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Nanocarriers in Tumor Targeting Delivery System

Cancer has been becoming among the leading causes of mortality globally. The major challenges of conventional cancer therapy was the failure of most chemotherapeutic agents to accumulate selectively in the tumor cells and severe systemic side effects. In past three decades, a number of drug delivery approaches have been discovered to overwhelmed the obstacles. Among these, nanocarriers have gained a lot of attention for their excellent and efficient drug delivery systems to improve specific tissue/organ/cell targeting. To further enhance the targeting effect, and reduce the some limitation associated with NPs, the surface of NPs were modified with different ligands., Nowadays, several kinds of ligand-modified nanomedicines have been reported. Recently, Cell-penetrating peptides (CPP) are emerging drug delivery system and attracting the attention of researchers due to their ability to transport bioactive molecules intracellularly. Currently, nanocarriers functionalized with cell penetrating and tumor targeting peptides have shown dramatically enhanced cellular uptake and specific cytotoxicity to cancer cells.
Therefore, in this review we focus on recent advances of tumor targeting strategies, cell penetrating peptides and its limitation as delivery systems, different classes of CPP; tumor targeting peptides. Furthermore, we discuss the application of CPP and/ or TTP in delivery of plant derived chemotherapeutic agents.
Cancer, Nanocarriers, cell penetrating peptide, targeting drug delivery, herb-based drug.

  1. Introduction

Despite huge effort in development of anticancer drugs, cancer nevertheless remain
one of the main reasons of morbidity and mortality worldwide. In 2015, cancer was accountable for 8.8 million deaths. Globally, from 6 deaths one is due to cancer. Within the coming two decades, it is estimated to be increased by about 70%. In addition, the significant and increasing economic impact of cancer has been observed. In 2010, the overall annual economic cost of cancer was estimated approximately 1.16 trillion US$  [1].
Chemotherapy, radiation, and surgery with chemotherapy are the major treatment
protocol of cancer.  Utilization of chemotherapy has demonstrated to enhance survival rate of malignancy patient to some degree. In spite of the fact that surgery and radiotherapy are the most effective treatments for local tumor and non-metastatic cancers, they are beneficial for cancer that has not been disiminated throughout the body. Therefore, chemotherapy is the treatment decision for the metastatic malignancies, since they are well distributed to every organ in the body[2]. However, most of conventional chemotherapeutic agents currently in clinical use are limited by their several undesirable properties, including poor solubility and bioavailability, rapid elimination from systemic circulation, narrow therapeutic index, and non-selective site of action after intravenous / oral administration and cytotoxicity to normal tissues, which might be the main reason for treatment  failure in cancertherapy[3].
Furthermore, the conventional chemotherapeutic agents often unable to penetrate and reach the internal part of solid tumors, leading to inefficient  cytotoxicity to the cancerous cell. The other problem of traditional chemotherapy is associated with Pglycoprotein, a multidrug resistance protein(MRP) that is overexpressed in  cancer cells, which is acting as the efflux pump and inhibit drug accumulation inside the tumor, and often mediates the development of resistance against anticancer drugsThus the administered drugs remain unsuccessful to produce the desired response[34]. Various drug delivery approaches constituting antibodies, growth factors, hormones, etc. have been designed and administered timely, however a sifnificant internalization the cancerous cells could not be achieved due to the presence reticuloendothelial system (RES) and intracellular enzymes[5]. Consequently, in late decades tremendous endeavors have been given to overcome the major drawbacks of the conventional cancer chemotherapy.
Various novel drug delivery stratiegies have been designed to date, including polymeric nanoparticles[6], polymeric micelles [7], dendrimers[8], liposomes[9], viral nanparticles[10], carbon-based systems(carbon nanotubes and grapheme oxide), magnetic nanoparticls, silica and gold nanoparticles[11] and lipid nanoparticles (solid lipid nanoparticles, and nanstructured lipid carriers). Nanoparicles possess several advantages including, the larger surface area in contrast to bigger particles, that can be easily modified to accommodate large quantity of drug, increase the circulation time of the drug in blood and improve the accumulation of drugs in solid tumors through the enhanced permeability and retention (EPR) effect and passive targeting of tumor cells. Nanocarriers have been also known to improve the solubility, bioavailability and pharmacokinetics profile of chemotherapeutics agents[9].
To date, decorating a surface of nanocarrier with different ligands targeting specific receptors that are over-expressed on the cancer cell have been developed for active targeting of chemotherapeutic agent to the cell [12]. Most importantly, nanocarriers functionalized with cell penetrating or/and tumor targeting peptides have been a highly promising strategies and attracting the attention of researchers. These peptides are very advantageous as they have been efficiently deliver a broad variety of cargo intracellularly [13]. In addition, CPP are biocompatible and the amino acids sequence can be easily modifiable to fine tune hydrophobicity, affinity, charge, solubility and stability. They can also be readily synthesised in large quantity [14]. CPP-mediated drug delivery are achieved either by the formation of stable, non-covalent complexes or the covalent bond with the cargo [15]. In this review we focuses on recent advances in tumor targeting approach of herbal based anticancer bioactive substances using cell penetrating and/or tumor targeting peptides modified nanocarriers.

