A Review on Delivery of Anti- Cancer Drugs by Smart Nanocarriers:

Data Obtained from Past One Decade

 

Sirisha. S

Dept. of Pharmaceutics, Sree Venkateswara University of Pharmaceutical Sciences, Tirupati-517 102,

Chittoor (Dist.), A.P., India.

 

ABSTRACT:

Problems associated with the administration of anticancer drugs, such as limited solubility, poor biodistribution, lack of selectivity, and healthy tissue damage, can be overcome by the implementation of Smart Drug Delivery Systems (SDDSs). Nonspecific distribution and uncontrollable release of drugs in conventional drug delivery systems (CDDSs) have led to the development of smart nanocarrier-based drug delivery systems, which are also known as Smart Drug Delivery Systems (SDDSs). SDDSs can deliver drugs to the target sites with reduced dosage frequency and in a spatially controlled manner to mitigate the side effects experienced in CDDSs. Chemotherapy is widely used to treat cancer, which is the secondly leading cause of death worldwide. Site-specific drug delivery led to a keen interest in the SDDSs as an alternative to chemotherapy. A smart drug delivery system consists of smart nanocarriers, targeting mechanisms, and stimulus techniques. This review highlights the recent development of SDDSs for a number of smart nanocarriers, including liposomes, micelles, den-drimers, meso-porous silica nanoparticles, gold nanoparticles, super paramagnetic iron-oxide nanoparti-cles, carbon nanotubes, and quantum dots. The nanocarriers are described in terms of their structures, classification, synthesis and degree of smartness.

 

 

 

INTRODUCTION:

Cancer is the second leading cause of death worldwide [1,2]. Chemotherapy [3,4] plays a vital role in treating undetectable cancer micro-focuses and free cancer cells. Chemotherapy uses chemicals to kill or block the growth of cancer cells [5]. As cancer cells grow faster than healthy ones, fast-growing cells are the main tar-gets of chemotherapeutics; however, because there are healthy cells which are also fast-growing, the drugs used in chemotherapy also attack those fast-growing healthy cells.

 

This unwanted attack results in the failure of conventional chemotherapy [6]. In addition, multi drug resistance (MDR) [7–9] is another major obstacle to successful chemotherapy. The limitations of conventional chemotherapy have led to the development of smart nanocarrier-based drug delivery systems, which are also known as Smart Drug Delivery System (SDDSs). SDDSs promise to apply drugs to specific and targeted sites [10] Nanocarriers are the base of SDDSs. Unfortunately, not all types of nanocarriers are reliable as drugs carriers in SDDSs. To qualify as an ideal nanocarrier in SDDSs, a nanocarrier should meet some basic criteria, discussed in detail in the subsequent sections. This review emphasizes the (4) most reported nanocarriers: (i)liposomes, (ii) micelles, (iii) dendrimers, (v) carbon nano tubes (CNTs), in the context of their structures, classification, synthesis and degree of smartness.

Smart drug delivery system:

A smart drug delivery system, as illustrated in Fig. 1, using liposomes as nanocarriers, consists of (i) smart nanocarriers which carry anti-cancer drugs to the cancer site, (ii) targeting mechanisms to locate the cancerous site and (iii) stimulus techniques to release the payloads at the pre-located cancer cell site. Most commonly used four nanocarriers as well as their targeting mechanisms and stimulus techniques are discussed in detail in the subsequent sections.

 

Nanocarriers:

Particles with at least one dimension on the order of 1–100 nm are popularly known as nanoparticles. Currently, nanoparticles are defined in terms of volume specific surface area (VSSA). Typically, particles with VSSA equal to or greater than 60 m2/cm3 volume of the material are defined as nanoparticles [11]. When Nanoparticles are used as transport modules for other substances, they are called nanocarriers. Conventional nanocarriers don’t have the ability to carry and release drugs at the right concentration at the targeted site under external or internal stimulation. They need to be modified or functionalized to make them smart. Smart nanocarriers should possess the following characteristics. First, smart nanocarriers should avoid the cleansing process of the body’s immune system. Second, they should be accumulated at the targeted site only. Third, smart nanocarrier should release the cargo at the targeted site at the right concentration under external or internal stimulation. In addition, finally, they should co-deliver chemotherapeutics and other substances, such as genetic materials, imaging agents, etc. [12–14].

