Surfactant-based drug delivery systems for treating drug-resistant lung cancer

Abstract

Among all cancers, lung cancer is the major cause of deaths. Lung cancer can be categorized into two classes for prognostic and treatment purposes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Both categories of cancer are resistant to certain drugs. Various mechanisms behind drug resistance are over-expression of superficial membrane proteins [glycoprotein (P-gp)], lung resistance-associated proteins, aberration of the intracellular enzyme system, enhancement of the cell repair system and deregulation of cell apoptosis. Structure–performance relationships and chemical compatibility are consequently major fundamentals in surfactant-based formulations, with the intention that a great deal investigation is committed to this region. With the purpose to understand the potential of P-gp in transportation of anti-tumor drugs to cancer cells with much effectiveness and specificity, several surfactant-based delivery systems have been developed which may include microspheres, nanosized drug carriers (nanoparticles, nanoemulsions, stealth liposomes, nanogels, polymer–drug conjugates), novel powders, hydrogels and mixed micellar systems intended for systemic and/or localized delivery.

• Drug resistance
• glycoprotein
• lung cancer
• nanotechnological carriers
• surfactants

Introduction

Among all cancers, lung cancer is the major cause of deaths. In lung cancer, survival rate is very low comparative to all other cancers. In 2008 survey, lung cancer was considered as the most commonly diagnosed cancer. Cancer-related deaths in males are mainly due to lung cancer and in females, due to breast cancer, which is another cause for cancer-related mortality (Jemal et al., 2011; Nurwidya et al., 2012). In 2012, estimation of mortality rate due to lung cancer is 26% in females and 29% in males (Siegel et al., 2012). Lung cancer is mainly due to tobacco usage in both males and females. The tumor is asymptomatic for a long-time duration due to poor diagnosis of lung cancer (Saintigny & Burger, 2012). Patients are diagnosed at advanced stage where surgery is no longer an option. Two major problems that lead to difficulty in treatment are metastasis and drug resistance. Lung cancer can be categorized into two classes for prognostic and treatment purposes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Both categories of cancer are resistant to certain drugs. NSCLC cells are resistant to some anticancer drugs and SCLC cells are resistant with persistent administration of drug.

Small cell lung cancer is a sort of lung cancer that involves characters like short cell doubling time, hasty, destructive and headway occurrence of blood-borne and lymph metastasis (Chen et al., 2012). It initiates from pulmonary neuroendocrine cells and recent studies suggest that a patient suffers ∼15–20% of other different types of lung cancers (Rodriguez & Lilenbaum, 2010). Among different types of lung cancer, patients suffering from SCLC express highest malignancy. When compared with NSCLC, SCLC is different in its clinical and biological characteristics. Malignancy of SCLC is higher when compared to other lung cancers due to destructive deeds, hasty growth and premature extend to different sites. Primarily, SCLC retort well to chemotherapy and relapse therapy (RT), but after the primary treatment, relapse is a well-known trouble. In general, ∼2% of SCLC patients continued existence after the initiation of disease. Moreover, drug resistance, mainly multi-drug resistance (MDR), has become major cause for decline in SCLC patients (Chen et al., 2012). Researchers concluded that mutually single factors and multiple factor cause multi-drug resistance (MDR) when both factors are in combination and neutralize the positive, preliminary possessions of chemotherapy. Patients having NSCLC treated with chemotherapeutic agents have survival of ∼8–10 months (Ohe et al., 2007). Histologically, both SCLC and NSCLC differ from each other due to dissimilar responses of their treatment therapies. NSCLC can be cured with surgery and radiotherapy, whereas SCLC does not respond to surgery or radiotherapy, whereas median survival rate can be increased from 7 weeks to 1 year by combination therapies, i.e. by combining chemotherapy or chemotherapy and radiotherapy. Consequent relapse is familiar ∼10% with 2-year survival (Vogelsang et al., 1985). Relapse arises during therapy due to huge extent of cells having drug resistance and leads to unsuccessful chemotherapy. Researchers show different mechanisms behind SCLC drug resistance that are as follows:

• Over-expression of superficial membrane proteins

• Lung resistance-associated proteins

• Aberration of the intracellular enzyme system

• Enhancement of the cell repair system

• Dysregulation of cell apoptosis (Chen et al., 2012)

