1. Introduction

Cancer is the major life threatening therapeutic consequence in the modern world as evidenced by estimates of World Health Organization in 2011 [1,2]. Mortality rate in global population due to cancer has crossed the number of deaths caused by morbid cardiovascular complications [1]. Adaptation of modern sedentary unhealthy life style, toxicants exposure untreated or ignored infections and use of immune-suppressant drugs etc. are assumed to be few of the underlying causes of this dangerous disease [3]. Surgery and/or radiation followed by compulsory use of chemotherapeutic agents are the basic/core treatments for healing cancer [4,5]. However, severe toxicities of the chemotherapeutic agents have brought challenge to the formulation scientists to deliver desired chemotherapeutics to the site of action in a therapeutic concentration with reduced toxicities towards healthy tissues.

PTX is a semisynthetic plant alkaloid, which is isolated from the bark of North American pacific yew tree, Taxus bravifolia and has been approved as chemotherapeutic agent by Food and Drug Administration. It blocks the mitotic pathway of cell division through stabilization of microtubule and triggers apoptosis/cell death [6,7]. It is an important chemotherapeutic agent in breast, ovarian, head and neck carcinoma, non-small cell lung carcinomas, and AIDS-related Kaposi's sarcoma etc. Despite of its clinical popularity in the treatment of life threatening cancer clutches, application of this chemotherapeutic agent is grossly restricted by poor water solubility (~0.4 μg/mL), development of resistance by the cancerous cells and quick elimination. Thus the commercial formulation is a concentrated solution of PTX in an organic mixture of dehydrated alcohol and polyoxyethylated castor oil (Cremophor-EL) at a ratio of 1:1 (v/v) [[7], [8], [9]]. However, severe toxicities of the marketed formulation of PTX, Taxol® is attributed by the presence of Cremophor-EL, viz. hypersensitivity, neurotoxicity and nephrotoxicity reactions [7,8]. Furthermore, Cremophor-EL disrupts the pharmacokinetic profile of the drug in vivo, leading to establishing unpredictable nonlinear pharmacokinetics [7]. Alternatively development of multi-drug-resistance (MDR) confines towards effective chemotherapy, where it can be developed by activation of detoxifying systems, decreasing drug uptake by means of increasing drug efflux, evasion of drug-induced apoptosis, DNA repair mechanisms etc. [[10], [11], [12]]. Therefore, stimulation of specific ATP-dependent transporter P-glycoprotein [P-gp] efflux or up-regulating the efflux protein expression [10]. Various approaches have been made to overcome the cellular efflux, potential by incorporating various P-gp inhibitors (e.g., PSC 833, verapamil, etc.) along the PTX formulation, although unsatisfactory outcomes with altered pharmacokinetics/bio-distribution and potential toxicity limits its progress [13,14]. Finally, metabolism by cytochrome P450 enzymes eliminates the drug rapidly from the circulation [15]. Thus, parenteral formulations requires increased dose of the formulation to maintain the therapeutic drug level for a significant period of time which ultimately results in severe toxicities [16]. Beside these noticeable issues with PTX, the marketed formulation is associated with pronounced toxicities including life threatening responses in 1.5–3.0% of the patients [17,18].

Nanoparticulate colloidal delivery systems constitute a developing approach with improved drug delivery options along with tumor targeting which resolves most of the limitations in conventional chemotherapy. Incorporation of biodegradable and biocompatible polymers, such methoxy-poly(ethylene-glycol)-poly(ε-caprolactone) (mPEG-PCL), poly(lactic-co-glycolic acid) (PLGA), poly(lactide) (PLA), etc., in consort with options to fabricate surface functionalization provides distinctive prospects to target and interact with the tumor microenvironment [[19], [20], [21]]. Such interactions of the nanoparticulate carriers with the cancer cell lead transportation of the chemotherapeutic agents to interact with intracellular organelles to produce favourable cytotoxic effect without producing non-specific toxicity to the normal cells, however they have some limitation like acid degradation, autocatalytic effect, slow degradation rate and rapid clearance via liver [22].

