Advanced search
Publication Cover

Artificial Cells, Nanomedicine, and Biotechnology

An International Journal
Volume 46, 2018 - Issue sup2
Submit an article Journal homepage
11,579
Views
68
CrossRef citations to date
0
Altmetric
Review

Nanoparticles as carriers for drug delivery in cancer

Ankita Dadwal Department of Pharmaceutics, I.S.F. College of Pharmacy, Moga, India; ; Department of Pharmaceutical Science and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, India
,
Ashish Baldi Department of Pharmaceutical Science and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, India
&
Raj Kumar Narang Department of Pharmaceutics, I.S.F. College of Pharmacy, Moga, India; Correspondencedrrknisf@gmail.com
Pages 295-305
Received 15 Dec 2017
Accepted 21 Mar 2018
Published online: 25 Jul 2018

Review

Nanoparticles as carriers for drug delivery in cancer

Abstract

Abstract

Cancer nanotherapeutics are swiftly progressing and are being applied to solve several limitations of conventional drug delivery systems such as non-specific biodistribution and targeting, lack of water solubility and poor oral bioavailability. Advances in protein engineering and materials science have contributed to novel nanoscale targeting approaches that may bring new hope to cancer patients. Several therapeutic nanocarriers have been approved for clinical use. Nanoparticles have been designed for optimal size and surface characteristics to improve their biodistribution and to increase their circulation time in the bloodstream. By selectively using the unique pathophysiology of tumours, such as their enhanced permeability and retention effect nanotherapeutics are able to carry loaded active drug to cancer cells. In addition to this passive targeting mechanism, active targeting strategies using ligands or antibodies directed against selected tumour targets magnify the specificity of these therapeutic nanoparticles. Drug resistance, another obstacle can also be overcome or reduced by using nanoparticles. Multifunctional and multiplex nanoparticles are now being actively investigated and are on the horizon as the next generation of nanoparticles, facilitating personalized and tailored cancer treatment.

Introduction

Cancer remains one of the world’s most devastating diseases, with more than 10 million new cases every year [1]. However, mortality has decreased in the past 2 years [2] owing to better understanding of tumour biology and improved diagnostic devices and treatments. Current cancer treatments include surgical intervention, radiation and chemotherapeutic drugs, which often also kill healthy cells and cause toxicity to the patient. Conventional chemotherapeutic agents also do not show targeted action and are distributed non-specifically in the body where they affect both cancerous and normal cells, thereby limiting the dose achievable within the tumour cells and also resulting in suboptimal treatment due to excessive toxicities. Molecular targeting therapy has emerged as one approach to overcome the lack of specificity of conventional chemotherapeutic agents [3]. However, the resistance development in cancer cells can dodge the cytotoxicity not only of conventional chemotherapeutics but also of newer molecular targeting therapeutics [4]. By using both passive and active targeting strategies, intracellular concentration of drugs in cancer cells can be improved by nanoparticles while avoiding toxicity in normal cells (Figure 1) [5,6]. Passive targeting feats the characteristic features of tumour biology that allows nanocarriers to accumulate in a tumour by the enhanced permeability and retention (EPR) [2]. Active approaches achieve this by conjugating nanocarriers containing chemotherapeutics with molecules that bind to overexpressed antigens or receptors on the target cells. However, although nanoparticles offer many advantages as drug carrier systems, there are still many limitations to be solved such as poor oral bioavailability, instability in circulation, inadequate tissue distribution and toxicity. In this reviews provide perspective on the use of nanotechnology as a fundamental tool in cancer research and nanomedicine [7,8]. Here we focus on the types and characteristics of nanoparticles, how nanoparticles are being used as drug delivery systems to kill cancer cells more effectively and also to reduce or overcome drug resistance and how nanoparticles will be developed to improve their therapeutic efficacy and functionality in future cancer treatments.

Figure 1. Improving cancer treatment.

Display full size

Targeted delivery of nanoparticles

Ideally, for the effectiveness of anticancer drugs in cancer treatment, they should first, after administration, be able to penetrate through the barriers in the body and reach the desired tumour tissues with minimal loss of their volume or activity in the blood circulation. Second, after reaching the desired site, drugs should have the ability to selectively kill tumour cells without affecting normal cells. These two basic approaches are also associated with improvements in patient survival and quality of life by increasing the intracellular concentration of drugs and reducing dose-limiting toxicities simultaneously. Increasingly, nanoparticles seem to have the potential to satisfy both of these requirements for effective drug carrier systems.