P-glycoprotein (P-gp) is a membrane of ATP-binding cassette (ABC) family which involves in over-expression of superficial membrane proteins; enzymes involving an aberration on intracellular enzyme system are topoisomerase (Top) and gamma-glutamyl transpeptidase (γ-GGT); and over-expression of anti-apoptotic genes involves in dysregulation of cell apoptosis which are Bcl-2 and c-myc. Moreover, alteration of key genes also leads to expansion of drug resistance in the body (Roberti et al., 2006). In SCLC patients, alteration in genes includes stimulation of proto-oncogenes and no or less stimulation of tumor suppressor genes (Fong et al., 1999). Fong et al. (1999) categorized SCLC into two types: classic and variant. Classic type shows large proliferation and susceptibility to chemotherapy and variant type show lesser proliferation, rapid progression rate and responds less to chemotherapy. C-myc expression level is high in variant type, whereas down-regulation of c-myc in classic type.

Among all the cancers, non-small cell lung cancer is the major cause for death (Haura, 2001). NSCLC can be classified by their histological bases which are squamous cell carcinoma, large cell carcinoma and adeno carcinoma (Pore et al., 2013). Classic therapy for NSCLC is platinum-planted double-drug combination therapy (Pfister et al., 2004). But, this therapy is not preferable (Greco et al., 2002; Scagliotti et al., 2002; Schiller et al., 2002; Smit et al., 2003) and endurance issue is poor (Mean endurance rate, 8–10 months; 1-year endurance rate 35–40%) (Ettinger, 2002). Consequently, novel, acceptable therapies can be necessarily required for better endurance in NSCLC. Novel NSCLC therapies gave indicative comfort and discrete growth in survival rate (Group, 1995); little change in response like development of progression time from 3 to 5 months. Development of platinum-based drug regimen by second-line therapy with docetaxel decreases mortality rate due to NSCLC (Fossella et al., 2000; Shepherd et al., 2000). Therefore, at present, there is no distinct need for third-line therapy. An ineffectiveness third line therapy was established (Massarelli et al., 2003), which examines increase in only 2% response and median survival of 4 months. Shepherd et al. (2000) demonstrated to facilitate patients treated with docetaxel following the unsuccessful double or more therapy regimens; endurance was similar to those patients with sympathetic concern. Epidermal growth factor receptor (EGFR) is a fraction of composite signal-induction system that is fundamental to many significant cellular movements. EGFR is frequently seen in NSCLC cells (Rusch et al., 1997; Brabender et al., 2001). Proliferation in NSCLC is not fast when compared with SCLC; thus patients who are detected at former phase are possibly healable, although NSCLC may frequently degenerate on supplementary metastatic point. Moreover, when compared with SCLC, NSCLC is not more reactive to chemotherapy, hence so as to yet by surgical incision at former diagnosis, ∼50% of patients suffers from relapse of NSCLC (Kelsey et al., 2006). Although, after surgery, yet ∼40–75% cannot survive for >5 years having Stage I to Stage IIIA of tumor growth which is stimulated by vascular endothelial growth factor (VEGF) (Folkman et al., 1971; Ferrara, 2002; Bergers & Benjamin, 2003; Ferrara et al., 2003) and rise in VEGF is familiar in case of NSCLC which leads to undesirable clinical results. A humanized monoclonal antibody having activity in decrease in VEGF, Bevacizumab (Ferrara et al., 2004) has better results in therapy of first line non-squamous NSCLC (Hurwitz et al., 2004; Hainsworth et al., 2005; Miller et al., 2005; Sandler et al., 2006; Giantonio et al., 2007).

Multiple drug resistance occurs not with single anticancer drug, but it is due to resistance of variety of anticancer moieties having distinct structures and cellular target. When drugs like doxorubicin, VP-16 and cisplatin used alone cause drug resistance but when used in combination with others anticancer drugs produce an increase in response rate in formerly untreated patients while less efficient in relapsed patients. P-gp is a major part of multidrug resistance in many malignancies which is due to P-glycoprotein drug efflux pump that is produced by the MDR gene but, there is no convincing fact about P-glycoprotein which is broadly concerned in the inherent resistance of NSCLC tumors or the acquired resistance of SCLC tumors. Mostly, anticancer drugs that cause MDR are hydrophobic in nature, amphipathic natural products, such as the taxanes (paclitaxel and docetaxel), vinca alkaloids (vinorelbine, vincristine and vinblastine), anthracyclines (doxorubicin, daunorubicin and epirubicin), epipodophyllotoxins (etoposide and teniposide), antimetabolites (methorexate, fluorouracil, cytosar, 5-azacytosine, 6-mercaptopurine and gemcitabine) topotecan, dactinomycin and mitomycin C.