  1. Overview of tumor targeting drug delivery approaches

Targeted cancer therapy is viewed as an irreplaceable component of current anticancer drug development [16]. The best strategy to improve the efficacy and reduce the toxicity of a cancer drug is directing the drug to its target and maintaining its concentration for a sufficient time at the site to produce the desired therapeutic effect. Cancer cells can be targeted by the two approaches: such as passive targeting and active targeting.
Passive targeting involvs the extravagation of drug preparation through leaky vasculature/capilary of tumor that results from abnormalangiogenesis at the site of tumor, resulting in accumulation and retention. This phenomenon was recognized as the Enhanced Permeation and Retention (EPR effect) (Fig. 1) [3]. In addition, administration of pH-sensitive drug release in acidic microenvironment inside the cancer cell [517] and particulate carrier phagocytosis by mononuclear phagocytosis systems (MPS) and privileged localization in the organs of reticuloendothelial system (RES) are considered as passive targeting [18].
The size of drug carriers and theabnormal and permeable vasculature of the tumor are the base for passive targeting[19]. Most of tumors manifest an abnormally dense and leaky vasculature formed via stimulation by vascular endothelial growth factor (VEGF). In normal vasculature, particles larger than 2 nm is prevented from crossing between endothelial cells due to tight junction [20]. However, in tumor vasculature, the tight junctions and basement membrane are disordered, allowing passage of particles ranged from 10 to 200 nm through the leaky neovasculature of the tumor and then retain in tumor site. Furthermore, the poor venous and lymphatic clearance system in tumor created an opportunity for the NPs to accumulate in the tumor with high concentration for long time [3]. However, the passive targeting occurs to almost all nanocarriers, deprived of a selective delivery, and insufficient tumor cell uptake.
The other, more advanced approach of targeting for oncology applications is the modification of surface of nanoparticles with a specific tumor-homing ligands [21]. The ligands are known to bind to receptors that can be overexpressed on the surface of cancer cell. The ligands, with selctive affinity toward a specific receptor or molecule differentially expressed at the target site, are presented on the surface of nanocarriers, resulting in the selective accumulation and cellular uptake at the site of action[22]. This strategy  significantly increase accumulation and retention of NPs in the tumor vasculature and specific and sucessful internalization by target tumor cells, which is known as “active tumor targeting”[23]. The ligands that have been used to modify NPs includes monoclonal antibodies, folic acid, hyaluronic acid, albumin, vitamins (folate , vitamin B12, thiamine, and biotin), transferrin,  lectins,  aptamers,  and peptides [5181924].
Depending on the degree of penetration, active targeting may occur at the tissue, cell, or subcellular level. In solid tumors it is vital to remember that, the active targeting processes starts with the accumulation of the drug delivery system in the tumor tissue by passive targeting, therefore, any actively targeted carrier need to fulfill the basic requirements mentioned for passively targeted systems[17].
Effective  targeting drug to tumors is achieved by using a combination of different independent concepts such as events EPR effect, the design and properties of nanoparticles, increased the circulation time by PEGylation, and ligand– receptor type interactions. [25]. The other important aspect in cancer treatment is targeting circulating tumor cells (CTCs). The existence of circulating tumor cells (CTCs) is closely related to tumor metastasis which is accountable for more than 90% of deaths due to cancer[26].  CTCs often express sialylated carbohydrate ligands that bind to selectin protein on their surfaces. Therefore, selective targeting as well as killing of CTCs could be achieved by using E-selectin functionalized nanocarriers[27].

