Journal of Controlled Release 176 (2014) 94–103

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Review

Emerging integrated nanohybrid drug delivery systems to facilitate the intravenous-to-oral switch in cancer chemotherapy Cong Luo a, Jin Sun a,b,⁎, Yuqian Du a, Zhonggui He a,⁎ a b

Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193,PR China

a r t i c l e

i n f o

Article history: Received 16 October 2013 Accepted 24 December 2013 Available online 2 January 2014 Keywords: Oral chemotherapy Multiple biobarriers Emerging trend Hybrid nanosystems Integrated

a b s t r a c t Nanohybrid drug delivery systems have presented lots of characteristic advantages as an efficient strategy to facilitate oral drug delivery. Nonetheless, oral administration of chemotherapy agents by nanoparticulate delivery technology still faces great challenges owing to the multiple biobarriers ranging from poorly physicochemical properties of drugs, to complex gastrointestinal disposition and to presystemic metabolism. This review briefly analyzes a series of biobarriers hindering oral absorption and describes the multiple aspects for facilitating the intravenous-to-oral switch in cancer therapy. Moreover, the developed nanoparticulate drug delivery strategies to overcome the above obstacles are provided, including metabolic enzyme inhibition, enteric-coated nanocarriers, bioadhesive and mucus-penetrating strategies, P-gp inhibition and active targeting. On these foundations, the emerging trends of integrated hybrid nanosystems in response to the present low-efficiency drug delivery of any single approach are summarized, such as mixed polymeric micelles and nanocomposite particulate systems. Finally, the recent advances of high-efficiency hybrid nanoparticles in oral chemotherapy are highlighted, with special attention on integrated approach to design drug delivery nanosystems. © 2013 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biobarriers encountered in oral chemotherapy . . . . . . . . . . . . . . . . . . Developed drug delivery strategies to overcome the multiple barriers . . . . . . . 3.1. Improving the stability of drugs and drug-loaded nanocarriers . . . . . . . 3.1.1. Metabolic enzyme inhibition . . . . . . . . . . . . . . . . . . 3.1.2. pH-sensitive drug-loaded carriers based on enteric polymers . . . . 3.2. Prolonging residence time in GI tract . . . . . . . . . . . . . . . . . . . 3.3. Promoting the transmembrane transport of drugs and drug-loaded nanocarriers 3.3.1. P-gp inhibition . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Targeting intestinal epithelia receptors/transporters . . . . . . . . 4. Hybrid DDSs: integrated approach to design oral nanoparticulate drug delivery systems 4.1. Emerging hybrid DDSs . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. The ideal hybrid drug-loaded nanocarriers . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction ⁎ Corresponding authors at: No. 59 Mailbox, Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Tel./fax: +86 24 23986321. E-mail addresses: [email protected] (J. Sun), [email protected] (Z. He). 0168-3659/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jconrel.2013.12.030

Malignant cancer still imposes great threat to human health, and strategies to cope with the challenges are limited [1,2]. Presently, the majority of effective chemotherapy agents are administrated by injection, resulting in reduced patient compliance. Oral delivery is

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considered to be a preferred route for drug administration because of its innate compliance [3,4]. Therefore, the superiority of the intravenousto-oral switch in cancer therapy lies in simplified therapeutic process, improved patient compliance and reduced injection-associated adverse events [5]. However, orally administered drugs would encounter many difficulties during oral absorption process, including low solubility, poor chemical stability and low permeability of drugs, variable pH values, short residence time and abundant metabolic enzymes in gastrointestinal (GI) tract and the liver, etc. For instance, oral administration of the taxanes (paclitaxel and docetaxel) is strongly hampered by their poor solubility, metabolism by cytochrome P-450 (CYP-450) enzymes and good affinity with drug efflux pump P-glycoprotein (P-gp) [6]. Moreover, oral administration of chemotherapeutic agents could also cause certain damages to mucosal tissue in GI tract elicited by high drug concentration. Before drugs or nanocarriers enter the systemic circulation, three consecutive stages during oral absorption process should be taken into consideration (Fig. 1): (i) disposition of drugs or nanocarriers inside GI tract, including dissolution or dispersion in GI fluid, stability and residence time in GI tract; (ii) passing through the GI epithelia or transmembrane transport; and (iii) presystemic drug metabolism in GI tract and the liver or avoiding first-pass effect by lymphatic transport. In response to the multiple biobarriers at the three consecutive stages, considerable efforts have been made for facilitating intravenous-tooral switch in cancer therapy in the past few decades [7–9]. In addition to the improvement in aqueous solubility or dissolution characteristic, three main strategies are currently adopted to improve oral delivery efficiency: (i) enhance the stability of anticancer drugs and drug-loaded carriers; (ii) prolong the residence time in GI tract; and (iii) increase the membrane permeability. Due to the multiple biobarriers in these consecutive stages, the oral delivery efficiency of any single approach is usually limited. As a result, there has been almost not a single product available switching from intravenous injection to oral administration in clinical therapy so far. Therefore, more rational and high-efficiency drug delivery systems (DDSs) should be designed to facilitate the progress of oral chemotherapy. Hybrid nanosystems, integrated multiple oral nanoparticulate drug delivery approaches, have become a notable trend over the recent years [10,11]. We have good reasons to believe that more rational and comprehensive hybrid nanocarriers will emerge to facilitate oral chemotherapy. Several excellent reviews concerning oral delivery of antitumor drugs have been reported, and advances and challenges in oral chemotherapy are profoundly discussed based on the development of pharmaceutical science, nanotechnology and drug delivery systems (DDSs) [7,8,12–15]. However, most of them focused only on the progresses of several drug delivery strategies on the basis of the fragmental

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absorption limiting factors, and there is no attention paid to the rational design in the integrated hybrid DDSs considering the whole absorption process. The present overview briefly analyzes multiple biobarriers encountered for oral delivery of anticancer drugs and describes several oral drug delivery approaches to overcome the multiple barriers with special emphasis on improved stability, prolonged residence time in GI tract and enhanced transmembrane transport efficiency. Finally, the distinct advantages and promising applications of hybrid nanosystems are highlighted. 2. Biobarriers encountered in oral chemotherapy According to statistics, more than 60% of all anticancer drugs are available for clinical therapy in oral dosage form, but very few of them are actually put into use in the clinic owing to the limited oral bioavailability [7]. The principal factors determining the oral absorption efficiency include aqueous solubility, stability in the GI tract, permeability through intestinal epithelia, and the presystemic metabolism, which depend on the physicochemical properties of antitumor drugs, the complex GI environment and the in vivo blood/lymph circulation after absorption [16]. As shown in Fig. 2, the principal biobarriers hindering intravenousto-oral switch in cancer therapy can be simply divided into three categories [17–20]: (i) physicochemical properties of anticancer drugs; (ii) physiological barriers in GI tract; and (iii) biochemical barriers in GI tract. The poorly physicochemical properties of antitumor agents are the innate factors limiting their oral absorption potential and the physiological and biochemical conditions impose the external challenges to drugs or drug-loaded nanocarriers. It is interesting to notice that some compounds can be readily absorbed but some can't when expose to the same environment of GI tract. Indeed, physicochemical properties of drug molecules have significant impact on oral absorption. Among them, solubility, pKa, log P, stability and P-gp affinity are essential properties determining oral absorption potential of drugs. As shown in Fig. 3, the main drug transport mechanisms across the intestinal cells can be broadly summarized as transcellular pathway and paracellular pathway. Transcellular pathway includes passive transport, carrier-mediated transport and P-gpmediated efflux. Oral absorption of hydrophilic drug is generally believed to use the paracellular pathway or carrier-mediated transport. And some hydrophilic drugs (e.g. acyclovir and famotidin) transported mainly by paracellular pathway (Fig. 3B) generally have low bioavailability due to its low coverage of the total intestinal surface area (0.01–0.1%), but some other hydrophilic drugs (e.g. ofloxacin and pregabalin) transported mainly by carrier-mediated transport can achieve a good absorption [22]. As for lipid-soluble drugs, they transport through intestinal membranes mainly by passive diffusion (Fig. 3A)

Fig. 1. Three consecutive stages before entering the whole body blood circulation in oral drug delivery process.

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Fig. 2. Multiple biobarriers hampering oral drug absorption.