Treatment strategies

Inhalation therapy is beneficial for pulmonary disease management rather than other routes like parenteral and oral (Figure 1). Formulations used for lung inflammation having extremely hydrophobic API, surfactants and co-solvents frequently exploit to prepare stable formulations utilized for pulmonary route (Mehnert & Mäder, 2001). Incorporation of hydrophobic ingredient in nanoparticulate system will give stable formulation through defending the main compound from deterioration and releases the incorporated drug in controlled mode for continued duration (Yang et al., 2008). Target to lung is interesting because of non-injectable through intake of aerosols, by-pass first pass metabolism, release directly at target site for management of pulmonary disorders, and accessibility of massive superficial site for drug action and penetration of drug. Colloidal carriers (i.e. nanocarrier systems) in pulmonary drug delivery offer many advantages such as the potential to achieve relatively uniform distribution of drug dose among the alveoli, achievement of improved solubility of the drug from its own aqueous solubility, a sustained drug release which consequently reduces dosing frequency, improves patient compliance, decreases incidence of side effects and the potential of drug internalization by cells (Patton & Byron, 2007; Sung et al., 2007). Nanotechnology-based formulations in respiratory disorders are beneficial in many ways which involves:

1. Probably to attain consistent delivery of drug dose along with the alveolus

2. Acquisition of improved solubility of the active ingredient over its own water solubility

3. Continuous-release lowers the dose repetition of drug

4. Appropriate release of macromolecules

5. Decline in occurrence of adverse effects

6. Better patient compatibility and

7. Probable of drug internalization through cells (Bailey & Berkland, 2009)

Figure 1. Benefits of inhalation therapy.

Initial new drug treatment to create a statistically endurance advantage above regular treatment is use of combination therapy of Vinorelbine or Vindesine and Cisplatin (Wozniak et al., 1998). Effectiveness of combination of Vinorelbine and cisplatin was proved for metastatic NSCLC (Hitzman et al., 2006). When cisplatin alone was used for 1 year, endurance was 20%; but, when used in combination, endurance was 36%. Thus, combination of Vinorelbine and cisplatin becomes novel treatment strategy. Along with some pulmonary therapies, nanoparticulate systems have established numerous benefits in conditions of defending the drug from deterioration and continuous release of drug at extended duration of time. For pulmonary delivery, nanoparticles and liposomes are used to carry anticancer moieties but having some disadvantages mainly the major limitations of these systems are alteration during nebulization, biodegradability, drug outflow and drug-related unfavorable conditions (Bonomi et al., 2000; Chougule et al., 2006). Paclitaxel is one more new drug for treatment in NSCLC which reports 20–25% rate in metastatic patients (Hande, 1998). Combination of paclitaxel with cisplatin recorded extended endurance in phase II trials leads to a phase III trial (Bunn & Kelly, 1998). Low-dose paclitaxel with cisplatin was reported as novel classic therapy for management of NSCLC. Etoposide is another anticancer drug which causes breakdown of DNA and then cell damage because of development of ternary compound through topoisomerase II and DNA (Smit et al., 1989) which becomes part of the first line treatment strategy for small cell lung carcinoma (Novello et al., 2007). Intended and modified strategies have been used based on the symptoms of cancer patients; thus, generally, endurance rates are unsuccessful to express the probable general endurance (Subramanian et al., 2011; García Sar et al., 2012). Additionally, resistance to anticancer drugs has been noticed mostly due to apoptotic mechanism in NSCLC cell lines (Hosomi et al., 2011). In SCLC, 5-year endurance noticed <10%, although different drug combinations have been utilized (Shepherd et al., 2007; Hunter et al., 2011). Besides, acquired resistance has been reported in SCLC (Schiller et al., 2002). Thus, new treatment strategies are largely required. For efficacious therapy, active ingredient must be reached in solid tumors and, so far drug concentration at the tumor location has been reached in short concentration behind systemic chemotherapy (De Vore & Johnson David, 2000; Minchinton & Tannock, 2006). In past studies from 1980s, basis for treatment of lung cancer is combination therapy that gives large progress in overall endurance prospects (Eberhardt & Korfee, 2003). Though, when cisplatin was used in cancer management strategy, endurance time period was 7–11 months, and in clinical trials reported shortens progress (Eberhardt & Korfee, 2003). Syndrome restricted toward chest, called limited-disease SCLC (LD-SCLC), can be treated by chemotherapy alone, and it results in endurance time of 10–14 months (Group, 1995; Eberhardt & Korfee, 2003). Though, when optimizing organization manage (exterior the brain) through the combination chemotherapy, management become critical.