Size and surface characteristics of nanoparticles

Nanoparticles must have the ability to remain in the bloodstream for a considerable time without being eliminated for effective delivery of drug to the targeted tumour tissue. Conventional surface particles and non-modified nanoparticles are usually caught in the circulation by the reticuloendothelial system, such as the liver and the spleen, depending on their size and surface characteristics [9]. The fate of injected nanoparticles can be controlled by adjusting their size and surface characteristics.

Surface characteristics. Surface characteristics of nanoparticles are an important factor for determining their lifespan and destiny during circulation relating to their capture by macrophages. Ideally, nanoparticles should have hydrophilic surface so that they can escape macrophage capture [10]. This can be achieved by two methods, first coating the surface of nanoparticles with a hydrophilic polymer, such as Peg, second, protects them from opsonization by repelling plasma proteins; alternatively, nanoparticles can be formed from block copolymers with hydrophilic and hydrophobic domains [11].

Size. In addition to their surface characteristics, there is also one more advantage of nanoparticles is that their size can be adjusted. The size of nanoparticles used in a drug delivery system should be small enough to escape capture by fixed macrophages that are lodged in the reticuloendothelial system, such as the liver and spleen but should be large enough to prevent their rapid leakage into blood capillaries. The size of the sinusoid in the spleen and fenestra of the Kuffer cells in the liver varies from 150 to 200 nm [12] and the size of gap junction between endothelial cells of the leaky tumour vasculature may vary from 100 to 600 nm [13]. Thus, the size of nanoparticles should be up to 100 nm to reach tumour tissues by passing through these two particular vascular structures.

Passive and active targeting

Nanocarriers come across numerous barriers in their route to the target, such as mucosal barriers and non-specific uptake [14,15]. To report the challenges in targeting tumours with nanotechnology, it is essential to combine the rational design of nanocarriers with the fundamental understanding of tumour biology. General features of tumours include Poor lymphatic drainage and leaky blood vessels. Whereas free drugs may diffuse non-specifically, a nanocarrier can escape into the tumour tissues via the leaky vessels by the enhanced permeability and retention effect (EPR effect) [16] (Figure 2). There is rapid and defective angiogenesis (formation of new blood vessels from existing ones) because of which there is increased permeability of blood vessels in tumour cells. Furthermore, the dysfunctional lymphatic drainage in tumours also helps in retaining the accumulated nanocarriers and allows them to release drugs into the locality of the tumour cells. Experiments using liposomes of different mean size suggest that the threshold vesicle size for extravasation into tumours is ∼400 nm [13], but other studies have shown that particles having diameters <200 nm are more effective [17,18]. Based on clinical therapy passive targeting approaches suffer from several limitations. Some drugs cannot diffuse efficiently so targeting cells within tumour is not always possible and the random nature of the approach makes it difficult to control the process because of this lack of control multiple-drug resistance (MDR) may induce – a situation where chemotherapy treatments fail patients shows resistance of cancer cells towards one or more drugs. MDR occurs because of the overexpression of transporter proteins that expel drugs from cells on the surface of cancer cells [4,19,20]. Expelling drugs inevitably lowers the therapeutic effect and cancer cells soon develop resistance to a variety of drugs. The passive strategy is further limited because certain tumours do not exhibit the EPR effect, and the permeability of vessels may not be the same throughout a single tumour [21]. One way to overcome these limitations is to modify the nanocarriers in such a way that they actively bind to specific cells after extravasation. This can be achieved by attaching targeting agents such as ligands – molecules that can bind to specific receptors on the cell surface – to the surface of the nanocarrier by a variety of conjugation chemistries. Nanocarriers will recognize the receptor and bind to target cells through ligand–receptor interactions, and drug will be released inside the cell (Figure 2). In general, targeting agent which is used to deliver nanocarriers to cancer cells, it is imperative that the agent should binds with high selectivity to molecules that are uniquely expressed on the cell surface. Other important consideration is that to maximize specificity, a surface marker which can be an antigen or receptor should be overexpressed on target cells than in the normal cells. For example, to efficiently deliver liposomes to B-cell receptors using the anti-CD19 monoclonal antibody (mAb), the density of receptors should be in the range of 104–105 copies per cell. Those with lower density are less effectively targeted [22]. In a breast cancer model, a receptor density of 105 copies of ErbB2 receptors per cell was necessary to improve the therapeutic efficacy of an anti-ErbB2-targeted liposomal doxorubicin relative to its non-targeted counterpart [23]. The binding of certain ligands to their receptors may cause receptor-mediated internalization, which is often necessary if nanocarriers are to release drugs inside the cells [6,24,25]. For example, when immunoliposomes targeted to human blood cancer (B-cell lymphoma) were labelled with an internalizing anti-CD19 ligand a more significant therapeutic outcome was achieved rather than a non-internalizing anti-CD20 ligand [26]. In contrast, owing to the bystander effect targeting nanocarriers to non-internalizing receptors may sometimes be advantageous in solid tumours, where cells lacking the target receptor can be killed through drug release at the surface of the neighbouring cells, where carriers can bind [27]. It is generally known that higher binding affinity increases targeting efficacy. However, for solid tumours due to a “binding-site barrier” high binding affinity can decrease penetration of nanocarriers, where the nanocarrier binds to its target so strongly that penetration into the tissue is prevented. In addition to enhanced affinity, multivalent binding effects may also be used to improve targeting. The collective binding in a multivalent interaction is much stronger than monovalent binding. For example, dendrimer nanocarriers conjugated to 3–15 folate molecules showed a 2500–170,000-fold enhancement in dissociation constants (KD) over free folate when attaching to folate-binding proteins immobilized on a surface. This was attributed to the avidity of the multiple folic acid groups on the periphery of the dendrimers [28].