[21]. In addition, different transporters on the intestinal epithelial cellular membrane play different roles in oral drug absorption [23]. Carrier-mediated transport (Fig. 3C) helps to promote the oral absorption of drugs, but P-gp efflux pump (Fig. 3D) acts exactly in the opposite way [24]. Compared to the relatively fragile biological drugs (e.g. protein, peptide and gene), the majority of chemical drugs show better chemical stability. Therefore, the limited oral absorption potential of anticancer drugs can be generally attributed to solubility-limited, permeabilitylimited, or both [25]. According to Biopharmaceutics Classification System (BCS), BCS class I drugs, with good water-solubility and high permeability, can be easily absorbed in GI tract. Usually, gastric empty is the limiting factor to the oral absorption of BCS class I drugs. As for BCS class II drugs with low solubility and high permeability, dissolution process is the rate-limiting factor, and appropriate efforts for solubility enhancement are necessary [26,27]. On the other hand, as for BCS class III drugs with high solubility and poor permeability, membrane transport is the rate-limiting factor and attempts to improve permeability are usually taken for good oral absorption [28,29]. However, with poor solubility and low permeability, measures taken to improve the oral absorption of BCS class IV drugs are very limited. GI tract is an extremely complex environment in terms of physical structure and chemical constituents. Digesting food and absorbing nutrients are the main function of GI tract, and these functions provide the possibility for oral absorption of drugs. Before oral absorption, drugs

Fig. 3. Graphical description of drug transport mechanisms across the intestinal cells: (A) Passive transport; (B) Paracellular pathway; (C) Carrier-mediated transport and (D) P-gp-mediated efflux.

or drug-loaded nanocarriers must pass through the GIT, and face the harsh GI environment. Intestinal mucus layer is one of the important obstacles for drug absorption [30,31]. Before drugs or drug-loaded carriers reach the intestinal epithelial cells, they must penetrate through an aqueous mucus layer secreted by the goblet cells and an unstirred water layer stemming from the glycocalyx structure of epithelial cells [32–35]. In addition, short residence time and various efflux transporters in GI tract further restrict oral absorption of drugs [23]. For instance, P-gp (Fig. 3D), richly expressed on intestinal epithelial membrane as a predominant ATP-binding cassette (ABC) efflux transporter, plays a negative role on oral absorption potential of P-gp substrates by pumping them back into the intestinal lumen [24]. The varying pH, surfactants (e.g. bile salt) and metabolizing enzymes in GI tract and the liver together constitute the biochemical barriers in oral drug absorption [36]. The pH environment along with the GI tract changes from acidic to alkaline condition, imposing a challenge for the stability of drugs and the integrity of nanocarriers. In addition, surfactants in GI tract could have a significant impact on the structural stability of drug-loaded nanocarriers, especially for liquid-crystal like micelles, liposomes and vesicles, etc. Moreover, metabolic enzymes (e.g. CYP450) in the intestinal cells and liver are another negative factor to limit oral drug absorption [36]. Among dozens of human CYP-450 homologues, CYP3A4 plays an extremely important role in overall metabolism of drugs [37]. 3. Developed drug delivery strategies to overcome the multiple barriers Given the poor physicochemical properties of the drugs, nanoparticulate DDSs are very promising platforms to improve druggability of poorly soluble or/and permeable compounds [38]. Nanotechnology holds great potential as an effective strategy to facilitate oral delivery of chemotherapeutical drugs [8,39]. At present, several prominent oral drug delivery strategies based on particulate DDSs can be summarized as follows: (i) enhance the stability of drugs and nanocarriers; (ii) extend the residence time of drugs and carriers in GI tract; and (iii) promote the transport of drugs and/or drug-loaded carriers through membrane of GI tract. 3.1. Improving the stability of drugs and drug-loaded nanocarriers To ensure the stability of drugs and drug-loaded nanocarriers is a priority for efficient oral drug delivery. Metabolic enzyme inhibition can efficiently enhance the metabolic stability of drugs. But for drugloaded nanocarriers, several factors can influence their stability in GI tract, including physical forces (e.g. GI motility and the interference of GI contents) and chemical pressures (e.g. varying pH, surfactants, proteolytic enzymes and lipases in GI fluid). Precisely because of the above restriction, solid-state nanoparticles (nanocrystals, solid lipid nanoparticles and PLGA nanoparticles, etc.) show better stability than the liquid-crystal like polymeric nanoassemblies (micelles, liposomes and lipid vesicles, etc.) [8,40]. In addition, pH-sensitive DDSs based on enteric polymer coating in recent years show distinct advantages in increasing the stability of both drug molecules and drug-loaded nanocarriers. 3.1.1. Metabolic enzyme inhibition The metabolism of CYP-450 enzymes imposes a great threat to the stability of drug molecules [41–43]. Although the physical encapsulation by nanocarriers can to a certain degree protect drugs, it wouldn't work with the released free drug molecules. Therefore, oral delivery of anti-cancer drugs, especially for the substrates of CYP-450 enzymes, will certainly benefit from metabolic enzyme inhibition. Application of low molecule weight compounds and functional polymers as CYP-450 enzyme inhibitors are the most common strategy in response to serious presystemic drug metabolism in GI tract and the liver. However, low

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molecule weight metabolic inhibitors have been limitedly used due to their in vivo wide distribution and potential serious drug–drug interactions [44]. In contrast to low molecule weight metabolic inhibitors, high molecule weight functional polymers and surfactants, e.g. PEG, Pluronic F68 (PEO-PPO-PEO) and Tween-80, possess the ability to suppress the metabolism of CYP-450 enzymes and have a limited in vivo biodistribution and low-probability polymer–drug interaction [11,13]. Philip Martin et al. have studied the impact of twenty-three commonly used excipients of polymers and surfactants on several cytochrome P450 (CYP450) isoforms, and a large portion of these polymers and surfactants were capable of inhibiting activity of several different CYP450 isoforms [45]. Therefore, application of these polymers as nanocarrier matrices holds great potential to enhance the metabolic stability of drugs by concurrently intracellularly delivered metabolic inhibitors. 3.1.2. pH-sensitive drug-loaded carriers based on enteric polymers Enteric materials and enteric coating technologies have been successfully developed and applied in the conventional oral controlled release preparations, such as Eudragit® products [46–50]. The superiority of enteric coating lies in avoiding the adverse effects of harsh acidic environment in the stomach and in regulating the drug release rate and site. For nanoparticulate DDSs, strong gastric acid environment strongly impairs the stability of most nanocarriers and then triggers a burst release of the encapsulated drugs, which is extremely detrimental to oral drug delivery efficiency. In recent years, application of enteric polymers in nanoparticulate DDSs has shown great advantages and potential applications [9,51], and the established pH-sensitive drugloaded particulate carriers can be summarized as the following three types (Fig. 4): 3.1.2.1. Core-shell type enteric nanoparticles. The group of Zhang Q has developed a silica-based pH-sensitive nanomatrix system for improving the oral absorption of peptides, proteins and poorly water-soluble drugs [52,53]. With nano-porous silica as the core and pH-sensitive Eudragit® as the pH sensitive shell, the silica-based pH-sensitive nanomatrix is a typical core-shell nanosystem (Fig. 4B). Selecting fenofibrate as a model drug, a silica-based pH-sensitive nanomatrix was developed by utilizing a combination of pH-sensitive polymethylacrylate and nanoporous silica, and this system showed great improvement in stability and oral bioavailability of fenofibrate [52]. In addition, they prepared another similar nanomatrix system for oral delivery of glucagon-like peptide-1 (GLP-1), and found a five-fold improvement of intestinal membrane permeability and significantly higher proteolytic stability, with relative bioavailability up to 35.7% in comparison to intraperitoneal

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GLP-1 [53]. The developed silica-based pH-sensitive nanomatrix system presents a higher stability and greater oral absorption efficiency, and holds great potential as a promising strategy for efficient oral delivery of anticancer drugs. 3.1.2.2. Matrix type enteric nanoparticles. As shown in Fig. 4 A, several matrix type nanosystems have been developed by using enteric polymers as nanocarrier materials [54–56]. Selecting Eudragit L100-55 and omeprazole as carrier material and model drug, Hao S et al. prepared enteric Eudragit L100-55 nanoparticles with an emulsion diffusion method by ultrasonic dispersion and diffusion solidification [54]. It turned out that these enteric nanoparticles showed a high physical stability and a strong pH-sensitive drug release in vitro, and the cellular uptake results indicated that they could be easily taken up by Caco-2 cells [54]. Zhang Y et al. grafted cysteine to the carboxylic acid group of Eudragit L100 and then prepared thiolated Eudragit L100-based polymeric nanoparticles as an oral insulin delivery system by the precipitation method [56]. Except for the pH-dependent release behavior, this system showed a great improvement in mucoadhesion compared with the unmodified polymer nanoparticles [56]. The common advantages of the pH-sensitive nanosystems are that they could protect the encapsulated drugs from being damaged by gastric acid environment, and pH-sensitive drug release can cooperate well with the uptake characteristics by distal intestinal epithelial cells, e.g. absorption window. 3.1.2.3. Nano-in-Micro type enteric microparticles. Drug-loaded nanoparticles are encapsulated into the enteric microparticles, namely Nano-inMicro type enteric microparticles (Fig. 4C), which is an effective approach to enhance the stability of the contained nanoparticles in GI tract. Nassar T et al. developed such a Nano-in-Micro system that docetaxel was encapsulated in PLGA [poly(lactic–co–glycolic acid)] nanoparticles, and then the PLGA nanoparticles were embedded in enteric microparticles by the spray-drying method [57]. Surprisingly, pharmacokinetic results indicated that oral administration of the Nano-in-Micro formulation had a dramatically higher AUC value (5754.5 ± 1338.8 ng·h/mL) than those of both intravenous injection of docetaxel solution (2080 ± 81.2 ng · h/mL) and free docetaxel PLGA nanoparticles (1441.9 ± 485.6 ng · h/mL) at the same single dose of 5 mg/kg [57]. Base on the obtained experimental results, the authors concluded that the unexpected enhanced absolute bioavailability was achieved by utilizing such a Nano-in-Micro system, since PLGA nanoparticles could be internalized intact in the enterocytes through an endocytosis process that gradually released drug into plasma bypassing P-gp efflux and circumventing CYP4A3 metabolism. In addition, the lymphatic route, involved in nanoparticle absorption, can help to bypass the first-pass effect in the liver and to act as a drug reservoir to slowly release drug [57]. Therefore, owing to its high oral absorption efficiency, this novel drug delivery system holds great potential as a promising strategy for oral administration of antitumor drugs. 3.2. Prolonging residence time in GI tract

Fig. 4. Graphical description of pH-sensitive drug-loaded nanoparticulate carriers based on enteric polymers: (A) Matrix type; (B) Core-shell type; and (C) Nano-in-Micro type.