Drugs inducing MDR

Curcumin

Curcumin is a phenolic complex extracted from the plant Curcuma longa. Curcumin shows cytotoxic activity in different types of cancer cell line in vitro, accompanied by hematologic malignancies, head and neck, genitourinary, gastrointestinal, breast, ovarian and neurologic cancer, melanoma and sarcoma (Lin, 2007; Anand et al., 2008). These anticancer behaviors are partially recognized to its property of various molecular targets concerned with cell cycle, apoptosis, alteration, proliferation, survival, invasion, angiogenesis and metastasis of cancer cells (Wu et al., 2010). Though, the mechanisms behind curcumin-inhibited cell growth and curcumin-induced apoptosis in NSCLC are still not clear. For assurance of its anticancer property, NCI-H460 (NSCLC cells) was treated with curcumin. Various concentrations of curcumin were treated with NCI-H460 cells at different time intervals that results in succeeding alterations in the cell structure, viability, cell cycle, mRNA and protein expressions (Figure 2). Apoptotic structural alterations in NSCLC cells due to curcumin were dependent upon the concentration of drug used. Then, results were concluded as over-regulation of BAX and BAD, and less regulation of BCL-2, BCL-XL and XIAP. This study leads to elevation of reactive oxygen species (ROS), intracellular Ca2+ and endoplasmic reticulum (ER) stress in NCI-H460 cells treated with curcumin. Apoptosis occurs due to too much enhancement of curcumin through the FAS/caspase-8 which is a exterior path and ER stress proteins, growth arrest- and DNA damage-inducible gene 153 (GADD153) and glucose-regulated protein 78 (GRP78) was stimulated in the NCI-H460 cells. Apoptosis which occurs due to curcumin was inverted considerably by pretreatment with ROS scavenger or caspase-8 inhibitor. Moreover, the NCI-H460 cells tended to be detained at the G2/M cell cycle stage following curcumin action and involvement of decrease in regulation of cyclin-dependent kinase 1 (CDK1). In evaluation, curcumin shows its anti-cytotoxic property on lung cancer NCI-H460 cells by apoptosis (Wu et al., 2010).

Figure 2. The proposed mechanisms of curcumin-induced apoptotic cell death in human non-small cell lung cancer NCI-H460 cells.

Erlotinib

Erlotinib is usually used on patients with EGFR alterations, however, normally does not effectively used in management of lung cancer lacking malignant cells relapse. Even though various mechanisms for drug resistance are observed, these mechanisms do not successfully explain the description in support of each and every case in drug resistance. Though, investigation gave the hopeful possibility in targeting numerous tumorigenic pathways concurrently. Erlotinib in combination with other anticancer drugs has already established achievement in several lung cancer cell lines. Antitumor activity has formerly been showed in numerous studies. In recent studies, novel drugs are examined that develop chemotherapy and target on identifying prospective aspects for beneficial management of cancer (Leighl, 2012). Further research on these pathways may progress our information of the anticancer efficiency and durability, which will confidently progress in management of lung cancer.

Surfactant-based delivery systems

Surfactants as wetting agents are widely used in pharmaceutical formulations to develop dissolution and absorption of poorly soluble drugs. Table 1 shows various examples of surfactants along with their nature. For this, rational and low molecular weight ionic surfactants like sodium lauryl sulfate are used in that concentration which are not harmful to the intestinal mucosa. Ionic surfactants have been observed in previous studies which are even more harmful to biological membrane than non-ionic surfactants (Davis et al., 1970). Furthermore, non-ionic surfactants which are lipophilic in nature have better capability to dissolve poorly soluble moieties. Thus, non-ionic surfactants are more effective than ionic surfactants in the dissolution of poorly soluble drugs. Non-ionic surfactants are extremely proficient emulsifiers which are to be used in self-emulsifying drug delivery systems. Non-ionic surfactants may effect on various factors of particles such as size, shape and stability of the particles. These factors can be determined by various analytical techniques such as dynamic light scattering (DLS), scanning electron microscopy (SEM), size-exclusion high-performance liquid chromatography (SEHPLC) and circular dichroism (CD). The most common non-ionic surfactants that can affect various factors of particles are Tween 80, Tween 20 and Brij 97. In earlier studies, it is concluded that the molecular configuration of surfactants can alter the self-assembly prototype of nanostructures (Tummala & Striolo, 2009; Suttipong et al., 2011). Various alterations can probably occur in the configuration of both the head and tail part of surfactants. The head part can be charged or neutral, small and compact in size, or a polymeric chain. The tail part is generally a single or double, straight or branched hydrocarbon chain, but may also be a fluorocarbon, or a siloxane, or contain aromatic group(s) (Parnami et al., 2013; Kataria et al., 2014). Chemical structures of typical double-chain surfactants are shown in Figure 3. Since the hydrophilic part generally attains its solubility due to ionic interactions or hydrogen bonding, the simplest classification is on the basis surfactant head group type, through further sub-groups on the basis of the nature of the lyophobic moiety (Holmberg, 2003; Singh et al., 2014a). Fundamental classes consequently appear as listed in Table 2.