  1. Nanocarriers in tumor targeting delivery system

Recently, carrier-based strategies have been employed to circumvent the majority of the obstacles in delivery of anticancer drug. Among the numerous approaches, nanocarriers particularly in the size range of 10 to 100 nm offer some unique properties [3], and  capable of transporting anticancer agents(drugs with small molecular weight or macromolecules as genes or proteins) to tumor tissue and achieving a cytotoxic concentration several-fold higher in the tumors with a reduced toxicity for the rest part of the body compared with free drugs [2].
The emerging of nanotechnology in cancer therapy is to overcome the limitations that are inherent with conventional drug delivery methods, which are nonspecific biodistribution, inefficient cellular uptake, and low therapeutic [28]. In addition, nanocarriers offer protection of the drug from degradation and, decrease the renal elimination and increase its half- life in the circulation, augment the payload of cytotoxic drugs, allow the controlled release kinetics of the drugs, improve the solubility, and also possess the potential ability to by pass multidrug-resistance mechanisms (MDR)[29], by various approaches [2].
The unique properties of nanoparticles (NPs), such as large surface-to-volume ratio,
small size, the potential to encapsulate wide varieties of drugs, and modifiable surface chemistry,  offer them several advantages including multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, improve internalization by cancer cell, and allow the sustained release of drug payload. These benefits make NPs a potentially superior approach of treatment to traditional cancer therapies [19]. The size and surface charge of NPs are known to affect the half-life and biodistribution of NPs significantly. The larger NPs (>100 nm) are usually cleared from the circulation by phagocytosis. Similarly, the very small nanoparticles of particle size less than 10 nm has high rate of clearance. The positive charge on the surface of particles assists internalization into the cancer cells. Moreover, surface modification of NPs with some polymers such as polyethylene glycol (PEGylation) can also increase the circulation time of particles via inhibition of clearance by reticuloendothelial system and increasing the accumulation of NPs in tumor site but, it can affect cellular uptake by cancer cells [30].
To date, several types of nanocarriers have been emerged for the drug delivery of chemotherapeutic agents  including magnetic and metallic nanoparticles, such as iron oxide or gold nanoparticles, silver NPs [31], nanodiamond[32], carbon based structures(graphene sheets and carbon nanotubes), polymeric nanoparticles, dendrimers, quantum dots, hydrogel-based delivery systems, and silica-based nanoparticles[33], lipid based NPs (liposomes, solid lipid nanoparticles and nanostructured lipid carrier) and Viral NPs and Hybrid NPs (combination of two or more of above) [3435].
Though nanoparticles are commonly considered as a promising concept for  delivery of drugs to specific tissues or cancer tumors,   the delivery efficiency in vivo remains low, and only a few of them are in clinical use including Abraxane®, Doxil®, and MyocetTM that are approved by FDA [3637].The main reason for the clinical failure of NPs could be due to the presence of different barriers which hinder internalization into the cancer cells after they penetrate into the tumor vasculature. Furthermore, in rapidly growing tumors, cancer cells are located adjacent to the endothelial barrier, and nanocarriers with targeting moieties will bind to the first receptors they find, not penetrating into the rest of the tumor There are also the issues associated with the possible toxicity and long-term effects of NPs made from non-biodegradable materials [2].
Chan et al, recently reviewed data from published studies conducted during
2005 – 2015 regarding tumor targeting with nanoparticles (passively or actively targeted), and concluded that, on average, nanoparticles demonstrate low delivery efficiency to solid tumors [38]. It is clear that new novel strategies should be inaugurated [39].In attempt  to overcome the above mentioned limitation of NPs,  a wide varieties of ligands have been used to modify the surface of NPs, permitting a selective recognition of different receptors or antigens overexpressed on the surfaces of tumor cell, improving the cytotoxicity of the anticancer agents in tumors and minimizing their toxic effects[40]. There are several targeting moieties that have been attached to the surface of NPs, and some  examples are mentioned as follows.
Transferrin is a membrane glycoprotein  which transports iron to rapidly growing cells [18]. Transferrin binds to the transferrin receptor (Tfr) and gets internalized by the cells via endocytosis and finally dissociates the iron inside the acidic pH of the endosomes. Tfr  are known to overexpressed in cancer cells up to 100-fold, which makes it as a promising candidate in targeted cancer therapy [41]. Albumin-receptors on the plasma membrane are responsible for albumin uptake by cell  [42]. Albumin-bound nanoparticles have found to accumulate in the  tumors by the EPR effect, and also by binding to glycoprotein 60  receptor that support the endothelial transcytosis[2].
The vitamins used for targeting potential includes folate, vitamin B12, thiamine, and biotin[18]. Their receptor have been known to be upregulated in numerous human cancers[43]. Particularly, folate has been extensively used as a targeting moiety for nano­carriers.
Lectins are a group of sugar-binding  cell surface protein receptors that distinguishes and binds to specifc sugar moieties. Some of these receptors were well-known to be overexpressed in specifc cancer cells, e.g asialoglycoprotein receptor in hepatic cancers [44]. It is suggested that binding of surface carbohydrates with their ligands (lectins) leads to accumulation of glycans into the cells via endocytotic process[30].
The  conjugation of  monoclonal antibodies (mAb) to the surface of nanoparticles (immuno-nanoparticles) can specifically target antigens or receptors overexpressed in  tumors.  EGFR is one of the mAb targets with a higher clinical relevance, which is known to be overexpressed in several type cancers[2]. Aptamer is a single-stranded  RNA or DNA molecules, with three-dimensional structures, having a specific high affinity to nucleolin protein on the surface of cancer cells[45].  Additionally, E3 is known to targets and internalizes into a variety of cancer, including lung, breast, ovarian, melanoma, colon, glioblastoma, leukemia, and liver cancers[46].
Most recently, peptide-based targeting ligands has been attracting the attention of
the researchers and is the main concern of this review. It provides several advantages over other ligands in terms of cellular targeting,  precise chemical structure and chemical stability. Manufacturing of  peptides is inexpensive, and easy to scaleup. Furthermore, peptide ligands show good biocompatibility and  their proteolytic degradation can be inhibited by chemical modifications, such as the cyclization or addition of D-amino acids or [47]. Moreover, peptide ligands are highly selective for target tissues or cells and multiple ligands can be conjugated to a single drug carrier to offer multivalent conjugation, thus increasing binding affinity to the target [48]. The detail of cell penetrating peptide is presented in the following section.

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