Prolonged retention time in GI tract is of great significance to oral nanoparticulate drug delivery systems [58], and only in this way that drug-loaded nanocarriers can make full contact with intestinal epithelial cells and then be transported into lymphatic or blood circulation. Due to the small size and large dispersibility, nanoparticles themselves have certain mucosal bioadhesion ability, but it plays only a marginal role. So far, many strategies aiming to further improve bioadhesion force by using bioadhesive materials and technologies have been developed [59–61]. After being orally administrated, drug-loaded nanocarriers cannot directly contact with GI epithelial cells due to the existence of an aqueous mucin layer, which is a first-line of defense to protect the body from invading parasites, bacteria and other intruders from GI tract [58]. From this perspective, the aqueous mucin layer hinders the

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oral absorption of nanoparticles via building a protective hydrophilic wall. It was recently found that the aqueous mucin layer is negatively charged (approximately −50 mv), and is rich in cysteine with sulfhydryl groups [62–67]. As shown in Fig. 5, these findings lay a good biological foundation on developing bioadhesive drug delivery systems. Two primary strategies have been widely applied to enhance bioadhesion of nanosystems (Fig. 5): (i) positively charged polymer materials prolong the retention time in GI tract by electrostatic forces with the mucin layer; and (ii) polymer materials with sulfhydryl groups increase the interaction with cysteine in the mucin layer by forming disulfide bond. Chitosan, with positive charge and good biocompatibility, has been widely applied as a building block for bioadhesive drug-loading nanocarriers [62,65]. Zhang X et al. prepared chitosan-coated PLGA nanoparticles (CS-PLGA-NPs) for oral delivery of insulin, and CSPLGA-NPs showed a better bioadhesion and higher oral delivery efficiency of insulin compared to the uncoated PLGA nanoparticles [68]. In addition to the improved bioadhesion by cationically modified nanocarriers, numerous works focused on thiolated mucoadhesive nanoparticles [65,69–72]. Jiang L et al. constructed the thiolated chitosan modified PLA-PCL-TPGS nanoparticles for oral administration of paclitaxel. The thiolated nanoparticles showed significant increase in the cellular uptake by intestinal epithelial cells than the unmodified ones due to the enhanced mucoadhesiveness and permeation properties [69]. Our group has synthesized acetylcysteine functionalized chitosan-vitamin E succinate copolymer (CS-VES-NAC, CVN) to develop multifunctional nanomicelles. With remarkable bioadhesion, this nanosystem possessed the ability to penetrate mucus and to enhance the oral absorption of paclitaxel. Compared with paclitaxel solution, the intestinal absorption of CVN nanomicelles was greatly improved by 4.5-fold, and the AUC0 − t of CVN nanomicelles was significantly enhanced in pharmacokinetic study [70]. Mucoadhesive nanocarriers, particularly positively charged or thiolated nanocarriers, have been designed to present strong interactions with the mucus and prolong the residence time of the nanocarriers on the mucosal surface. On the other hand, mucoadhesive nanocarriers can also be trapped in the sticky mucus and then be readily swept away by epithelial cell turnover [73]. Therefore, in addition to the adhesiveness, the penetration capability of nanocarriers through the mucus is equally critical. The group of Hanes J has put forward “mucus-penetrating particles” (MPPs) concept. MPPs, namely PEGylated muco-inert nanoparticles, can be obtained by densely modifying particle surface with low-molecular-weight PEG, and can easily penetrate the mucus compared to the unmodified ones[73–75]. Taken together, a reasonably designed nanocarrier should maintain a balance between mucoadhesion and penetration capability through the mucus layer. 3.3. Promoting the transmembrane transport of drugs and drug-loaded nanocarriers In order to enhance the oral absorption potential, most of the studies focused on two aspects: (i) inhibiting the efflux effect of P-gp and

Fig. 5. Biological foundations for designing bioadhesive DDSs: (A) electrostatic forces between the positive charge and the negative charge; (B) anchored by disulfide bond.

(ii) active targeting to the specific receptors or transporters located in intestinal epithelia. 3.3.1. P-gp inhibition P-gp inhibition is a simple but very effective strategy to efficiently improve transmembrane transport in both multidrug resistant (MDR) tumor cells and P-gp highly expressing intestinal epithelia. As shown in Fig. 6, a series of approaches have been developed to inhibit P-gp efflux pump [7,76–82]: (i) structural modification of drugs; (ii) generegulation therapy; (iii) small molecule P-gp inhibitors; and (iv) high molecule polymer-based P-gp inhibitors. The first two approaches have obvious deficiencies to limit their uses in oral drug delivery. As to the structural modification of drugs, it is difficult to balance the pharmacological activity and P-gp affinity; and for gene-regulation therapy approaches, it is well known that gene medicines are unstable and undergo readily inactivation in GI tract. The development of small molecule P-gp inhibitors has experienced three generations [7,83]. Cyclosporin A and verapamil were typical representatives of the first-generation P-gp inhibitors, and were once widely applied in improving the oral absorption efficiency of various P-gp substances. For instance, coadministration of cyclosporine A could dramatically enhance the oral bioavailability of vincristine, docetaxel and paclitaxel [84–86]. The second-generation P-gp inhibitors, e.g. valspodar (PSC833) [87], failed to be further developed for their poor binding affinity and some potential adverse effects. With high P-gp specific affinity, the latest generation P-gp inhibitors (e.g. HM30181, GF120918, LY335979 and XR9576 etc.) were gradually developed over the past two decades [88–91]. However, despite the high affinity and inhibitory effect to P-gp, small molecule P-gp inhibitors have been seldom used in clinical therapy owing to their potential side effects associated with suppression of immune system and central nervous system by unspecific biodistribution. The functional excipient-based P-gp inhibition was commonly used in the oral nanohybrids, including some natural polymers, surfactants and cyclodextrins, etc. [92–95]. These functional excipients showed unique superiority in the case of safety and effectiveness, and have been utilized as modifiers or emulsifiers for improving oral drug delivery efficiency. For instance, numerous studies have shown that Pluronic copolymers could inhibit P-gp activity effectively [96–98]. Ma L et al. studied the impacts of Pluronic F68 on P-gp transport, and found that Pluronic F68 produced similar inhibitory effect of P-gp as verapamil, thereby increasing intestinal absorption of rifampicin [97]. Guan Y et al. studied the effect of Pluronic P123 and F127 block copolymer on P-gp, and demonstrated that Pluronic P123 and F127 have obvious inhibitory effect on the intestinal P-gp activity [98]. In recent years, various novel polymers were synthesized in response to P-gp efflux. Although most of them were to be initially designed for intravenous administration aiming at MDR reversal of tumor cells, they were also widely applied in oral delivery of Pgp substrates. One of the most remarkable polymers is D -alphatocopheryl polyethylene glycol 1000 succinate (TPGS) [99,100], and the group of Feng SS has made notable efforts to facilitate oral chemotherapy based on vitamin E-TPGS [100–106]. For example, they evaluated the effects of PLGA nanoparticles (NPs) with TPGS as emulsifier for oral delivery of paclitaxel, the oral bioavailability of nanoparticulate formulation is more than 10-fold higher than Taxol, resulting in a higher therapeutic effect and longer sustainable therapeutic time [101]. In addition, Varma MV et al. investigated the effects of TPGS on the intestinal permeability of paclitaxel, and demonstrated that coadministration of TPGS could improve the oral delivery efficiency of P-gp substrates [107]. Our group have designed and synthesized a star-shape P-gp reversible inhibitor and anticancer enhancer, lysine-linked di-tocopherol polyethylene glycol 2000 succinate (PLV2K), to overcome the high critical micellar concentration (CMC) value and ready leakage from nanoparticles of TPGS [108].

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Fig. 6. Developed strategies to inhibit P-gp efflux pump.

Doxorubicin (DOX) was encapsulated into the hydrophobic core of PLV2K (PLV2K-DOX), with encapsulation efficiency as high as 94.5%. DOX release from PLV2K-DOX nanomicelles (16.4 nm) was pHdependent, ensuring micelles stable in blood circulation and DOX release within tumor cells [108]. In addition, due to the enhanced cytotoxicity and P-gp inhibition by PLV2K, PLV2K-DOX showed greater cytotoxicity compared with DOX solution with increased intracellular accumulation in resistant MCF-7/Adr cells. Therefore, with lower CMC value (1.14 μg/mL) and excellent P-gp reversible inhibition [108], PLV2K holds great potential as an effective modifier or emulsifier applying in oral chemotherapy.