Figure 3. Chemical structures of typical double-chain surfactants.

Table 1. Classification of surfactants long with suitable examples.

S. No.	Class	Nature of surfactant	Examples
1	Anionics	Dissociate in water into negative (−) charged	Ammonium lauryl sulfate, sodium lauryl sulfate, sodium laureth sulfate, sodium myreth sulfate
2	Cationics	Dissociate in water into positive (+) charged	Benzalkonium chloride, benzethonium chloride, cetrimonium bromide, cetrimonium chloride, tetramethylammonium hydroxide
3	Non-ionics	Highly polar (non-charged) moiety	Triton X-100, glyceryl laurate, polysorbate, spans, poloxamers
4	Zwitterionics (or amphoterics)	Combine both a positive and a negative (− or +) group.	Cocamidopropyl betaine, lecithin

Table 2. Commercially available hydrophobic and hydrophilic surfactants (Griffin, 1955).

Surfactant	Category	HLB	Groups
Span 85	Non-ionic	1.8	Hydrophobic
Arlacel 85	Non-ionic	1.8	Hydrophobic
Span 65	Non-ionic	2	Hydrophobic
Emcol ES-50	Non-ionic	2.7	Hydrophobic
Atmul 67	Non-ionic	3.8	Hydrophobic
Span 80	Non-ionic	4.3	Hydrophobic
Span 60	Non-ionic	4.7	Hydrophobic
Atlas G-2146	Non-ionic	4.7	Hydrophobic
Emcol DP-50	Non-ionic	5.1	Hydrophobic
Aldo 28	Anionic	5.5	Hydrophobic
Tegin	Anionic	5.5	Hydrophobic
Glaurin	Non-ionic	6.5	Hydrophobic
Atlas G-2242	Non-ionic	7.5	Hydrophobic
Atlas G-2140	Non-ionic	7.7	Hydrophobic
Span 20	Non-ionic	8.6	Hydrophobic
Emulphor VN-430	Non-ionic	9	Hydrophobic
Brij 30	Non-ionic	9.5	Hydrophobic
Tween 61	Non-ionic	9.6	Hydrophobic
Tween 81	Non-ionic	10.0	Hydrophobic
Tween 65	Non-ionic	10.5	Hydrophobic
Tween 85	Non-ionic	11	Hydrophobic
Myrj 45	Non-ionic	11.1	Hydrophobic
PEG 400 monooleate	Non-ionic	11.4	Hydrophobic
PEG 400 monostearate	Non-ionic	11.6	Hydrophobic
Atlas G-2127	Non-ionic	12.8	Hydrophillic
Igepal CA-630	Non-ionic	12.8	Hydrophillic
S-307	Non-ionic	13.1	Hydrophillic
PEG 400 monolaurate	Non-ionic	13.1	Hydrophillic
Tween 21	Non-ionic	13.3	Hydrophillic
Atlas G-1441	Non-ionic	14	Hydrophillic
Tween 60	Non-ionic	14.9	Hydrophillic
Tween 80	Non-ionic	14.9	Hydrophillic
Myrj 49	Non-ionic	15.0	Hydrophillic
Atlas G-2144	Non-ionic	15.1	Hydrophillic
Atlas G-3915	Non-ionic	15.3	Hydrophillic
Emulphor ON-870	Non-ionic	15.4	Hydrophillic
Tween 40	Non-ionic	15.6	Hydrophillic
Myrj 51	Non-ionic	16.0	Hydrophillic
Tween 20	Non-ionic	16.7	Hydrophillic
Brij 35	Non-ionic	16.9	Hydrophillic
Myrj 52	Non-ionic	16.9	Hydrophillic
Myrj 53	Anionic	18	Hydrophillic
Atlas G-2159	Anionic	20	Hydrophillic