Figure 2. Schematic representation of different mechanisms by which nanocarriers can deliver drugs to tumours. (A) Passive tissue targeting and (B) active cellular targeting.

Display full size

Types of nanoparticles used as drug delivery systems

Nanoparticles useful as drug delivery systems these are submicron sized particles (3–200 nm), devices or systems that can be made by using a variety of materials including lipids (liposomes), polymers (polymeric nanoparticles, micelles or dendrimers), viruses (viral nanoparticles) and even organometallic compound (nanotubes; Table 1).

Table 1. Representative examples of nanocarrier-based drugs on the market.

Polymer-based drug carriers

Depending on the method of preparation of polymeric-based drug carriers, the drug is either covalently bound to or physically entrapped in polymer matrix [40]. The resulting compounds may have the structure of capsules (polymeric nanoparticles or polymer–drug conjugates), amphiphilic core/shell (polymeric micelles), or may be hyperbranched macromolecules (dendrimers; Figure 3). Polymers used as drug conjugates can be divided into two groups one is natural polymers and other is synthetic polymers.

Figure 3. Types of nanocarriers for drug delivery. (A) polymeric nanoparticles: polymeric nanoparticles in which drugs are conjugated to or encapsulated in polymers. (B) Polymeric micelles: amphiphilic block copolymers that form to nanosized core/shell structure in aqueous solution. The hydrophobic core region serves as a reservoir for hydrophobic drugs, whereas hydrophilic shell region stabilizes the hydrophobic core and renders the polymer to be water-soluble. (C) Dendrimers: synthetic polymeric macromolecule of nanometer dimensions, which is composed of multiple highly branched monomers that emerge radially from the central core. (D) Liposomes: self-assembling structures composed of lipid bilayers in which an aqueous volume is entirely enclosed by a membranous lipid bilayer. (E) Viral-based nanoparticles: in general structure are the protein cages, which are multivalent, self-assembles structures. (F) Carbon nanotubes: carbon cylinders composed of benzene rings.

Display full size

Polymeric nanoparticles (polymer–drug conjugates)