3.3.2. Targeting intestinal epithelia receptors/transporters Despite the promising outcomes obtained from nanocarriers with high stability and long residence time, the bioavailability and therapeutic effect of oral chemotherapy still remain unpleasant [109–111]. Active targeting modification of nanocarriers by conjugating certain ligands or specific substrates to the carrier surface can facilitate intestinal cells–nanocarriers interactions and is an effective strategy to enhance intestinal cellular uptake [112]. The frequently used ligands include antibody, peptide or mimetic peptide sequences, lectins, cholic acids, folic acid, mannose derivatives and vitamins, etc. The recent advances of active targeting oral nanoparticulate drug delivery systems are summarized in Fig. 7. All these ligands of drug-loaded nanocarriers demonstrated higher cellular uptake efficiency by targeting specific receptors or transporters on various intestinal cells (e.g. enterocytes, M cells and immune cells) [129], and held great potential as an effective oral drug delivery method. As shown in Fig. 7, a variety of active targeting DDSs could dramatically increase the oral delivery efficiency of nanoparticles. And most of active targeting ligands belong to non-peptidic category, except for RGD (Arginine–Glycine–Aspartic acid). Rieux A et al. had profoundly discussed the limitations and superiorities of peptidic and nonpeptidic ligands conjugated to the nanoparticles surface, and nonpeptidic ligands show obvious advantages over peptidic ligands in terms of good safety, high stability, easy operability and low cost [129]. Thus, non-peptidic targeting ligands are more suited to develop orally active targeting DDSs. For instance, RGD peptidomimetic (RGDp) sequences have been developed in response to the poor stability of RGD in GI tract [130], and non-peptidic RGDp showed distinct

superiority over peptidic RGD as active ligands of PLGA nanoparticles (NPs) for oral vaccination [128]. 4. Hybrid DDSs: integrated approach to design oral nanoparticulate drug delivery systems Admittedly, all the developed strategies have made striking progresses in promoting the oral absorption of drugs. However, due to the complexity stemming from oral drug delivery process, the efficiency of any single approach is still limited. For this reason, more reasonable and comprehensive DDSs should been developed. Hybrid carriers, an integrated approach to rationally design multicomponent oral nanoparticulate drug delivery based on multistage and multitarget oral absorption process, are designed to develop multifunctional composite structure by integrating functional excipients with bioactive compounds, and have become an emerging trend in response to the limited drug delivery efficiency of any single approach in oral chemotherapy. 4.1. Emerging hybrid DDSs In recent years, several hybrid nanosystems have been developed for facilitating oral drug delivery, and showed great potential as an effective approach to overcome the numerous obstacles hindering oral delivery of anticancer drugs. As summarized in Table. 1, these hybrid DDSs can be roughly summarized as the following four categories: (i) mixed polymeric micelle systems; (ii) PLGA hybrid nanoparticles; (iii) enteric polymers based hybrid DDSs; and (iv) lipid-based hybrid nanosystems. Mixed polymeric micelles, consisting of several polymers or/and surfactants, show distinct advantages in overcoming multiple GI barriers owing to the integration of different functional components. For instance, Pluronic F127-polyethylenimine-folate (PF127-PEI-FA) copolymer was synthesized and applied in constructing mixed micelles with Pluronic P123 for oral delivery of paclitaxel. PF127-PEI-FA/PP123 mixed polymeric micelles showed superior oral absorption efficiency via integrating the triple functions of enhanced bioadhesion of positively charged micelles (PEI), P-gp inhibition by Pluronic copolymers and active targeting by folate [131]. As the stable solid-state polymer nanomaterial, PLGA nanoparticles lend themselves to oral drug delivery for their strong tolerance to harsh environment of GI tract [40,143]. Moreover, PLGA nanoparticles

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Fig. 7. Active targeting modified DDSs enhance oral delivery efficiency of anticancer drugs [113–128].

can be easily modified. For instance, cholic acid functionalized PLGA nanoparticles was constructed by integrating targeting function of cholic acid and P-gp inhibition ability of TPGS into one nanoparticle [134]. In addition, our group designed self-assembled hybrid nanoparticles by utilizing dextran sulfate and PLGA as nanomaterials for improved encapsulation efficiency. Vincristine sulfate was highly encapsulated in this system (encapsulation efficiency up to 93.6%) by forming electrostatic complex with negative polymer of dextran sulfate sodium [135]. Pharmacokinetic results in rats indicated that the oral bioavailability of hybrid nanoparticles was increased by 3.3-fold compared to that of vincristine sulfate solution. And the cellular uptake experiments in MCF-7 and P-glycoprotein over-expressing MCF-7/Adr cells showed that the relative cellular uptake of hybrid nanoparticles was 12.4-fold higher than that of vincristine sulfate solution in MCF-7/ Adr cells, implying that P-glycoprotein-mediated drug efflux was diminished by the introduction of hybrid nanoparticles [135]. pH-sensitive hybrid DDSs based on enteric polymers have been discussed in the previous Section 3.1.2 [52–57], and will not be repeated here. Lipid-based oral hybrid DDSs are constructed by inserting or coating lipid-based formulations (nanoemulsions, microemulsions and liposomes, etc.) with protective layers. Lipid oral hybrid DDSs can be approximately grouped into three categories: lipid colloids stabilized by nanoparticle layers, polyelectrolytes and neutral polymers. Several lipid-based colloids stabilized by assembling nanoparticle coatings have been reviewed by Spomenka Simovic et al., and the stability and

encapsulation of emulsions and liposomes could be significantly improved by silica nanoparticles, gold nanoparticles and Fe3O4 nanoparticles, etc. [144]. For instance, Prestidge CA group developed several silica-lipid hybrid (SLH) systems, lipid-based formulations stabilized by silica nanoparticles, for high-efficiency oral delivery of poorly watersoluble drugs owing to the eliminated influence of food and the reduced enzymatic digestion of lipid colloids [136–138,145–147]. In addition, gelatin and carboxymethyl-chitosan were also utilized to stabilize lipid vesicles. Joshi N et al. developed a hybrid nanoblanket, a hybrid lipo-polymeric system comprised of carboxymethyl chitosan and phosphatidylethanolamine, for oral delivery of paclitaxel [10]. With 1.5-fold increase in oral absorption and 5.5-fold increase in t1/2 comparing to Taxol, these hybrid nanosystems showed distinct superiority that they provided not only a gastric resistant coating layer, but also prevented the reticuloendothelial system (RES) clearance of absorbed nanoparticles owing to the imposed stealth feature as good as PEGylation [10]. 4.2. The ideal hybrid drug-loaded nanocarriers Oral drug absorption from GI tract into blood is a continuous and complex process, and any unconquered obstacle may lead to reduced absorption efficiency. Therefore, the ideal hybrid DDSs should display great superiority in simultaneously integrating several feature advantages into drug-loaded nanocarriers to overcome as many important barriers as possible. As shown in Fig. 8, such hybrid nanosystems should

Table 1 List of several developed hybrid nanosystems for facilitating oral drug delivery. Hybrid DDSs

Typical examples

Drugs loaded

References

Mixed micelle systems

PF127-PEI-FA copolymer & Pluronic P123 Pluronic copolymers & LHR conjugate Sodium deoxycholate & phospholipid TPGS & medium chain triglyceride & Solutol® HS-15 Cholic acid & block copolymer consisting of PLGA and TPGS Dextran sulfate & PLGA Silica-based pH-sensitive nanomatrix system Eudragit® based polymeric nanoparticles Nanoparticles dispersed in enteric microparticles Emulsions stabilized by nanoparticle layers Liposomes stabilized by nanoparticle layers Polyelectrolyte-stabilized liposomes by layer-by-layer assembly Carboxymethyl-chitosan anchored lipid vesicles Gelatin coated hybrid lipid nanoparticles

Paclitaxel Paclitaxel Glycyrrhizin Teniposide Docetaxel Vincristine Glucagon-like peptide-1 Omeprazole; insulin Docetaxel Celecoxib; indomethacin Insulin; Paclitaxel; doxorubicin Paclitaxel Amphotericin B

[131] [11] [132] [133] [134] [135] [53] [54–56] [57] [136–138] [139] [140,141] [10] [142]

PLGA based hybrid nanoparticles Enteric polymers based DDSs Lipid based hybrid DDSs

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Fig. 8. The ideal hybrid drug-loaded nanocarriers for overcoming multiple oral absorption barriers.