Surfactants having low HLB value provide a w/o emulsion, whereas surfactants having high HLB range give an o/w emulsion. NLC is resulting from an o/w emulsion method, thus the surfactant available here were of a high HLB range which are preferably dissolved in an aqueous external phase of the emulsion. Through the regular investigation for improving surfactant properties, novel structures have latterly emerged that display affecting synergistic relations or improved surface and aggregation effects (Singh et al., 2014b). These new surfactants have great significance and consist of the catanionics, bolaforms, gemini (or dimeric) surfactants, polymeric and polymerizable surfactants (Dickinson, 1992; Solans & Kunieda, 1996). Characteristics and typical examples are shown in Figure 4. An additional significant motivation for this investigate is required for improved surfactant biodegradability. In exacting for special care products and household detergents, regulations require high biodegradability and constituents which are not harmful are required in the formulation.

Figure 4. Structural characteristics of novel surfactants.

Surfactant uses and development

Surfactants can exist from natural or synthetic sources. Naturally existing amphiphiles are primary standard surfactant which include lipids that are glycerol-based surfactants and are essential factor of the cell membrane (Solans & Kunieda, 1996). When animal and vegetable oils were combined with alkaline salts, soap-like matter was produced which may be beneficial for management of skin-related disease and also used for washing (Garg et al., 2013). Currently, synthetic surfactants are fundamental ingredients in various manufacturing processes and formulations (Dickinson, 1992). Depending on the specific chemical character of the product, the effects like emulsification, detergency and foaming may be displayed in changeable extent. The numeric and arrangement factors of the hydrocarbon groups collectively among the character and position of the hydrophilic groups merge to find out the surface-active effects of the molecule (Kaur et al., 2014a). As C12 to C20 is usually regarded as the vary covering optimal detergency, even though wetting and foaming are achieved greatest through shorter chain lengths. Structure–performance relationships and chemical compatibility are consequently major fundamentals in surfactant-based formulations, with the intention that a great deal investigation is committed to this region (Kaur et al., 2014b). Table 3 discusses some common uses of surfactant with their special features.

Table 3. Common uses of surfactant categories with their features (Dickinson, 1992; Solans & Kunieda, 1996).

S. No.	Surfactant category	Features	Uses
1	Anionics	Easy to manufacture and cost is less in manufacturing	Mostly applicable in detergency, personal care products, emulsifiers and soaps
2	Cationics	Negatively charged (e.g. metal, plastics, minerals, fibres, hairs and cell membranes) can be altered when treated with cationic surfactants. Cationics are used because of their absorption at surfaces	Used as anticorrosion and antistatic agents, flotation collectors, fabric softeners, hair conditioners and bactericides
3	Non-ionics	Strong attraction with water because of strong dipole-dipole interactions arising from hydrogen bonding	Used in low temperature detergents and emulsifiers
4	Zwitterionics	Smallest surfactant class due to their high cost of manufacture	Have excellent dermatological effects and skin compatibility. Because of their low eye and skin irritation, generally used in shampoos and cosmetics

Pharmaceutical excipients as P-gp inhibitors

A variety of pharmaceutical products produced from either synthetic or natural origin, associated with the classes of co-solvents, surfactants, polymers and lipid ingredients have been publicized to have P-gp inhibition (Figure 5). These workings enhance the absorptive transportation of P-gp substrates by inhibiting discharge intended for transport (Kaur et al., 2014c). The mechanism changes with the type of excipients that inhibit P-gp inhibition which is presently under research (Lo, 2003). Though some theories have been anticipated (Figure 6).

Figure 5. Pharmaceutical excipients as P-gp inhibitors.

Figure 6. Mechanism undertaken for P-glycoprotein-mediated efflux for excipients (Bansal et al., 2009).

Solvents and surfactants act together by the polar head of the lipid bilayers which may change hydrogen bonding and ionic forces and this polar head may embed between the lipophillic tails of the bilayers (Gagandeep et al., 2014). These membrane disturbances have been exposed to alter P-gp activity leads to fluidization of the lipid layers (Cornaire et al., 2004). Batrakova & Kabanov (2008) showed that pluronics can excite P-gp which causes prohibition of ATPase activity leading to depletion in ATP, whereas peceol and Gelucire 44/14 downregulate MDR1 gene expression and P-gp protein expression in Caco-2 cells (Batrakova & Kabanov, 2008). It is concluded from studies that several ingredients too influence direct binding to the P-gp, reduce Protein kinase C action, decrease phosphorylation of P-gp and alter P-gp-mediated efflux. Verapamil is familiar with P-gp inhibition by which mixed micelles have been noted to circumvent P-gp drug efflux, while the drug augmentation does not change (Garg, 2014).