Albumin, chitosan and heparin are naturally occurring polymers and have been used as a material of choice for the delivery of DNA, oligonucleotides and protein, as well as drugs. Recently, serum albumin is included as a carrier for the formulation of paclitaxel nanoparticle [nanometer-sized albumin-bound paclitaxel (Abraxane); Figure 3(A)], has been used in the clinic for the treatment of metastatic breast cancer [29]. Besides metastatic breast cancer, Abraxane has also been evaluated in clinical trials for many other cancers including non-small-cell lung cancer (phase II trial) and advanced non-haematologic malignancies (phase I and pharmacokinetics trials; [41,42]). PGA was the first biodegradable polymer to be used for conjugate synthesis among other synthetic polymers such as N-(2-hydroxypropyl)-methacrylamide copolymer (HPMA), polystyrene-maleic anhydride copolymer, polyethylene glycol (PEG) and poly-l-glutamic acid (PGA). Several representative chemotherapeutics that are used widely in the clinic have been tested as conjugates with PGA in vitro and in vivo and showed encouraging abilities to circumvent the shortcomings of their free drug counterparts [43]. Among them, Xyotax (PGA paclitaxel; [30]) and CT-2106 (PGA-camptothecin; [31]) are now in clinical trials. HPMA and PEG are the most widely used non-biodegradable synthetic polymers [44]. PK1, which is a conjugate of HPMA with doxorubicin, was the synthetic polymer-drug conjugate to be evaluated in clinical trials as an anticancer agent. A phase I clinical trial has been completed in patients with a variety of tumours that were refractory or resistant to prior therapy such as chemotherapy and/or radiation [32]. PK1 should be further evaluated in the next level of clinical trials.

Polymeric micelles (amphiphilic block copolymers)

Amphiphilic block copolymers are responsible for the functional properties of micelles, which accumulate to form a nanosized core/shell structure in aqueous media (Figure 3(B)). For hydrophobic drugs hydrophobic core region serves as a reservoir, while the hydrophilic shell region helps in stabilizing the hydrophobic core and renders the polymers water-soluble, making the particle a suitable candidate for i.v. administration [45]. There are two methods of drug loading into a polymeric micelle: first is physical encapsulation [36] and second is chemical covalent attachment [37]. The first polymeric micelle formulation of paclitaxel, Genexol-PM (PEG-poly(d,l-lactide)-paclitaxel), is a cremophor-free polymeric micelle-formulated paclitaxel. A phase I trial and pharmacokinetic study has been conducted in patients with advanced refractory malignancies [38]. Multifunctional polymeric micelles containing targeting ligands, imaging and therapeutic agents are being actively developed [46] and will become conventional among several models of the micellar formulation in the near future.

Dendrimers

Dendrimers are synthetic polymeric macromolecules of nanometer dimensions, composed of multiple highly branched monomers that emerge outward from the central core (Figure 3(C)). Properties allied with these dendrimers such as their monodisperse size, multivalency, modifiable surface functionality, water solubility and available internal cavity make them attractive for drug delivery [4]. Dendrimer which is most widely used as a scaffold is polyamidoamine dendrimer, which was conjugated with cisplatin [39]. The easily modifiable surface characteristic of dendrimers permits them to be simultaneously conjugated with several molecules such as imaging contrast agents, targeting ligands or therapeutic drugs, yielding a dendrimer-based multifunctional drug delivery system [4].

Lipid-based drug carriers

Liposomes

First described in 1965, liposomes are one of the first nanoparticle platforms to be applied in medicine [47]. Today, there are more than 11 formulations which are approved for clinical use, with many more in clinical and preclinical development. Liposomes are self-assembling closed colloidal structures composed of lipid bilayers having a spherical shape in which an outer lipid bilayer surrounds a central aqueous space (Figure 3(D)) [17]. Their biocompatible and biodegradable compositions, as well as their unique ability to encapsulate hydrophilic agents in their aqueous core and hydrophobic agents within their lamellae, make liposomes excellent therapeutic carriers. To improve their stability and circulation half-life, liposomes can also be coated with polymers such as polyethylene glycol (PEG) [17]. Liposomal drug formulations typically improve the pharmacokinetics and biodistribution of a drug. For example, pegylated liposomal doxorubicin reduces the volume of distribution of doxorubicin from ∼1000 l/m2 in the free drug form to 2.8 l/m2 by restricting the distribution within the plasma. Furthermore, it can achieve higher drug concentrations within tumour while reducing drug concentration in normal tissues, such as heart [48]. Currently, several kinds of cancer drugs have been applied to this lipid-based system using a variety of preparation methods. Among them, liposomal formulations of the anthracyclines doxorubicin (Doxil, Myocet) and daunorubicin (DaunoXome) are approved for the treatment of metastatic breast cancer and AIDS-related Kaposi’s sarcoma [33,39]. Besides these approved agents, many liposomal chemotherapeutics are currently being evaluated in clinical trials [34]. The next generation of liposomal drugs may be immunoliposomes, which selectively deliver the drug to the desired sites of action [35].