be at least equipped with the following capabilities: improved solubility and stability of anticancer drugs, prolonged residence time in GI tract, and enhanced transmembrane transport efficiency of chemotherapy agents and drug-loaded nanocarriers from GI lumen to blood. Based on the above analysis, we look forward to designing more rational and comprehensive DDSs, and combinational application of the developed oral drug delivery technologies, in order to facilitate the intravenousto-oral switch in anticancer chemotherapy. 5. Conclusions Oral nanoparticulate delivery of anticancer agents has shown promising applications in simplifying the therapeutic procedures, prolonging survival time for patients and improving the cancer patient's life quality. And the oral nanoparticulate drug delivery systems show such distinct advantages that they are able to bypass a series of biobarriers during oral absorption. Despite the achieved advances from single strategy developed for oral nanoparticulate drug delivery, it is still very difficult to realize the desired therapeutical efficacy for intravenous-to-oral switch in cancer therapy. The integrated hybrid nanosystems, that is, multiple-target multiple-stage and multiple-component approach, have held tremendous potential to facilitate oral chemotherapy by rational formulation design and system integration. The poorly physicochemical properties associated with the anticancer drugs and the complex oral absorption process can be effectively overcome by applying various functional excipients and pharmaceutical approaches. In summary, designing more reasonable and comprehensive hybrid nanocarriers, as a combination of multiple drug delivery strategies, is bound to be the focal points of oral chemotherapy researches in the near future. Acknowledgments This work was financially supported by the National Nature Science Foundation of China (No. 81173008), the National Basic Research Program of China (973 Program, No. 2009CB930300) and the Program for New Century Excellent Talents in University (No. NCET-12-1015). References [1] http://www.who.int/mediacentre/factsheets/fs297/en/index.htm(Accessed on October 12th, 2013). [2] http://www.who.int/cancer/publicat/WHOCancerBrochure2007.FINALweb. pdf(Accessed on October 12, 2013). [3] S.S. Feng, L. Zhao, J. Tang, Nanomedicine for oral chemotherapy, Nanomedicine (London) 6 (2011) 407–410. [4] V.J. O'Neill, C.J. Twelves, Oral cancer treatment: developments in chemotherapy and beyond, Br. J. Cancer 87 (2002) 933–937. [5] K. Ruddy, E. Mayer, A. Partridge, Patient adherence and persistence with oral anticancer treatment, CA Cancer J. Clin. 59 (2009) 56–66.

101

[6] S.L. Koolen, J.H. Beijnen, J.H. Schellens, Intravenous-to-oral switch in anticancer chemotherapy: a focus on docetaxel and paclitaxel, Clin. Pharmacol. Ther. 87 (2010) 126–129. [7] K. Thanki, R.P. Gangwal, A.T. Sangamwar, S. Jain, Oral delivery of anticancer drugs: challenges and opportunities, J. Control. Release 170 (2013) 15–40. [8] L. Mei, Z. Zhang, L. Zhao, L. Huang, X.L. Yang, J. Tang, S.S. Feng, Pharmaceutical nanotechnology for oral delivery of anticancer drugs, Adv. Drug Deliv. Rev. 65 (2013) 880–890. [9] X.Q. Wang, Q. Zhang, pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs, Eur. J. Pharm. Biopharm. 82 (2012) 219–229. [10] N. Joshi, R. Saha, T. Shanmugam, B. Balakrishnan, P. More, R. Banerjee, Carboxymethylchitosan-tethered lipid vesicles: hybrid nanoblanket for oral delivery of paclitaxel, Biomacromolecules 14 (2013) 2272–2282. [11] C. Li, Y. Zhang, T. Su, L. Feng, Y. Long, Z. Chen, Silica-coated flexible liposomes as a nanohybrid delivery system for enhanced oral bioavailability of curcumin, Int. J. Nanomedicine 7 (2012) 5995–6002. [12] F. Bassan, F. Peter, B. Houbre, M.J. Brennstuhl, M. Costantini, E. Speyer, C. Tarquinio, Adherence to oral antineoplastic agents by cancer patients: definition and literature review, Eur. J. Cancer Care 23 (2013) 22–35. [13] P. Calleja, J. Huarte, M. Agueros, L. Ruiz-Gaton, S. Espuelas, J.M. Irache, Molecular buckets: cyclodextrins for oral cancer therapy, Ther. Deliv. 3 (2012) 43–57. [14] Y. Tian, S. Mao, Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs, Expert Opin. Drug Deliv. 9 (2012) 687–700. [15] V. Foulon, P. Schoffski, P. Wolter, Patient adherence to oral anticancer drugs: an emerging issue in modern oncology, Acta Clin. Belg. 66 (2011) 85–96. [16] C.A. Lipinski, Drug-like properties and the causes of poor solubility and poor permeability, J. Pharmacol. Toxicol. Methods 44 (2000) 235–249. [17] K. Berginc, J. Trontelj, N.S. Basnet, A. Kristl, Physiological barriers to the oral delivery of curcumin, Pharmazie 67 (2012) 518–524. [18] T. Loftsson, Drug permeation through biomembranes: cyclodextrins and the unstirred water layer, Pharmazie 67 (2012) 363–370. [19] J.M. Rabanel, V. Aoun, I. Elkin, M. Mokhtar, P. Hildgen, Drug-loaded nanocarriers: passive targeting and crossing of biological barriers, Curr. Med. Chem. 19 (2012) 3070–3102. [20] C. Schleh, M. Semmler-Behnke, J. Lipka, A. Wenk, S. Hirn, M. Schaffler, G. Schmid, U. Simon, W.G. Kreyling, Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration, Nanotoxicology 6 (2012) 36–46. [21] M.N. Martinezand, G.L. Amidon, A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals, J. Clin. Pharmacol. 42 (2002) 620–643. [22] C.A. Larregieuand, L.Z. Benet, Drug discovery and regulatory considerations for improving in silico and in vitro predictions that use Caco-2 as a surrogate for human intestinal permeability measurements, AAPS J. 15 (2013) 483–497. [23] G. Szakacs, A. Varadi, C. Ozvegy-Laczka, B. Sarkadi, The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox), Drug Discov. Today 13 (2008) 379–393. [24] T. Murakami, M. Takano, Intestinal efflux transporters and drug absorption, Expert Opin.Drug Metabol.Toxicol. 4 (2008) 923–939. [25] K. Sugano, Fraction of a dose absorbed estimation for structurally diverse low solubility compounds, Int. J. Pharm. 405 (2011) 79–89. [26] S. Kumar, D. Bhargava, A. Thakkar, S. Arora, Drug carrier systems for solubility enhancement of BCS class II drugs: a critical review, Crit. Rev. Ther. Drug Carrier Syst. 30 (2013) 217–256. [27] M. Linn, E.M. Collnot, D. Djuric, K. Hempel, E. Fabian, K. Kolter, C.M. Lehr, Soluplus(R) as an effective absorption enhancer of poorly soluble drugs in vitro and in vivo, Eur. J. Pharm. Sci. 45 (2012) 336–343. [28] E. Gundogdu, I.G. Alvarez, E. Karasulu, Improvement of effect of water-in-oil microemulsion as an oral delivery system for fexofenadine: in vitro and in vivo studies, Int. J. Nanomedicine 6 (2011) 1631–1640. [29] D.D. Deshmukh, R. Nagilla, W.R. Ravis, G.V. Betageri, Effect of dodecylmaltoside (DDM) on uptake of BCS III compounds, tiludronate and cromolyn, in Caco-2 cells and rat intestine model, Drug Deliv. 17 (2010) 145–151. [30] J.R. Turner, Intestinal mucosal barrier function in health and disease, Nat. Rev. Immunol. 9 (2009) 799–809. [31] M.M. Doherty, W.N. Charman, The mucosa of the small intestine: how clinically relevant as an organ of drug metabolism? Clin. Pharmacokinet. 41 (2002) 235–253. [32] A. Ermund, A. Schutte, M.E. Johansson, J.K. Gustafsson, G.C. Hansson, Studies of mucus in mouse stomach, small intestine, and colon. I. Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer's patches, Am. J. Physiol. Gastrointest. Liver Physiol. 305 (2013) G341–G347. [33] M.E. Johansson, H. Sjovall, G.C. Hansson, The gastrointestinal mucus system in health and disease, Nat. Rev. Gastroenterol. Hepatol. 10 (2013) 352–361. [34] M.E. Johansson, D. Ambort, T. Pelaseyed, A. Schutte, J.K. Gustafsson, A. Ermund, D.B. Subramani, J.M. Holmen-Larsson, K.A. Thomsson, J.H. Bergstrom, S. van der Post, A.M. Rodriguez-Pineiro, H. Sjovall, M. Backstrom, G.C. Hansson, Composition and functional role of the mucus layers in the intestine, Cell. Mol. Life Sci. 68 (2011) 3635–3641. [35] Y.S. Kim, S.B. Ho, Intestinal goblet cells and mucins in health and disease: recent insights and progress, Curr.Gastroenterol.Rep. 12 (2010) 319–330. [36] B. Agoram, W.S. Woltosz, M.B. Bolger, Predicting the impact of physiological and biochemical processes on oral drug bioavailability, Adv. Drug. Deliv. Rev.Suppl. 1 (2001) S41–S67. [37] A.E. van Herwaarden, R.A. van Waterschoot, A.H. Schinkel, How important is intestinal cytochrome P450 3A metabolism? Trends Pharmacol. Sci. 30 (2009) 223–227.