Surfactants used in P-gp efflux

The initial surfactant which expressed as chemosensitizing agent was polysorbate 80, which was used with daunomycin (Riehm & Biedler, 1972). Then research was preceded by Woodcock et al. (1992) which then conclude some other non-ionic surfactants, e.g. Tweens, Spans, Cremophors (EL and RH40), Pluronics and vitamin E TPGS having P-gp inhibition action (Collnot et al., 2007). Cremophor EL was used as a component of marketable formulations of paclitaxel (Taxol), however this formulation was found to be toxic. Usually, non-ionic surfactants can improve dissolution in water insoluble moieties because of being highly hydrophobic and comparatively lesser toxicity to biological membranes (Rege et al., 2002). Further research reveals the capability of Tweens to inhibit efflux pumps. Lo (2003) established that Tween 20, Tween 80, Myrj 52 and Brij 30 enhance the epirubicin transport and decrease in efflux of diffusion chambers with excised rat intestinal mucosa. P-gp inhibition action is based on two essential parameters, i.e. surfactant concentration and hydrophilic–lipophilic balance (HLB). Surfactant concentrations which are non-hazardous to the intestinal mucosa may be usually preferred for the inhibition of P-gp. Greater than the crucial micelle concentration (CMC) surfactants become much beneficial in the solubilization of lipophilic substrates, while they would gave double achievement of solubilizing lipophilic drugs and inhibiting efflux. Though, the prototype of P-gp inhibition alters on the basis of kind of excipients used. On the basis of research, P-gp inhibitory activity raises when CMC is achieved and after CMC there is failure of the inhibitory activity lead to drug (P-gp substrate) entrapment in the micelles (Garg & Goyal, 2012). In a further development, inhibitory action raises yet beyond CMC and this could be accredited to the information that substrate entrapped in micelles avoid P-gp-mediated efflux. The most advantageous HLB range of surfactant systems among appropriate hydrocarbon chains and polar part is a significant issue in designing potential drug formulations (Garg & Goyal, 2014b). The most favorable development on the intracellular aggregation of epirubicin was attributing among intermediary HLB ranges ranging from 10 to 17 (Lo, 2003). Pluronics may possibly increase Caco-2 cell aggregation of rhodamine at concentrations less than the CMC while they demonstrate larger permeability by such concentrations (Batrakova et al., 1998). Pluronics (poloxomers) are extremely effective, non-hazardous, realistic and near-market utilize pharmaceutical ingredients. The biological effect of Pluronics is accredited toward their capability in the direction of incorporation into membranes followed via consequent translocation into the cells along with disturbing different cellular functions, such as mitochondrial respiration, ATP production, action of drug efflux transporters, apoptotic signal transduction and gene expression (Goyal et al., 2013a; Garg & Goyal, 2014a). Consequently, Pluronics cause extreme sensitization of MDR tumors to different anti-cancer drugs, improve drug transportation towards the blood brain and intestinal barriers, with causes transcriptional stimulation of gene expression both in vitro and in vivo (Batrakova & Kabanov, 2008; Garg et al., 2014).

Formulation advances on the basis of P-gp modulation

With the purpose to understand the prospective of P-gp in transportation of anti-tumor drugs to cancer cells along with much effectiveness as well as specificity, numerous delivery systems have been developed which may include microspheres, nanosized drug carriers (nanoparticles, nanoemulsions, stealth liposomes, nanogels, polymer–drug conjugates), novel powders, hydrogels, mixed micellar systems intended for systemic and/or localized delivery (Garg et al., 2012; Goyal et al., 2013b) (Table 4).

Table 4. Advanced formulations on the basis of P-gp modulation.

