribution and having good chemical and thermal stability. Convenient surface functionalization of these nanocarriers through chemical modification of the active targeting mechanism and several attractive features such as good biocompatibility, large specific surface area, high loading capacity of these devices many anticancer drugs, including doxorubicin, methotrexate, paclitaxel have been loaded and delivered effectively via MSN (Figure 10) [54]. MSNs are preferably studied for targeted drug delivery, diagnosis, bio sensing and cellular uptake in the modern field of cancer chemotherapies. Mon disperse spherical nanoparticles (SNP) with diameter ranges of 20–200 nm were employed to study the size, dose and cell type-dependent cytotoxicity in A549 and Hep G2 epithelial cells and NIH/3T3fibroblastas [55]. The extension mechanism of SNP cytotoxicity (such as cell viability, oxidative stress, cellular uptake, membrane disruption were found to be not only size and dose dependent but also highly cell type dependent. Generally, 60 nm size of SNPs was preferentially endocytosed by cells and high doses, because a disproportionate decrease cell bioavailability [56].

Figure 10.

Schematic diagram of mesoporous nanoparticle and its application.

12. Polymeric nanogels

Above the critical micelle concentration (CMC) polymer-based micelles and vesicles maintain their structure. They lose the function as drug carriers with the dissociation of their self-assembled nanostructures into single polymer chains below the CMC. To overcome this problem the employment of chemically or physically crosslinked polymer network to obtain nanogels which is effective approach to obtain more stable nanocarriers in different biological conditions [57].

Nanogels are the three dimensional hydrophilic networks with three-dimensional (3D) porous structures which are cross-linked hydrogel nano-size devices ranges from 20 to 200 nm. These are either co-polymerized or monomers and ionic or non-ionic. Nanogels are physically or chemically crosslinked polymer networks that are swell in a good solvent [58]. Due to their nano size nanogel showed the prolonged serum half-life period and escape renal clearance. These devices have tendency to imbibe water or physiological fluid in large amount, without changing in internal network structure. By incorporating of ligands molecules into nanogels can be applicable for targeted delivery in cancer chemotherapy [57]. These nano devices shows better thermodynamic stability, relatively low viscosity, and also form elevated capacity of the solubilization. These nanocarriers have the capability of undergoing vigorous sterilization techniques. Nanogels possess a hydrophilic nature which limits good encapsulation property of hydrophobic drugs. Nanogels can entrap anticancer drugs and the biological molecules and also employed in protein and gene delivery [59]. For this reason, suitable structure engineering of the polymer was taken to permit high encapsulation efficiency. Therefore, nanogels provided novel strategy of drug delivery for poorly soluble drugs which does not only improve their solubility and stability but increasing the opportunity of their cellular uptake than the free drug. They show high biocompatibility as well as better biodegradability compare to other nanodevices. Because of their extremely small size in nature they enhanced permeation capability. Nanogels permits both passive and active drug targeting for cancer chemotherapy [58].

Polymer-based nanogels are three-dimensional network consisting of chemically or physically crosslinked polymer containing both hydrophilic (polar) and hydrophobic monomers. They form semisolid states (hydrogels) when dispersed in aqueous media, which may be swollen by a large amount of water [59]. The needs of application of hydrogels tuned to match the properties of hydrogels. By the choice of specific polymers (molecular structure and segment length), the crosslinking mechanism, and the eventual presence of acidic (or basic) polymer moieties, whose protonation can be easily controlled with the pH or salt concentration (Table 2) [60]. The composition of polymeric nanogel i.e. hydrogels depends on the specific biomedical application and may require specific properties such as biocompatibility, transport mechanical properties, chemical stability and the ability to respond to microenvironment changes. Another crucial factor for hydrogel performance is the nature of the involved (chemical or physical) crosslink interaction, as it influences many of the network properties like swelling, elastic modulus, and transport properties (Figure 11) [61].

Clinical products	Formulation	Indication	Company	Year
Genexol-PM	mPEG-PLA micelle loaded with paclitaxel	Metastatic breast cancer	Samyang Corporation	2007; South; Korea
Cimzia/certolizumabpegol	PEGylated antibody fragment (certolizumab)	Crohn’s disease; Rheumatoid/psoriatic arthritis; Ankylosing spondylitis	UCB	2008–2013
Adynovate	Polymer-protein conjugate (PEGylated factor VIII)	Hemophilia	Baxalta	2015
Eligard	Leuprolide acetate and polymer PLGA (poly(DL-lactide-co-glycolide)	Prostate cancer	Tolmar	2002
Renagel	Poly(allylamine hydrochloride)	Chronic kidney disease	Sanofi	2000
Estrasorb	Micellarestradiol	Menopausal therapy	Novavax	2003

Table 2.