Viral nanoparticles

A variety of viruses including cowpea mosaic virus, canine parvovirus, cowpea chlorotic mottle virus and bacteriophages have been developed for biomedical and nanotechnology applications that include drug delivery and tissue targeting (Figure 3(E)). By using chemical or genetic means on the capsid surface a number of targeting molecules and peptides can be displayed in a biologically functional. Therefore, for specific tumour targeting in vivo several ligands or antibodies, including transferrin, folic acid and single-chain antibodies, have been conjugated to viruses [48]. Besides this artificial targeting, a subset of viruses, such as canine parvovirus, have natural affinity for receptors such as transferrin receptors that are up-regulated on a variety of tumour cells [49]. By targeting heat shock protein, a dual-function protein cage with specific targeting and doxorubicin encapsulation has been developed [50,51] the permeability of vessels and the EPR effect may not be the same throughout a single tumour [10]. To overcome these limitations is to programme the nanocarriers in such a way so they actively bind to specific cells after extravasation. This binding may be achieved by attaching targeting agents such as ligands molecules that bind to specific receptors on the cell surface to the surface of the nanocarrier by a variety of conjugation chemistries. Nanocarriers will recognize and bind to target cells through ligand–receptor interactions, and bound carriers are internalized before the drug is released inside the cell. In general, when using a targeting agent to deliver nanocarriers to cancer cells, it is imperative that the agent binds with high selectivity to molecules that are uniquely expressed on the cell surface. Other important considerations are outlined below. To maximize specificity, a surface marker (antigen or receptor) should be overexpressed on target cells relative to normal cells. For example, to efficiently deliver liposomes to B-cell receptors using the anti-CD19 monoclonal antibody (mAb), the density of receptors should be in the range of 104–105 copies per cell. Those with lower density are less effectively targeted [11]. In a breast cancer model, a receptor density of 105 copies of ErbB2 receptors per cell was necessary to improve the therapeutic efficacy of an anti-ErbB2-targeted liposomal doxorubicin relative to its non-targeted counterpart [14]. The binding of certain ligands to their receptors may cause receptor-mediated internalization, which is often necessary if nanocarriers are to release drugs inside the cell [13,15,16]. For example, a more significant therapeutic outcome was achieved when immunoliposomes targeted to human blood cancer (B-cell lymphoma) were labelled with an internalizing anti-CD19 ligand rather than a non-internalizing anti-CD20 ligand [17]. In contrast, targeting nanocarriers to non-internalizing receptors may sometimes be advantageous in solid tumours owing to the bystander effect, where cells lacking the target receptor can be killed through drug release at the surface of the neighbouring cells, where carriers can bind [18]. It is generally known that higher binding affinity increases targeting efficacy. However, for solid tumours, there is evidence that high binding affinity can decrease penetration of nanocarriers due to a “binding-site barrier”, where the nanocarrier binds to its target so strongly that penetration into the tissue is prevented [19]. In addition to enhanced affinity, multivalent binding effects (or avidity) may also be used to improve targeting. The collective binding in a multivalent interaction is much stronger than monovalent binding. For example, dendrimer nanocarriers conjugated to 3–15 folate molecules showed a 2500–170,000-fold enhancement in dissociation constants (KD) over free folate when attaching to folate-binding proteins immobilized on a surface. This was attributed to the avidity of the multiple folic acid groups on the periphery of the dendrimers [20].

Carbon nanotubes

Carbon nanotubes are carbon cylinders composed of benzene rings (Figure 3(G)) that have been applied in biology as sensors for detecting DNA and protein, diagnostic devices for the discrimination of different proteins from serum samples, and carriers to deliver vaccine or protein [47]. Carbon nanotubes are completely insoluble in all solvents, generating some health concerns and toxicity problems. However, the introduction of chemical modification to carbon nanotubes can render them water-soluble and functionalized so that they can be linked to a wide variety of active molecules such as peptides, proteins, nucleic acids and therapeutic agents [17]. Antifungal agents (amphotericin B) or anticancer drugs (methotrexate) have been covalently linked to carbon nanotubes with a fluorescent agent (FITC). In an in vitro study, drugs bound to carbon nanotubes were shown to be more effectively internalized into cells compared with free drug alone and to have potent antifungal activity [48,52]. Single-walled carbon nanotube (SWNT)-based drug delivery system was developed by conjugation of human serum albumin (HSA) nanoparticles for loading of antitumour agent PTX. The SWNT-based drug carrier displayed high intracellular delivery efficiency (cell uptake rate of 80%) in breast cancer MCF-7 cells, as examined by fluorescence-labelled drug carriers, suggesting the needle-shaped SWNT-HSA drug carrier was able to transport drugs across cell membrane despite its macromolecular structure. The drug loading on SWNT-based drug carrier was through high binding affinity of PTX to HSA proteins. The PTX formulated with SWNT-HSA showed greater growth inhibition activity in MCF-7 breast cancer cells than PTX formulated with HSA nanoparticle only (cell viability of 63 versus 70% in 48 h and 53 versus 62% in 72 h). The increased drug efficacy could be driven by SWNT-mediated cell internalization [53]. The multiple covalent functionalizations on the sidewall or tips of carbon nanotubes allow them to carry several molecules at once, and this strategy provides a fundamental advantage in the treatment of cancer.