102

C. Luo et al. / Journal of Controlled Release 176 (2014) 94–103

[38] S.S. Suri, H. Fenniri, B. Singh, Nanotechnology-based drug delivery systems, J. Occup. Med. Toxicol 2 (2007) 16. [39] S. Mazzaferro, K. Bouchemal, G. Ponchel, Oral delivery of anticancer drugs III: formulation using drug delivery systems, Drug Discov. Today 18 (2013) 99–104. [40] G. Kumar, N. Shafiq, S. Malhotra, Drug-loaded PLGA nanoparticles for oral administration: fundamental issues and challenges ahead, Crit. Rev. Ther. Drug Carrier Syst. 29 (2012) 149–182. [41] Z. Yan, G.W. Caldwell, Metabolism profiling, and cytochrome P450 inhibition & induction in drug discovery, Curr. Top. Med. Chem. 1 (2001) 403–425. [42] Q.Y. Zhang, D. Dunbar, A. Ostrowska, S. Zeisloft, J. Yang, L.S. Kaminsky, Characterization of human small intestinal cytochromes P-450, Drug Metab. Dispos. 27 (1999) 804–809. [43] M.F. Paine, H.L. Hart, S.S. Ludington, R.L. Haining, A.E. Rettie, D.C. Zeldin, The human intestinal cytochrome P450 “pie”, Drug Metab. Dispos. 34 (2006) 880–886. [44] D.F. Lewis, 57 varieties: the human cytochromes P450, Pharmacogenomics 5 (2004) 305–318. [45] P. Martin, M. Giardiello, T.O. McDonald, S.P. Rannard, A. Owen, Mediation of in vitro cytochrome P450 activity by common pharmaceutical excipients, Mol. Pharm. 10 (2013) 2739–2748. [46] L.A. Felton, S.C. Porter, An update on pharmaceutical film coating for drug delivery, expert opin. drug deliv. 10(2013) 421–435. S. Thakral, N.K. Thakral, D.K. Majumdar, Eudragit: a technology evaluation, Expert Opin. Drug Deliv. 10 (2013) 131–149. [47] S. Thakral, N.K. Thakral, D.K. Majumdar, Eudragit: a technology evaluation, Expert Opin. Drug Deliv. 10 (2013) 131–149. [48] E. Mehuys, C. Vervaet, Oral controlled release dosage forms, J. Pharm. Belg. (2010) 34–38. [49] H.M. Mansour, M. Sohn, A. Al-Ghananeem, P.P. Deluca, Materials for pharmaceutical dosage forms: molecular pharmaceutics and controlled release drug delivery aspects, Int. J. Mol. Sci. 11 (2010) 3298–3322. [50] D. Gallardo, B. Skalsky, P. Kleinebudde, Controlled release solid dosage forms using combinations of (meth)acrylate copolymers, Pharm. Dev. Technol. 13 (2008) 413–423. [51] M.C. Chen, K. Sonaje, K.J. Chen, H.W. Sung, A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery, Biomaterials 32 (2011) 9826–9838. [52] Z. Jia, P. Lin, Y. Xiang, X. Wang, J. Wang, X. Zhang, Q. Zhang, A novel nanomatrix system consisted of colloidal silica and pH-sensitive polymethylacrylate improves the oral bioavailability of fenofibrate, Eur. J. Pharm. Biopharm. 79 (2011) 126–134. [53] W. Qu, Y. Li, L. Hovgaard, S. Li, W. Dai, J. Wang, X. Zhang, Q. Zhang, A silica-based pH-sensitive nanomatrix system improves the oral absorption and efficacy of incretin hormone glucagon-like peptide-1, Int. J. Nanomedicine 7 (2012) 4983–4994. [54] S. Hao, B. Wang, Y. Wang, L. Zhu, T. Guo, Preparation of Eudragit L 100–55 enteric nanoparticles by a novel emulsion diffusion method, Colloids Surf. B: Biointerfaces 108 (2013) 127–133. [55] M. Jelvehgari, P. Zakeri-Milani, M.R. Siahi-Shadbad, B.D. Loveymi, A. Nokhodchi, Z. Azari, H. Valizadeh, Development of pH-sensitive insulin nanoparticles using Eudragit L100-55 and chitosan with different molecular weights, AAPS PharmSciTech. 11 (2010) 1237–1242. [56] Y. Zhang, X. Wu, L. Meng, R. Ai, N. Qi, H. He, H. Xu, X. Tang, Thiolated Eudragit nanoparticles for oral insulin delivery: preparation, characterization and in vivo evaluation, Int. J. Pharm. 436 (2012) 341–350. [57] T. Nassar, S. Attili-Qadri, O. Harush-Frenkel, S. Farber, S. Lecht, P. Lazarovici, S. Benita, High plasma levels and effective lymphatic uptake of docetaxel in an orally available nanotransporter formulation, Cancer Res. 71 (2011) 3018–3028. [58] L.M. Ensign, R. Cone, J. Hanes, Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers, Adv. Drug Deliv. Rev. 64 (2012) 557–570. [59] J. Reineke, D.Y. Cho, Y.L. Dingle, P. Cheifetz, B. Laulicht, D. Lavin, S. Furtado, E. Mathiowitz, Can bioadhesive nanoparticles allow for more effective particle uptake from the small intestine? J. Control. Release 170 (2013) 477–484. [60] K. Yoncheva, S. Gomez, M.A. Campanero, C. Gamazo, J.M. Irache, Bioadhesive properties of pegylated nanoparticles, Expert Opin. Drug Deliv. 2 (2005) 205–218. [61] Z. Zhu, Y. Zhai, N. Zhang, D. Leng, P. Ding, The development of polycarbophil as a bioadhesive material in pharmacy, Asian J. Pharm. Sci. 8 (2013) 218–227. [62] M.C. Chen, F.L. Mi, Z.X. Liao, C.W. Hsiao, K. Sonaje, M.F. Chung, L.W. Hsu, H.W. Sung, Recent advances in chitosan-based nanoparticles for oral delivery of macromolecules, Adv. Drug Deliv. Rev. 65 (2013) 865–879. [63] S.K. Maurya, K. Pathak, V. Bali, Therapeutic potential of mucoadhesive drug delivery systems—an updated patent review, Recent Pat. Drug Deliv. Formul. 4 (2010) 256–265. [64] L. Serra, J. Domenech, N.A. Peppas, Engineering design and molecular dynamics of mucoadhesive drug delivery systems as targeting agents, Eur. J. Pharm. Biopharm. 71 (2009) 519–528. [65] M. Werle, A. Bernkop-Schnurch, Thiolated chitosans: useful excipients for oral drug delivery, J. Pharm. Pharmacol. 60 (2008) 273–281. [66] H. Takeuchi, H. Yamamoto, Y. Kawashima, Mucoadhesive nanoparticulate systems for peptide drug delivery, Adv. Drug Deliv. Rev. 47 (2001) 39–54. [67] G. Ponchel, J. Irache, Specific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract, Adv. Drug Deliv. Rev 34 (1998) 191–219. [68] X. Zhang, M. Sun, A. Zheng, D. Cao, Y. Bi, J. Sun, Preparation and characterization of insulin-loaded bioadhesive PLGA nanoparticles for oral administration, Eur. J. Pharm. Sci. 45 (2012) 632–638. [69] L. Jiang, X. Li, L. Liu, Q. Zhang, Thiolated chitosan-modified PLA-PCL-TPGS nanoparticles for oral chemotherapy of lung cancer, Nanoscale Res. Lett. 8 (2013) 66.