Vitamin E TPGS-the water-soluble derivative of vitamin E is a well-known surfactant in nanocarrier science. It contains a hydrophilic polar head and the lipophilic alkyl tail, which has shown to have beneficial effect in solubilisation of PTX, inhibition of P-gp mediated MDR and enhancement of permeation in the cancer cell. Being amphiphilic in nature and existence of several advantages of TPGS, viz.: PEG molecule of TPGS act as polar head whereas tocopherol succinate group work as lipophilic tail, large surface area, bulky shape, miscibility with water and solubility in oil establish TPGS as an important surface active agent to the formulation scientists for different oil in water immiscible systems. TPGS is pharmaceutically advantageous to improve oral bioavailability of P-gp substrates by hindering P-gp efflux on intestinal brass borders alongside assist in permeability of the drug. Additionally, TPGS has proved its important role in chemotherapy through inducing arrest of cell cycle and promoting apoptosis [5,23]. The aforesaid limitations of hydrophobic polymers could perfectly be overcome through the incorporation of TPGS into the hydrophobic polymer backbone. Various roles of TPGS in the advancement of chemotherapy have been discussed in our previous article [5]. Thus, it can be inferred incorporation of TPGS and specific ligand in nanocarriers facilitates active and passive transport of chemotherapeutics into the cancer microenvironment to achieve effective therapy (Fig. 1). Although, process and formulation variable have significant effect on physiochemical properties of NP which governs the drug loading, drug release, cellular uptake and targeted delivery of NPs. For instance, selection criteria for surfactant plays critical role in order to obtain stable particles in nano-range. Sharma and team evaluated the effect of homogenization speed, aqueous and organic phase ratio, surfactant concentration, polymer type and concentration, on physicochemical properties of PTX-loaded biodegradable polymeric NPs, where high homogenization speed (15,000 rpm) resulted smaller particle size (438 nm) in comparison to NPs (899 nm) prepared at lower homogenization speed (10,000 rpm). This difference in the particle size due to reduction in emulsion globules allows the formation of smaller NPs. Similarly, encapsulation efficiency has been increased from 65.3% to 77.5% as the speed increased, however this increment was not in linear pattern. Furthermore, larger particles exhibited slower rate of release of the drug, due to decreased surface area as well as longer pathways for diffusion of drug to travel to reach dissolution medium. Additionally, ratio of aqueous and organic phase directly affects in the viscosity of the emulsion, thus effect on particle size and also on cumulative drug release. The cumulative drug release also decreased with increase in surfactant concentration due to larger particle size. Inclusion of other surfactant including TPGS had achieved decreased particles size and fast release of drug. The results of this investigation elucidates that the formulation and process variables could be effectively altered to achieve the desired characteristics [24]. In the report by Mu and Feng combined TPGS and biodegradable polymers as matrix material for fabrication of NPs with excellent encapsulation efficiency of almost 100% in conjunction with controlled release profile [25]. It is important to mention that the cracks and/or caves existed on the particle surfaces with rough and smooth surface reinforced the hypothesis that both diffusion and matrix erosion mechanism may involve in release of drug from the developed formulation. Thus the authors commented that combination of TPGS and hydrophobic polymer can develop a controlled release nanocarrier of lipophilic chemotherapeutics including gene delivery [25]. In another approach of using TPGS decorated reduced bovine serum albumin NP of PTX, where it showed a sustained release of the drug at specified pH to exhibit enhanced cytotoxicity via inducing apoptosis in even MDR cells, which may be attributed by significant inhibition of reduced ATPlevel and P-gp activity due to the presence of TPGS [26]. In this current manuscript, we focussed on TPGS based nanoparticulate approaches to overcome the limitations associated with PTX chemotherapy. With the emerging field of nanotechnology, research outcomes of this chemotherapeutic agent have been improved by various means, which has been briefed in the connecting section.

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Fig. 1. Schematic representation of potential bio-function of TPGS-based delivery nanosystem for the treatment of cancer [23].

2. Nanotechnology based strategies in PTX delivery: pharmaceutical attributes and clinical outcomes

Recent advancement of nanotechnology has gained attention towards diagnosis, prevention, and treatment of cancer patients where nanocarrier tool deals with the challenges in the delivery of chemicals to the diseased site [[27], [28], [29], [30], [31], [32]]. Hence, a unique structure of modern nanocarrier is considered to be the leading platform for PTX delivery by overcoming aforementioned limitations:

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  Solubility could be increased greatly when entrapped into the lipid based nanocarrier, or else conjugated with water soluble polymers

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  EPR effect due to their nanometric size range (10–200 nm) where these carriers can escape recognition by the endogenous RES

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  Improved efficacy due to delivery of drugs to the target site

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  Modification of the pharmacokinetic profile of the entrapped drug

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  Increased tumor uptake through attachment of specific functionalized ligand for active targeting to the specific cancerous cells, simultaneously, decreases systemic cytotoxicities and increases maximum tolerated dose (MTD) (Fig. 2) [[33], [34], [35]].

  

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  Fig. 2. TPGS-based nanoparticle-mediated active and passive targeting in the management of cancer [35].

Therefore, nanocarriers are being investigated around the world with diverse composition and biological properties to deliver therapeutic components to the target site, however several underline factors are to be considered while formulating and delivering nanocarriers, including release pattern of drug(s), stability of entrapped drug, biological interactions and targeting behaviour and molecular mechanisms of cell signalling with safer delivery [5,29,36]. In due course, different characterisation methods are incorporated to analyse the optimization of the developed formulation and reproducibility of the nanocarrier; such characterisation process incorporate utilization of analytical instruments such as Fourier transform infrared (FTIR), high performance liquid chromatography (HPLC), scanning electron microscopy (SEM), dynamic light scattering (DLS), atomic-force microscopy (AFM), transmission electron microscopy (TEM) and nuclear magnetic resonance (NMR) [32,37]. In the subsequent section of the article we have summarised diverse TPGS based nanoparticulate strategies adopted to improve the efficacy and safety of the deliverable PTX formulation.

3. PTX containing TPGS nanoparticles for treatment of various cancers

As discussed earlier, being a good chemotherapeutic agent, PTX incurs low therapeutic index and limited aqueous solubility which limits clinical application of PTX. Moreover, Taxol® and Abraxane®, the available commercial product of PTX also exhibit severe side effects such as neuro- and nephrotoxicity, hypersensitivity reaction, lower blood cell count etc. [18,38,39]. To setback such constrain, many research has been done to enhance the drug accumulation at tumor site by using nanocarriers. In construction of nanocarrier, TPGS functionalized polymeric nanoparticles is well accepted in which TPGS acts as stabilizer, solubilizer, penetration enhancer and emulsifier [5]. The most fascinate use of TPGS in cancer therapy is P-gp inhibition by reducing P-gp ATPase activity which leads in reduction of efflux of drug from cell. TPGS won't influence the P-gp expression on cancer cell surface, however it exert its effect by inhibiting the bio-function of receptor. P-gp inhibiting ability of TPGS improves drug accumulation and treatment efficacy in various types of cancer [5,23]. Accumulation of drug to the cancer environment also enhances by interaction of vitamin-E moiety of TPGS with additional surface receptor which induces receptor-mediated endocytosis and improves the absorption [40].