List of relevant (polymer-based and lipid-based) organic and inorganic (and metallic) nanomedicines approved by the FDA.

Figure 11.

Anticancer drug loaded polymeric nanogel and its application.

13. Micelles-based delivery systems or micellar nanoparticles

Micellar nanoparticles are commonly made up with an amphiphilic block of copolymers which is the main component of micelles. Micellar characteristics are based on the properties and hydrophilic nature of copolymers, in buffered media. Their structure made up to form a nano-sized shell or core structure. Because of their nature of biodegradability and biocompatibility, copolymers are commonly used owing to their ability to entrap hydrophobic drugs. For lipophilic drug component, the hydrophobic cavity of micelles acts as a reservoir and outer hydrophilic shell maintain the stability of micelle in an aqueous environment, and these features form micelles for intravenous administration [62]. Drug molecules can be incorporated into micelles by using two methods, one method is chemical covalent attachment and another one is physical encapsulation. PEG is generally used as a hydrophilic shell; shells with hydrophobic domains include PLA, PLGA, polystyrene, poly(cyanoacrylate), poly(vinylpyrrolidone), and polycaprolactone. Above the critical micelle concentration, micellar nanoparticles are collected from self-assembly of amphiphilic block copolymers in aqueous media (Figure 12) [63]. The core, consisting of hydrophilic shell maintains steric stability and aqueous solubility to the micellar structure whereas the hydrophobic domain, acts as a reservoir and protects the drug from being dissolved. Recently, the first formulation was designed paclitaxel loaded polymeric micelles, known as Genexol-PM, are cremophor-free polymeric micelle [64]. Paclitaxel loaded in micelle was fabricated with steering ligands which is another type of micelles has been undergone a clinical trial therapeutic agents and for imaging also. These results are applicable for conventional amid numerous models of the micellar preparation (Table 2). In the modern field of nanotechnology for cancer treatment, a research group designed the novel nanodevices polymeric micelles incorporated with of ursolic acid- (UA-PMs). Undissolvable drugs, such as docetaxel and paclitaxel, can be covered with a water-solute layer to modify their hydrophilicity and improve their bioavailability in this modern technology. The hydrophilic shell maintains lengthens and protection circulation in vivo, influencing the enhanced permeability and retention effect [65].

Figure 12.

Schematic diagram of micellar nanoparticles.

14. Nanosponge

Nanosponges are can be defined as hydrophilic, water-insoluble, and supramolecular nano devices with three-dimensional (3D) hyper-reticulated nanoporous structures which exhibit significant stability over a wide range of temperatures and pH levels. These nanodevices have high entrapment efficiency, are widely engineered for cancer therapy and drug delivery purposes [66]. They are applicable for cancer treatment for their property, such as high biocompatibility, biodegradability, and low cytotoxicity, making them suitable for biomedical applications also.

For instance, cyclodextrin-based nanosponges have excellent potential for the production of inclusion and non-inclusion complexes with a variety of drugs/active with low bioavailability [67]. In inclusion complex nanosponges, the drug forms an inclusion complex with the cyclodextrin molecule. However, in non-inclusive complex nanosponges, the drug molecule becomes entrapped or imbibed into their porous nanostructures. Among nanosponges, cyclodextrin-based structures have been widely explored for drug delivery, remediation, sensing, and catalytic applications [68].

The use of anticancer drug loaded nanosponge that can improve the therapeutic efficacy and could increase drug concentration at the tumor site, reducing the side effects during chemotherapy. In particular, cyclodextrin-based nanosponges (NS) have been proposed for cancer nanotherapeutic development.

The fabrication of self-catabolic DNAzyme nanosponges, in bioinspired for controllable drug delivery behaviors and suitable gene silencing functions have been reported which is a novel and smart nanosystem for biomedical commitments [67].

Ethylcellulose nanosponges were designed via an ultrasonic-assisted emulsion by solvent evaporation method for targeted drug delivery of withaferin-A for cancer chemotherapy. Ribociclib loaded nanosponges revealed maximum drug release and exhibited high cytotoxic effects in MCF-7 and MDA-MB-231 breast cancer cell lines [69].