[70] H. Lian, T. Zhang, J. Sun, X. Liu, G. Ren, L. Kou, Y. Zhang, X. Han, W. Ding, X. Ai, C. Wu, L. Li, Y. Wang, Y. Sun, S. Wang, Z. He, Enhanced oral delivery of paclitaxel using acetylcysteine functionalized chitosan-vitamin E succinate nanomicelles based on a mucus bioadhesion and penetration mechanism, Mol. Pharm. 10 (2013) 3447–3458. [71] Y. Zambito, F. Felice, A. Fabiano, R. Di Stefano, G. Di Colo, Mucoadhesive nanoparticles made of thiolated quaternary chitosan crosslinked with hyaluronan, Carbohydr. Polym. 92 (2013) 33–39. [72] L. Yin, J. Ding, C. He, L. Cui, C. Tang, C. Yin, Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery, Biomaterials 30 (2009) 5691–5700. [73] L.M. Ensign, C. Schneider, J.S. Suk, R. Cone, J. Hanes, Mucus penetrating nanoparticles: biophysical tool and method of drug and gene delivery, Adv. Mater. 24 (2012) 3887–3894. [74] O. Mert, S.K. Lai, L. Ensign, M. Yang, Y.Y. Wang, J. Wood, J. Hanes, A poly(ethylene glycol)-based surfactant for formulation of drug-loaded mucus penetrating particles, J. Control. Release 157 (2012) 455–460. [75] S.K. Lai, Y.Y. Wang, J. Hanes, Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues, Adv. Drug Deliv. Rev. 61 (2009) 158–171. [76] Z. Binkhathlan, A. Lavasanifar, P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer: current status and future perspectives, Curr. Cancer Drug Targets 13 (2013) 326–346. [77] N. Akhtar, A. Ahad, R.K. Khar, M. Jaggi, M. Aqil, Z. Iqbal, F.J. Ahmad, S. Talegaonkar, The emerging role of P-glycoprotein inhibitors in drug delivery: a patent review, Expert Opin. Ther. Pat. 21 (2011) 561–576. [78] R.A. Darby, R. Callaghan, R.M. McMahon, P-glycoprotein inhibition: the past, the present and the future, Curr. Drug Metab. 12 (2011) 722–731. [79] M. Abbasi, A. Lavasanifar, H. Uludag, Recent attempts at RNAi-mediated P-glycoprotein downregulation for reversal of multidrug resistance in cancer, Med. Res. Rev. 33 (2013) 33–53. [80] C. Pauli-Magnus, D.L. Kroetz, Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1), Pharm. Res. 21 (2004) 904–913. [81] M.V. Varma, Y. Ashokraj, C.S. Dey, R. Panchagnula, P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement, Pharmacol. Res. 48 (2003) 347–359. [82] J.A. Shabbits, R. Krishna, L.D. Mayer, Molecular and pharmacological strategies to overcome multidrug resistance, Expert. Rev. Anticancer. Ther. 1 (2001) 585–594. [83] P. Breedveld, J.H. Beijnen, J.H. Schellens, Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs, Trends Pharmacol. Sci. 27 (2006) 17–24. [84] X.R. Song, Y. Zheng, G. He, L. Yang, Y.F. Luo, Z.Y. He, S.Z. Li, J.M. Li, S. Yu, X. Luo, S.X. Hou, Y.Q. Wei, Development of PLGA nanoparticles simultaneously loaded with vincristine and verapamil for treatment of hepatocellular carcinoma, J. Pharm. Sci. 99 (2010) 4874–4879. [85] M.M. Malingre, D.J. Richel, J.H. Beijnen, H. Rosing, F.J. Koopman, W.W. Ten Bokkel Huinink, M.E. Schot, J.H. Schellens, Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel, J. Clin. Oncol. 19 (2001) 1160–1166. [86] J.M. Meerum Terwogt, M.M. Malingre, J.H. Beijnen, W.W. ten Bokkel Huinink, H. Rosing, F.J. Koopman, O. van Tellingen, M. Swart, J.H. Schellens, Coadministration of oral cyclosporin A enables oral therapy with paclitaxel, Clin. Cancer Res. 5 (1999) 3379–3384. [87] F. Loor, Valspodar: current status and perspectives, Expert Opin. Investig. Drugs 8 (1999) 807–835. [88] Y.J. Cha, H. Lee, N. Gu, T.E. Kim, K.S. Lim, S.H. Yoon, J.Y. Chung, I.J. Jang, S.G. Shin, K.S. Yu, J.Y. Cho, Sustained increase in the oral bioavailability of loperamide after a single oral dose of HM30181, a P-glycoprotein inhibitor, in healthy male participants, Basic Clin. Pharmacol. Toxicol. 113 (2013) 419–424. [89] F. Hyafil, C. Vergely, P.Du. Vignaud, T. Grand-Perret, In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative, Cancer Res. 53 (1993) 4595–4602. [90] A.H. Dantzig, R.L. Shepard, J. Cao, K.L. Law, W.J. Ehlhardt, T.M. Baughman, T.F. Bumol, J.J. Starling, Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979, Cancer Res. 56 (1996) 4171–4179. [91] P. Mistry, A.J. Stewart, W. Dangerfield, S. Okiji, C. Liddle, D. Bootle, J.A. Plumb, D. Templeton, P. Charlton, In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576, Cancer Res. 61 (2001) 749–758. [92] T. Yamagata, H. Kusuhara, M. Morishita, K. Takayama, H. Benameur, Y. Sugiyama, Effect of excipients on breast cancer resistance protein substrate uptake activity, J. Control. Release 124 (2007) 1–5. [93] Y.L. Lo, Relationships between the hydrophilic–lipophilic balance values of pharmaceutical excipients and their multidrug resistance modulating effect in Caco-2 cells and rat intestines, J. Control. Release 90 (2003) 37–48. [94] B.D. Rege, J.P. Kao, J.E. Polli, Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers, Eur. J. Pharm. Sci. 16 (2002) 237–246. [95] M. Agueros, V. Zabaleta, S. Espuelas, M.A. Campanero, J.M. Irache, Increased oral bioavailability of paclitaxel by its encapsulation through complex formation with cyclodextrins in poly(anhydride) nanoparticles, J. Control. Release 145 (2010) 2–8. [96] F.Z. Dahmani, H. Yang, J. Zhou, J. Yao, T. Zhang, Q. Zhang, Enhanced oral bioavailability of paclitaxel in pluronic/LHR mixed polymeric micelles: preparation, in vitro and in vivo evaluation, Eur. J. Pharm. Sci. 47 (2012) 179–189. [97] L. Ma, Y. Wei, Y. Zhou, X. Ma, X. Wu, Effects of Pluronic F68 and Labrasol on the intestinal absorption and pharmacokinetics of rifampicin in rats, Arch. Pharm. Res. 34 (2011) 1939–1943.

C. Luo et al. / Journal of Controlled Release 176 (2014) 94–103 [98] Y. Guan, J. Huang, L. Zuo, J. Xu, L. Si, J. Qiu, G. Li, Effect of Pluronic P123 and F127 block copolymer on P-glycoprotein transport and CYP3A metabolism, Arch. Pharm. Res. 34 (2011) 1719–1728. [99] Y. Guo, J. Luo, S. Tan, B.O. Otieno, Z. Zhang, The applications of vitamin E TPGS in drug delivery, Eur. J. Pharm. Sci. 49 (2013) 175–186. [100] Z. Zhang, S. Tan, S.S. Feng, Vitamin E TPGS as a molecular biomaterial for drug delivery, Biomaterials 33 (2012) 4889–4906. [101] L. Zhao, S.S. Feng, Enhanced oral bioavailability of paclitaxel formulated in vitamin E-TPGS emulsified nanoparticles of biodegradable polymers: in vitro and in vivo studies, J. Pharm. Sci. 99 (2010) 3552–3560. [102] S.S. Feng, L. Mei, P. Anitha, C.W. Gan, W. Zhou, Poly(lactide)-vitamin E derivative/ montmorillonite nanoparticle formulations for the oral delivery of docetaxel, Biomaterials 30 (2009) 3297–3306. [103] Z. Zhang, S.S. Feng, Nanoparticles of poly(lactide)/vitamin E TPGS copolymer for cancer chemotherapy: synthesis, formulation, characterization and in vitro drug release, Biomaterials 27 (2006) 262–270. [104] K.Y. Win, S.S. Feng, In vitro and in vivo studies on vitamin E TPGS-emulsified poly(D, L-lactic–co–glycolic acid) nanoparticles for paclitaxel formulation, Biomaterials 27 (2006) 2285–2291. [105] L. Mu, S.S. Feng, A novel controlled release formulation for the anticancer drug paclitaxel (Taxol): PLGA nanoparticles containing vitamin E TPGS, J. Control. Release 86 (2003) 33–48. [106] L. Mu, S.S. Feng, Vitamin E TPGS used as emulsifier in the solvent evaporation/ extraction technique for fabrication of polymeric nanospheres for controlled release of paclitaxel (Taxol), J. Control. Release 80 (2002) 129–144. [107] M.V. Varma, R. Panchagnula, Enhanced oral paclitaxel absorption with vitamin E-TPGS: effect on solubility and permeability in vitro, in situ and in vivo, Eur. J. Pharm. Sci. 25 (2005) 445–453. [108] J. Wang, J. Sun, Q. Chen, Y. Gao, L. Li, H. Li, D. Leng, Y. Wang, Y. Sun, Y. Jing, S. Wang, Z. He, Star-shape copolymer of lysine-linked di-tocopherol polyethylene glycol 2000 succinate for doxorubicin delivery with reversal of multidrug resistance, Biomaterials 33 (2012) 6877–6888. [109] A.T. Florence, “Targeting” nanoparticles: the constraints of physical laws and physical barriers, J. Control. Release 164 (2012) 115–124. [110] L. Plapied, N. Duhem, A. des Rieux, V. Préat, Fate of polymeric nanocarriers for oral drug delivery, Curr. Opin. Colloid Interface Sci. 16 (2011) 228–237. [111] A.T. Florence, Nanoparticle uptake by the oral route: fulfilling its potential? Drug Discov. Today Technol. 2 (1) (2005) 75–81. [112] B. Devriendt, B.G. De Geest, B.M. Goddeeris, E. Cox, Crossing the barrier: targeting epithelial receptors for enhanced oral vaccine delivery, J. Control. Release 160 (2012) 431–439. [113] M. Garinot, V. Fievez, V. Pourcelle, F. Stoffelbach, A. des Rieux, L. Plapied, I. Theate, H. Freichels, C. Jerome, J. Marchand-Brynaert, Y.J. Schneider, V. Preat, PEGylated PLGA-based nanoparticles targeting M cells for oral vaccination, J. Control. Release 120 (2007) 195–204. [114] Y. Liu, P. Wang, C. Sun, N. Feng, W. Zhou, Y. Yang, R. Tan, Z. Chen, S. Wu, J. Zhao, Wheat germ agglutinin-grafted lipid nanoparticles: preparation and in vitro evaluation of the association with Caco-2 monolayers, Int. J. Pharm. 397 (2010) 155–163. [115] Y. Yin, D. Chen, M. Qiao, X. Wei, H. Hu, Lectin-conjugated PLGA nanoparticles loaded with thymopentin: ex vivo bioadhesion and in vivo biodistribution, J. Control. Release 123 (2007) 27–38. [116] N. Mishra, S. Tiwari, B. Vaidya, G.P. Agrawal, S.P. Vyas, Lectin anchored PLGA nanoparticles for oral mucosal immunization against hepatitis B, J. Drug Target. 19 (2011) 67–78. [117] P.N. Gupta, S.P. Vyas, Investigation of lectinized liposomes as M-cell targeted carrier-adjuvant for mucosal immunization, Colloids Surf. B: Biointerfaces 82 (2011) 118–125. [118] F. Roth-Walter, B. Bohle, I. Scholl, E. Untersmayr, O. Scheiner, G. Boltz-Nitulescu, F. Gabor, D.J. Brayden, E. Jensen-Jarolim, Targeting antigens to murine and human M-cells with Aleuria aurantia lectin-functionalized microparticles, Immunol. Lett. 100 (2005) 182–188. [119] E. Roger, S. Kalscheuer, A. Kirtane, B.R. Guru, A.E. Grill, J. Whittum-Hudson, J. Panyam, Folic acid functionalized nanoparticles for enhanced oral drug delivery, Mol. Pharm. 9 (2012) 2103–2110. [120] S. Jain, V.V. Rathi, A.K. Jain, M. Das, C. Godugu, Folate-decorated PLGA nanoparticles as a rationally designed vehicle for the oral delivery of insulin, Nanomedicine (London) 7 (2012) 1311–1337. [121] J.M. Irache, H.H. Salman, C. Gamazo, S. Espuelas, Mannose-targeted systems for the delivery of therapeutics, Expert Opin. Drug Deliv. 5 (2008) 703–724. [122] Z. Khatun, M. Nurunnabi, G.R. Reeck, K.J. Cho, Y.K. Lee, Oral delivery of taurocholic acid linked heparin-docetaxel conjugates for cancer therapy, J. Control. Release 170 (2013) 74–82.