 

Depending on the types and applications of nanocarriers, there are some steps to transform conventional nanocarriers into smart ones. First, nanocarriers face many biological barriers, including cleansing by the reticuloendothelial system (RES) on the way to the targeted site. The RES takes the nanocarrier out of circulation shortly and accumulates those anti-cancer drug-carrying nanocarriers in the liver, spleen or bone marrow. PEGylation is a unique solution to avoid this cleansing process. PEGylation helps nanocarriers escape the RES. Davies and Abuchowsky reported the PEGylationfor the first time [15]. Unfortunately, PEGylation reduces the drug uptake significantly by the cells [16, 17]. This twist is known as the PEGylation dilemma [18, 19] Second, nanocarriers can be functionalized to identify the cancer cells precisely out of healthy ones. The physiochemical differences between cancer cells and healthy ones are the identification marker to separate the two types of cells. The surface of cancer cells overexpresses some proteins. The overexpressed proteins are the key targets of the smart nanocarrier. Nanocarriers are modified with ligands matching the overexpressed proteins. The ligands of smart nanocarriers identify the cells with the receptor proteins. Third, conveying the drug to the target site is not the termination of the process. Releasing the drug from the smart carrier under stimulation is the next big challenge. To make nanocarriers responsive to the stimulus system, various chemical groups can be grafted on the surface of the nanocarriers. Fourth, modifications are also done for the codelivery of anti-cancer drugs together with other substances, including genetic materials [20], imaging agents or even additional anti-cancer drugs. Liposomes, micelles, dendrimers, show promise for co-delivery [21–25]. Four promising nanocarriers are discussed in detail below in terms of their structure, classification, synthesis and smartness.

 

Liposome’s:

Liposome [26], are naturally occurring phospholipid-based amphipathic nanocarriers. Phospholipids, consist of a fatty acid based hydrophobic tail and a phosphate-based hydrophilic head. In 1973, Gregory Greg ordians showed that when phospholipids are introduced in an aqueous medium, they self-assemble into a bi-layer vesicle with the polar ends facing the water and non-polar ends forming a bilayer. The core formed by the bilayer can entrap water or water-soluble drugs [27]. On the basis of the and the size of the liposome, number of bilayers there are two types: multi-lamellar vesicles and uni-lamellar vesicles.

 

Fig. 1. Step-wise illustration of liposome-based smart drug delivery for the treatment of cancer

 

Fig. 2. Schematic diagram of cross-linked micelle formation in aqueous solution.

 

 

Uni-lamellar vesicles can be further divided into two groups, namely, large uni-lamellar vesicles (LUV) and small uni-lamellar vesicles (SUV) [28,29]. There are several methods to prepare liposomes [30,31], namely, the thin film hydration method or Bangham method [32], solvent injection technique [33], and detergent dialysis [34], reverse phase evaporation [35], Conventional methods have many setbacks. To remove those limitations, some novel technologies have been devised, such as supercritical fluid technology, supercritical reverse phase evaporation [36] and the supercritical anti-solvent method [37]. Conventional liposomes have many problems including instability, insufficient drug loading, faster drug release and shorter circulation times in the blood; therefore, they are not smart. Functionalization of conventional liposomes, [38], makes them smart. They are responsive to various external and internal stimulation, including pH change, enzyme transformation, redox reaction, light, ultrasound and microwaves [39-41]. A liposome functionalized with a radio-ligand is known as a radiolabeled liposome. Radiolabeled liposomes [42] can be used to determine the bio-distribution of liposomes in the body and to diagnose the tumor along with carrying out therapy. Liposomes that can carry both therapeutics and imaging agents [43] are known as theranostic liposomes [44,45]. In addition to delivering imaging agents together with chemotherapeutics, liposomes are promising in the co-delivery of two chemotherapeutic drugs, gene agents [46] with chemotherapeutics as well as chemotherapeutics with anticancer metals [47].

 

Micelles:

Amphiphilic molecules, having both hydrophilic and hydrophobic portions, show unique characteristics of self-assembly when exposed to a solvent. If the solvent is hydrophilic and its concentration exceeds the critical micelle concentration (CMC), the polar parts of the co-polymer are attracted toward the solvent, while hydrophobic parts orient away from the solvent. In this way, the hydrophobic portions form a core, while hydrophilic portions form acenter. This type of arrangement is called a direct or regular polymeric micelle [48,49], depicted in Fig. 2. On the other hand, amphiphilic molecules exposed to a hydrophobic solvent produce a reverse structure known as a reverse micelle. That is, the hydrophilic portions make the core and the hydrophobic portions make the corona in a reverse micelle [50-52]. PG-PCL, PEEP-PCL [53],

 

PEG-PCL [54] and PEG-DSPE are examples of some micelles [55]. The preparation of micelles depends on the solubility of the copolymer used [56]. For a relatively water-soluble co-polymer, two methods are used, namely, the direct dissolution method and the film casting method. In contrast, dialysis or an oil in water procedure is used if the co-polymer is not readily water-soluble [57.58].

 

There are two types of cross-linking schemes: core cross-linked polymer micelles and the shell cross-linked polymer micelles. To actively target cancer cells, different types of ligands are used to decorate the micelle surface, namely, folic acid, peptides, carbohydrates, antibodies, aptamers, etc. [55]. To release the anti-cancer drug atthe right concentration, the core or the corona of the micelle can be functionalized. The stimuli used in micelle based SDDSs are pH gradients, temperature changes, ultrasound [59], enzymes, and oxidation [55]. Using a multifunctional micelle, the co-delivery strategy is very important for the synergetic effects in cancer treatment. Seo et al. reported a temperature-responsivemicelle-based co-delivery system which can carry genes along with anti-cancer drugs [60]. In cancer diagnosis and monitoring, single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and ultrasonography play vital roles. The surface of micelle can be decorated with the imaging agent [61]. Combined delivery of doxorubicin and the imaging oftumors via ultrasound has been reported by Kennedy and coworkers [62].