Thermoresponsive systems

Thermoresponsive drug delivery is among the most explored stimuli-responsive strategies and has been widely explored in oncology. Thermoresponsiveness is usually governed by a nonlinear sharp change with temperature in the properties of at least one component of the nanocarrier material. Such a sharp response triggers the release of the drug following a variation in the surrounding temperature. Ideally, thermosensitive nanocarriers should retain their load at body temperature (∼37 °C), and rapidly deliver the drug within a locally heated tumour (∼40–42 °C) Figure 4 to nanochemotherapeutics counteract rapid blood-passage time and washout from the tumour.

Figure 4. Temperature-based mechanisms of drug delivery.

Display full size

Metallic nanocapsules

The advantage of using a magnetic field relies on the different nature that the magnetic response can take, which can be a magnetic guidance under a permanent magnetic field, a temperature increase when an alternating magnetic field is applied, or both when alternately used. Therefore, magnetically responsive systems allow for diversity in the drug delivery pathway. Furthermore, there is the possibility of performing magnetic resonance imaging, and hence to associate diagnostics and therapy within a single system (the so-called theranostic approach) [54]. Magnetic guidance is typically obtained by focusing an extracorporeal magnetic field on the biological target during the injection of a magnetically responsive nanocarrier. This concept has demonstrated great potential in experimental cancer therapy because of improved drug accumulation inside solid-tumour models Figure 5. Candidate nanosystems for such a therapeutic approach are core–shell nanoparticles (a magnetic core made of magnetite (Fe3O4) coated with silica or polymer) [55,56] magnetoliposomes (Fe3O4 or maghemite (Fe2O3) nanocrystals encapsulated in liposomes) [57] and porous metallic nanocapsules [58]. Most core–shell nanoparticles have shown promising results in vitro, yet only some of them have demonstrated improved tumour accumulation and anticancer pharmacological efficacy in various in vivo models. To avoid limitations related to physical drug entrapment (for instance, uncontrolled burst release or poor drug loading), the drugs and the nanocarriers can be covalently linked [56,59]. For example, Fe3O4 nanocrystals loaded into squalene–gemcitabine conjugate nanoassemblies exhibiting high drug payloads have demonstrated the absence of burst release, enhancement of the magnetic resonance imaging contrast in the targeted L1210 solid-tumour nodule and significant therapeutic efficacy [59].

Figure 5. Magnetically responsive systems.

Display full size

Nanoshells

Owing to their non-invasiveness and the possibility of remote spatial and temporal control, in the past few years a large variety of photoresponsive systems has been engineered to achieve on-demand drug release in response to illumination of a specific wavelength (in the ultraviolet, visible or near-infrared (NIR) regions) Figure 6. The different strategies available rely on either repeatable on–off drug-release or one-time event triggered by photosensitiveness-induced structural modifications of the nanocarriers. For instance, doxorubicin-loaded hollow gold nanospheres showed accelerated drug release when irradiated at 808 nm, allowing enhanced anticancer activity and reduced systemic toxicity compared with the free-drug treatment [60]

Figure 6. Light-triggered drug delivery systems.

Display full size

Important concepts in nanoparticle drug delivery for cancer

There are several general concepts that are important in nanoparticle drug delivery. These include the enhanced permeability and retention (EPR) effect, nanoparticle clearance by the mononuclear phagocyte system (MPS) and desirable nanoparticle characteristics for cancer applications.