Dosage form	Method of preparation	Drug	Cell model	Ref.
Tablet	Compression	Rhodamine-123	Rat intestinal	Föger et al. (2006)
Liposomes	Encapsulation	Doxorubicin and verapamil and conjugated to transferrin	K562 leukemia cells	Wu et al. (2007)
Polyalkylcyanoa-crylate (PACA) nanoparticles	Emulsion polymerization process	Cyclosporin A	Doxorubicin-resistant leukemia (P388/ADR) cells	Emilienne Soma et al. (2000)
Stealth liposomes	Encapsulation	Verapamil	Multidrug-resistant rat prostate adenocarcinoma Mat-LyLu-B2 (MLLB2) cells	Xiao Yan et al. (2005)
Micelles	Solubilization	Paclitaxel	Caco-2 cells	Dabholkar et al. (2006)
Nanoparticles	Emulsion-solvent evaporation method	Paclitaxel	MCF-7 tumor cells	Chavanpatil et al. (2006)
Polymer–lipid hybrid nanoparticles (PLN)	Emulsion solvent evaporation method	Elacridar	Human breast carcinoma (MDA435/LCC6/MDR1) cells	Wong et al. (2006)
			Clonogenic assay in MDA435/LCC6/MDR1 cells
Copolymer conjugate	Chemically modified	Doxorubicin	CEM/VLB, P388-MDR	Št’astný et al. (1999)
Transferrin-conjugated liposomes	Conjugation	Verapamil	Chronic myelogenous leukemia (K562/DOX) cells	Wu et al. (2007)
Lipid nanocapsules	Phase inversion	Etoposide	C6, F98 and 9L glioma cell lines	Lamprecht & Benoit (2006)
Wheat germ agglutinin-conjugated liposomes	Conjugation	Tamoxifen	Murine glial tumor (C6) cells	Du et al. (2009)
			Transport across BBB (brain microvascular endothelial cells/rat astrocytes) – (BMVECs/RAs)
Emulsifying wax nanoparticles	Micro emulsification	Paclitaxel	HCT-15 mouse xenograft model	Koziara et al. (2006)
Poly(d,l-lactide-co-glycolide acid) (PLGA) nanoparticles	Emulsion solvent evaporation method	Tariquidar	Murine mammary adenocarcinoma (JC) and human	Patil et al. (2009)
SMEDDS	Self-emulsification	Paclitaxel	Rat model	Yang et al. (2004)
Poly(d,l-lactide-co-glycolide acid) (PLGA) nanoparticles	Emulsion solvent evaporation and salting-out method	Verapamil	Human breast cancer (MCF-7/ADR) cells	Song et al. (2009)
Stealth liposomes	Encapsulation	Tariquidar	Paclitaxel-resistant human ovarian adenocarcinoma (SK-OV-3TR) cells	Patel et al. (2011)
Polymer–lipid hybrid nanoparticle	Ultrasonication	Doxorubicin	Breast cancer cell line	Wong et al. (2006)
Nanogels	Emulsification/solvent evaporation	Fludarabine	MCF-7 cells and Caco-2 cell	Vinogradov et al. (2005)
Nanoparticles	Solvent extraction/evaporation	Paclitaxel	Tube shaker	Zhang & Feng (2006a)
Nanoparticles	Microemulsification	Paclitaxel	Mouse model	Patil et al. (2009)
Nanoparticles	Dialysis method	Paclitaxel	HT-29; Caco-2 cells	Zhang & Feng (2006b)
Liposome	Encapsulation	Daunorubicin	Breast cancer cell line and resistant sublines	Iffert et al. (2000)
Micro-particles	Solvent extraction/evaporation	Paclitaxel	Brain tissue	Elkharraz et al. (2006)
Hydrogel	Solubilization	Doxorubicin	Drug diffusion and Bcl1 leukemia	Št’astný et al. (2002)
Monoclonal antibody	Structural Modification	Doxorubicin	Tumor cells	Guillemard & Saragovi (2004)
Films	Homogenization	Paclitaxel	Human ovarian xenograft model	Ho et al. (2007)

Conclusion

Surfactant-based delivery system has infinite potential with novel applications continuously being developed for use in cancer diagnosis, detection, imaging and treatment. These systems are previously assisting to address key matters with traditional anticancer agents such as non-specific targeting, low therapeutic efficiencies, untoward side effects and drug resistance as well as greater their forerunners with the skill to sense early metastasis. The ability of above systems to be personalized for an adapted medicine strategy makes them ideal vehicles for the treatment of lung cancer. In general, above systems allow design flexibility in drug delivery of poorly water-soluble molecules as well as imparting the ability to overcome biological barriers and selectively target desired sites within the body.

Acknowledgements

Authors Dr. Amit K. Goyal thankful to Indian Council of Medical Research, New Delhi, INDIA for providing financial assistance to carry out research.

Declaration of interest

The authors report no conflict of interest.