 

Dendrimers:

Polymers with many branches are known as dendrimers, which can be graphically presented as a suction ball. As shown in Fig. 3, a dendrimer has three distinguishable parts: a core, branching dendrons and surface-active groups [63]. The active groups on the dendrimer surface determine the physiochemical properties of the dendrimer. Based on the surface groups, it may be either hydrophobic or hydrophilic. Due to its nanoscale size, monodisperse nature [64], water solubility, bio-compatibility, and highly branched structure, it is of high interest. Because of the nanoscale size, it can be used as a drug carrier [65]. The branched structure makes the dendrimer versatile. Moreover, all of its active groups on the surface face outward, which results in a higher drug encapsulation rate. Various types of dendrimer, such as poly (propylene-imine) (PPI or POPAM), PAMAM, POPAM, POMAM [66], polylysine dendrimer, dendritic hydrocarbon, carbon/oxygen-based dendrimer, porphyrin-based dendrimer, ionic dendrimer, silicon-based dendrimer, phosphorus-based [67] dendrimer, and Newkome dendrimer [68] have been reported. The commonly reported methods to produce dendrimers include thedivergent method [69] and the convergent method [70]. To actively target the cancer site, the surface of dendritic structures can be modified by peptides, proteins, carbohydrates, aptamers, antibodies, etc. The dendrimer surface can also be modified for various stimuli responsive systems, such as light, heat, pH change, protein, and enzyme transformation [71, 72].

 

Fig.3. General structure of dendrimer

 

Smartness of CNTs:

CNTs are a type of fullerene, a class of carbon allotropes in the shape of hollow spheres, ellipsoid, tubes and many other forms [73,74]. When a graphene sheet is rolled up into a seamless cylindrical tube, the shape is known as a CNT. There are two types of CNTs: single walled (SWCNT) and multi-walled (MWCNT) [75,76]. The strong optical absorption in the nearinfrared region by the CNT makes this particle a strong candidate for photo thermal ablation; furthermore, nanoparticles with sizes ranging from 50 to 100 nm are easy to be engulfed. MWCNTs can pass through the barrier of various cellular compartments, and PEGylated SWCNTs are able to localize in a specific cellular compartment. CNTs can be synthesized via heating carbon black and graphite in a controlled flame environment.

 

Due to the better defined walls of SWCNTs and relatively more structural defects of MWCNTs, SWCNTs are more efficient than MWCNTs in drug delivery [5] CNTs should be functionalized [77] either chemically or physically, to make them smart. PEGylation is a very important step to increase solubility, avoid the RES and to lower the toxicity [78]. Poly (N-isopropyl acrylamide) (PNIPAM) is a temperature-sensitive polymer. Due to their low critical stimulus temperature (LCST), PNIPAM could be used to modify CNTs for temperature stimulus. The disulfide cross-linker, based on methacrylate cysteine, is used for enzyme responsive drug release. For pH responsiveness, an ionizable polymer with a pKa value between 3 and 10 is an ideal candidate. Weak acids and bases show a change in the ionization state upon pH variation [179]. Recent studies exhibit that functionalized CNTs can overcome the BBB [80,81]. CNTs have shown promise in carrying plasmid DNA, small-interfering ribonucleic acid (siRNA), antisense oligonucleotides, and aptamers [82]. In addition to gene delivery, it can also be used for the thermal ablation of a cancer site [83]. Functionalized CNTs can be used as diagnostic tools for the early detection of cancer [84].

 

CONCLUSIONS:

Nanocarriers, a wonder of modern science, play vital roles in anti-cancer drug delivery. To conquer the limitations associated with conventional chemotherapy, smart nanocarrier-based drug delivery systems, also known as SDDSs. have been introduced. However, thereare still many challenges ahead for SDDSs to be effectively applied as a promising alternative to chemotherapy for cancer treatment; therefore, the technology behind SDDSs is under continuous research. The toxicity of the nanocarriers is a major barrier in the way of a successful SDDS. Studies have been conducted to either optimize the toxicity of existing nanocarriers or to develop some other new nanocarriers with lower toxicity. This review considers the assessment of the four most common nanocarriers used in SDDSs. The associated challenges and future research scope in SDDSs, which may favor the enduring perspectives and development of nanocarrier-based SDDSs for cancer treatment, have also been discussed.

 

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Received on 12.05.2020          Modified on 24.05.2020

Accepted on 01.06.2020     ©AandV Publications All right reserved