103

[123] Z. Khatun, M. Nurunnabi, K.J. Cho, Y.K. Lee, Imaging of the GI tract by QDs loaded heparin-deoxycholic acid (DOCA) nanoparticles, Carbohydr. Polym. 90 (2012) 1461–1468. [124] S.K. Kim, J. Huh, S.Y. Kim, Y. Byun, D.Y. Lee, H.T. Moon, Physicochemical conjugation with deoxycholic acid and dimethylsulfoxide for heparin oral delivery, Bioconjug. Chem. 22 (2011) 1451–1458. [125] H.H. Salman, C. Gamazo, P.C. de Smidt, G. Russell-Jones, J.M. Irache, Evaluation of bioadhesive capacity and immunoadjuvant properties of vitamin B(12)-Gantrez nanoparticles, Pharm. Res. 25 (2008) 2859–2868. [126] M.F. Francis, M. Cristea, F.M. Winnik, Exploiting the vitamin B12 pathway to enhance oral drug delivery via polymeric micelles, Biomacromolecules 6 (2005) 2462–2467. [127] H.H. Salman, C. Gamazo, M. Agueros, J.M. Irache, Bioadhesive capacity and immunoadjuvant properties of thiamine-coated nanoparticles, Vaccine 25 (2007) 8123–8132. [128] V. Fievez, L. Plapied, A. des Rieux, V. Pourcelle, H. Freichels, V. Wascotte, M.L. Vanderhaeghen, C. Jerome, A. Vanderplasschen, J. Marchand-Brynaert, Y.J. Schneider, V. Preat, Targeting nanoparticles to M cells with non-peptidic ligands for oral vaccination, Eur. J. Pharm. Biopharm. 73 (2009) 16–24. [129] A. des Rieux, V. Pourcelle, P.D. Cani, J. Marchand-Brynaert, V. Preat, Targeted nanoparticles with novel non-peptidic ligands for oral delivery, Adv. Drug Deliv. Rev. 65 (2013) 833–844. [130] D. Heckmann, A. Meyer, B. Laufer, G. Zahn, R. Stragies, H. Kessler, Rational design of highly active and selective ligands for the alpha5beta1 integrin receptor, Chembiochem 9 (2008) 1397–1407. [131] Y. Li, Y. Bi, Y. Xi, L. Li, Enhancement on oral absorption of paclitaxel by multifunctional pluronic micelles, J. Drug Target. 21 (2013) 188–199. [132] S. Jin, S. Fu, J. Han, Q. Lv, Y. Lu, J. Qi, W. Wu, H. Yuan, Improvement of oral bioavailability of glycyrrhizin by sodium deoxycholate/phospholipid-mixed nanomicelles, J. Drug Target. 20 (2012) 615–622. [133] Z. Zhang, L. Ma, S. Jiang, Z. Liu, J. Huang, L. Chen, H. Yu, Y. Li, A self-assembled nanocarrier loading teniposide improves the oral delivery and drug concentration in tumor, J. Control. Release 166 (2013) 30–37. [134] X. Zeng, W. Tao, L. Mei, L. Huang, C. Tan, S.S. Feng, Cholic acid-functionalized nanoparticles of star-shaped PLGA-vitamin E TPGS copolymer for docetaxel delivery to cervical cancer, Biomaterials 34 (2013) 6058–6067. [135] G. Ling, P. Zhang, W. Zhang, J. Sun, X. Meng, Y. Qin, Y. Deng, Z. He, Development of novel self-assembled DS-PLGA hybrid nanoparticles for improving oral bioavailability of vincristine sulfate by P-gp inhibition, J. Control. Release 148 (2010) 241–248. [136] T.H. Nguyen, A. Tan, L. Santos, D. Ngo, G.A. Edwards, C.J. Porter, C.A. Prestidge, B.J. Boyd, Silica-lipid hybrid (SLH) formulations enhance the oral bioavailability and efficacy of celecoxib: an in vivo evaluation, J. Control. Release 167 (2013) 85–91. [137] A. Tan, A.K. Davey, C.A. Prestidge, Silica-lipid hybrid (SLH) versus non-lipid formulations for optimising the dose-dependent oral absorption of celecoxib, Pharm. Res. 28 (2011) 2273–2287. [138] S. Simovic, H. Hui, Y. Song, A.K. Davey, T. Rades, C.A. Prestidge, An oral delivery system for indomethicin engineered from cationic lipid emulsions and silica nanoparticles, J. Control. Release 143 (2010) 367–373. [139] V.J. Mohanraj, T.J. Barnes, C.A. Prestidge, Silica nanoparticle coated liposomes: a new type of hybrid nanocapsule for proteins, Int. J. Pharm. 392 (2010) 285–293. [140] S. Jain, D. Kumar, N.K. Swarnakar, K. Thanki, Polyelectrolyte stabilized multilayered liposomes for oral delivery of paclitaxel, Biomaterials 33 (2012) 6758–6768. [141] S. Jain, S.R. Patil, N.K. Swarnakar, A.K. Agrawal, Oral delivery of doxorubicin using novel polyelectrolyte-stabilized liposomes (layersomes), Mol. Pharm. 9 (2012) 2626–2635. [142] S. Jain, P.U. Valvi, N.K. Swarnakar, K. Thanki, Gelatin coated hybrid lipid nanoparticles for oral delivery of amphotericin B, Mol. Pharm. 9 (2012) 2542–2553. [143] A.K. Jain, M. Das, N.K. Swarnakar, S. Jain, Engineered PLGA nanoparticles: an emerging delivery tool in cancer therapeutics, Crit. Rev. Ther. Drug Carrier Syst. 28 (2011) 1–45. [144] S. Simovic, T.J. Barnes, A. Tan, C.A. Prestidge, Assembling nanoparticle coatings to improve the drug delivery performance of lipid based colloids, Nanoscale 4 (2012) 1220–1230. [145] A. Tan, A. Martin, T.H. Nguyen, B.J. Boyd, C.A. Prestidge, Hybrid nanomaterials that mimic the food effect: controlling enzymatic digestion for enhanced oral drug absorption, Angew. Chem. Int. Ed. Engl. 51 (2012) 5475–5479. [146] A. Tan, S. Simovic, A.K. Davey, T. Rades, B.J. Boyd, C.A. Prestidge, Silica nanoparticles to control the lipase-mediated digestion of lipid-based oral delivery systems, Mol. Pharm. 7 (2010) 522–532. [147] A. Tan, S. Simovic, A.K. Davey, T. Rades, C.A. Prestidge, Silica-lipid hybrid (SLH) microcapsules: a novel oral delivery system for poorly soluble drugs, J. Control. Release 134 (2009) 62–70.

Emerging integrated nanohybrid drug delivery systems to facilitate the intravenous-to-oral switch in cancer chemotherapy.

Nanohybrid drug delivery systems have presented lots of characteristic advantages as an efficient strategy to facilitate oral drug delivery. Nonethele...
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