Glutathione-responsive β cyclodextrin nanosponges (GSH-NSs) were designed with improve the solubilization of Reveratrol, which is natural polyphenolic compound obtained from various natural sources used for targeting to the cancer cells without any harmful effect of normal cells (Figure 13) [68].

Figure 13.

Internal structure of nanosponge and its application.

15. DNA based nanoparticles and gene therapy

DNA which plays an important role in the pathological as well as physiological action of the organisms and also act as an important carrier of the genetic information in the organisms. DNA based nanoparticles have significant merits with excellent biocompatibility and biodegradability for sequence programming. DNA based nanoparticles or nanodevices can load several anticancer drugs and applicable for targeted drug delivery to malignant cells with the assistance of functional elements. These types of devices improving the cellular uptake and stimuli responsive of drug release. At present days, DNA based nanodevices have successfully achieved effective delivery of chemotherapeutic drugs such as doxorubicin, daunorubicin, platinum etc. [69].

Scientists have begun to treat various complicated diseases by site gradient by gene manipulation technologies such as gene silencing and gene editing by site gradient, which can form stable complexes with mRNA to achieve high loading rates such as ionisable lipid NPs, polymer-lipid hybrids nanodevices and biological nanostructures with high biocompatibility [70].

16. Mechanism of action of several anticancer drug loaded nanoformulations

Among various anticancer drug loaded nanoformulations such as nanoparticles, nanolipid vesicles, nano micelles, nanotubes achieve therapeutic goal in modern cancer chemotherapy for its high drug loading capacity and shows effective therapeutic efficacy and due to their smaller size easily can be entrapped or penetrated by malignant cells for its leaky vasculature of basement membrane [64].

These types of devices are applicable for delivery of antineoplastic drugs to the target site of specific neoplastic cells, where the active medicament may release in pre-programmed manner. Grafting with various targeting ligand molecules such as antibody fragments or may be aptamers by tagging with the surface of nanocarriers, so that they can easily recognize the malignant cells and entrapped by the neoplastic cells as a result cellular uptake will be enhance [71].

Translatable phospholipid-mimic OXA prodrug (Oxalipid) clinically synthesized which could self-assemble to form nanolipid vesicles showed longer blood circulation time, enhanced tumor accumulation, and inhibited the progression of metastatic triple negative breast cancer [72]. Silibinin loaded organic/inorganic hybrid mesoporous nanoparticles was fabricated could inhibit the invasion of metastatic breast cancer cells MDA-MB-231 [73]. Doxorbicin (DOX) loaded mesoporous silica nanoparticles (HMCNs) was constructed which is hollow-structured and after oxidization with concentrated H₂SO₄ and HNO₃ endow HMCNs entering tumor cells, DOX was released in acid lysosomes to inhibit migration, growth and invasion of neoplastic metastatic cells [74].

The redox-sensitive strategy combining with nanoparticles were constructed to elevate in tumor cells for antimetastatic treatment was reported. A reduction-sensitive amphiphilic block polymer Tween 85-disulfide bond-polyethyleneimine 2K (TSP), was manufactured which could self-assemble in aqueous nature to deign or frame micelles for carrying the shRNA silencing NF-κB (shp65) with positive charges. As a result these are capable for suppress the growth and metastasis of MDA-MB-435 tumors [75].

17. Conclusion and future perspectives

We focus on recent advances of anticancer drug loaded nanocarriers for targeted drug delivery in cancer chemotherapy which are novel strategy in the field of oncology. The main objective of these nanodevices is to avoid the adverse drug reaction, decrease unwanted side effects as well as reducing cytotoxicity during chemotherapy. Further, these newer drug delivery systems will reduce dose frequency due to the nature of their controlled and sustained release or preprogramed drug release pattern in different time intervals, so that these nanodevices enhance therapeutic efficacy as well as reach in therapeutic range for recovery of the patients. Due to very small or nanosize they can easily entrap by malignant cells due to nature of leaky vasculature of basement membrane and so therefore easily applicable for passive targeting. Ligand molecules such as antibody or aptamer can be attached to the surface of nanocarrier so that they can easily recognize the tumor cells or may be applied for active targeting purposes.

Several researches have been carried out by using various anticancer drug loaded nanocarriers and has been studied for cellular uptake in different cancer cell lines via passive and active targeting. It is important to note that several nano drug delivery systems should apply for approval via clinical trial and may be started in commercial use of human beings in future field of cancer treatment. This may be beneficial for minimizing the cytotoxicity as well as enhance the pharmaceutical elegance for human health care.