Enhanced permeability and retention effect

Tumour vasculatures are generally abnormal, with aberrant branching and leaky walls [21]. This leakiness is due to the decreased number of pericytes and rapid proliferation of endothelial cells. These characteristics result in large pores in the tumour vasculatures, ranging from 100 nm to several hundred nanometers in diameter, as compared to normal vessel junctions of 5–10 nm [22]. These large pores allow higher vascular permeability and hydraulic conductivity in tumours, enabling macromolecules such as nanoparticles to pass into tumours [21,23]. In normal tissue, lymphatic system clears the macromolecules. However, solid tumours are generally characterized by impaired lymphatics [6]. Proliferating tumour cells compress lymphatic vessels and collapse most of the vessels, especially at the centre of tumours. The impaired lymphatic system coupled with increased permeability of tumour vasculature results in the EPR effect. Nanoparticles, like other macromolecules, have extended retention times in tumour, which results in higher concentrations than in plasma or in other tissues. Thus, nanoparticles can achieve passive targeting to tumours through the EPR effect.

Nanoparticle clearance by the mononuclear phagocyte system

To fully take advantage of the EPR effect, nanoparticles must remain in circulation long enough for tumour accumulation. However, nanoparticles are prone to clearance by the mononuclear phagocyte system, previously called the reticuloendothelial system. The MPS is part of the immune system that is mainly responsible for clearing macromolecules from circulation. Immunotoxin therapy of cancer [24]. The MPS comprises bone marrow progenitors, blood monocytes and tissue macrophages. It also includes the Kupffer cells of the liver and macrophages of the spleen, which are responsible for clearance of macromolecules from circulation. Nanoparticles can interact with MPS cells and lead to their opsonization. Since premature elimination from circulation will prevent nanoparticles from accumulating in tumours, much effort has been devoted to creating “stealth” nanoparticles. The most common strategy has been grafting PEG or other macromolecules such as polysaccharides onto the nanoparticle surface [25]. The presence of PEG or other molecules enables steric stabilization, preventing protein adsorption, interactions among particles and interactions with immune cells.

Future directions

Although nanomedicine is a relatively new branch of science, its translation into clinical care has been rapid. The unique properties of nanoparticle drug carriers make them well suited for oncology applications. Nanoparticle chemotherapeutics are composed to influence the treatment of most cancers. However, there are still limited clinical data and a limited number of nanotherapeutics approved for clinical use. To fully understand the advantages and disadvantages of nanoparticle therapeutics, more clinical data are needed it can also help in identifying the best applications for nanochemotherapeutics. Thus, it is crucial to develop and carry out well-designed clinical trials to further the development of these drugs. Clinical investigators should fully understand the particular nanoparticles they are investigating and design trials that take advantage of nanoparticle properties. More complex targeted systems, which can release nanochemotherapeutics at a target site when exposed to external stimuli such as light and temperature, are also under development. Another potential is to develop more nanoparticles capable of delivering combination chemotherapeutics. CPX-351, a liposomal formulation of cytarabine and daunorubicin, showed promising results in its first human study [18]. Together with the progression of nanoscale drug delivery systems, advances in nanoscale imaging suggest the potential for the development of multifunctional “smart” nanoparticles that may facilitate the realization of individualized cancer therapy. Almost all types of nanoparticles including polymeric nanoparticles [61], nanocrystals [62], polymeric micelles [17], dendrimers [63] and carbon nanotubes [64] have been evaluated for their suitability as multifunctional nanoparticles that can be applied for simultaneous in vivo imaging and treatment of cancers. Eventually, multiplex nanoparticles may be capable of detecting malignant cells (active targeting moiety), visualizing their location in the body (real-time in vivo imaging), killing the cancer cells with minimal side effects by sparing normal cells (active targeting and controlled drug release or photothermal ablation) and monitoring treatment effects in real time.

Related Research Data

Anti-Estrogen-Loaded Superparamagnetic Liposomes for Intracellular Magnetic Targeting and Treatment of Breast Cancer Tumors
Source: Wiley-Blackwell

Barriers to Drug Delivery in Solid Tumors
Source: Springer Nature

Bevacizumab in Combination With Fluorouracil and Leucovorin: An Active Regimen for First-Line Metastatic Colorectal Cancer
Source: American Society of Clinical Oncology (ASCO)

Biofunctionalized targeted nanoparticles for therapeutic applications
Source: Informa Healthcare

CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma
Source: New England Journal of Medicine (NEJM/MMS)

Cancer nanotechnology: opportunities and challenges
Source: Springer Nature

Current Status of Liposomal Anthracycline Therapy in Metastatic Breast Cancer
Source: Elsevier BV

Dendrimer-platinate
Source: Ovid Technologies (Wolters Kluwer Health)

Development of the polymer micelle carrier system for doxorubicin
Source: Elsevier BV

Effective Photothermal Chemotherapy Using Doxorubicin-Loaded Gold Nanospheres That Target EphB4 Receptors in Tumors
Source: American Association for Cancer Research (AACR)

Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia
Source: New England Journal of Medicine (NEJM/MMS)

Engineering Nanocomposite Materials for Cancer Therapy
Source: Wiley

Fluoxetine and reversal of multidrug resistance
Source: Elsevier BV

General Route to Multifunctional Uniform Yolk/Mesoporous Silica Shell Nanocapsules: A Platform for Simultaneous Cancer-Targeted Imaging and Magnetically Guided Drug Delivery
Source: Wiley-Blackwell

Immunotoxin Therapy of Cancer
Source: Springer Science and Business Media LLC

Liposomal encapsulated anti-cancer drugs
Source: Ovid Technologies (Wolters Kluwer Health)

Liposomes: the Babraham connection
Source: Elsevier BV

Multidrug resistance in cancer: role of ATP–dependent transporters
Source: Springer Nature

Multifunctional Polymeric Micelles as Cancer-Targeted, MRI-Ultrasensitive Drug Delivery Systems
Source: American Chemical Society (ACS)

Nanocarriers: Promising Vehicle for Bioactive Drugs
Source: Pharmaceutical Society of Japan

Nanomedicines for overcoming biological barriers
Source: Elsevier BV

Nanotechnology: Intelligent Design to Treat Complex Disease
Source: Springer Nature

Pegylated liposomal doxorubicin in the treatment of cancers of the breast and ovary
Source: Informa Healthcare

Pegylation
Source: Springer Nature

Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies
Source: American Association for Cancer Research (AACR)

Phase I and Pharmacokinetics Trial of ABI-007, a Novel Nanoparticle Formulation of Paclitaxel in Patients With Advanced Nonhematologic Malignancies
Source: American Society of Clinical Oncology (ASCO)

Phase II Study of CT-2103 in Patients With Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma
Source: American Society of Clinical Oncology (ASCO)

Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared With Polyethylated Castor Oil–Based Paclitaxel in Women With Breast Cancer
Source: American Society of Clinical Oncology (ASCO)

Phase IV Study of Liposomal Daunorubicin (DaunoXome) in AIDS-Related Kaposi Sarcoma
Source: Ovid Technologies (Wolters Kluwer Health)

Poly(l-glutamic acid)–anticancer drug conjugates
Source: Elsevier BV

Polymer conjugates as anticancer nanomedicines
Source: Springer Nature

Recent advances with liposomes as pharmaceutical carriers
Source: Springer Nature

Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment
Source: Proceedings of the National Academy of Sciences

Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1
Source: Proceedings of the National Academy of Sciences

Self-protecting core-shell magnetic nanoparticles for targeted, traceable, long half-life delivery of BCNU to gliomas
Source: Elsevier BV

Squalene Based Nanocomposites: A New Platform for the Design of Multifunctional Pharmaceutical Theragnostics
Source: American Chemical Society (ACS)

Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties
Source: Elsevier BV

Structure and Function of Sinusoidal Lining Cells in the Liver
Source: SAGE Publications

Targeted Therapies for Cancer 2004
Source: Oxford University Press (OUP)

The Binding Avidity of a Nanoparticle-Based Multivalent Targeted Drug Delivery Platform
Source: Elsevier BV

The dawning era of polymer therapeutics
Source: Springer Nature

The effectiveness of a magnetic nanoparticle-based delivery system for BCNU in the treatment of gliomas
Source: Elsevier BV

The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting
Source: Elsevier BV

Therapeutic Nanoparticles for Drug Delivery in Cancer
Source: American Association for Cancer Research (AACR)

Virus-based nanoparticles (VNPs): Platform technologies for diagnostic imaging☆
Source: Elsevier BV


Linking provided by 

Disclosure statement

The authors have declared no conflict of interest. The authors alone are responsible for the content and writing of the paper.

References

 

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.