Send Orders for Reprints to reprints@benthamscience.ae Current Pharmaceutical Design, 2016, 22, 000-000 Nanoparticulate Drug Delivery to Colorectal Cancer: Formulation Strategies and Surface Engineering Thao Truong-Dinh Tran1,3, Phuong Ha-Lien Tran2, Yichao Wang4, Puwang Li1 and Lingxue Kong1,* Institute for Frontier Materials, Deakin University, Waurn Ponds, Victoria 3216, Australia; 2School of Medicine, Deakin University, Waurn Ponds, Victoria 3216, Australia; 3Pharmaceutical Engineering Laboratory, Biomedical Engineering Department, International University, Vietnam National University – Ho Chi Minh City, Vietnam; School of Electrical and Computer Engineering, RMIT University, Melbourne, Australia Abstract: The evolution of polymer-based nanoparticle as a drug delivery carrier has greatly contributed to the development of advanced nano and micro-medicine in the past few decades The polymer-based nanoparticles of biodegradable and biocompatible polymers such as poly (lactide-co-glycolide) and chitosan which have been approved by Food & Drug Administration and/or European Medicine Agency can particularly facilitate the maintaining of specific properties for a real transition from laboratory to the clinical oral and parental administration This review presents an overview of the strategies of preparing polymeric nanoparticles and using them for targeting colorectal cancer Theranostics and surface engineering aspects of nanoparticle design in colonic cancer delivery are also highlighted Lingxue Kong Keywords: Nanoparticles, poly (lactide-co-glycolide), chitosan, colorectal cancer, theranostic, surface engineering INTRODUCTION Colorectal cancer is one of the major universal public health problems and causes of death worldwide [1, 2] A major draw-back of conventional formulations for colorectal cancer is their side effects and toxicity caused by the distribution of drug around the body due to its design in systematic delivery therapeutics [3, 4] In other words, these approaches to colorectal cancer treatment are nonspecific One of other major limitations of some promising anticancer drugs such as docetaxel and paclitaxel is the insolubility property in water and therefore, leading to the poor absorption and bioavailability of these drugs [5, 6] Targeted drug delivery, therefore, is one of indispensable strategies against this type of cancers by state-of-the-art techniques of controlled solid dosage forms or micro/nanoparticles to improve solubility and bioavailability, and enhance drug distribution to the target organ The delivery would also improve the stability of model drugs while also reducing systemic side-effects [7-9] Potential applications of nanoparticles have been demonstrated by 40 nanomedicine products that have been approved for clinical use in the past two decades [10] Polymer-based nanoparticles have received particular attentions in design and fabrication of targeted drug delivery systems recently Overall, it is evident that polymer-based nanoparticles could contribute to a promising tumor-targeted drug delivery system with great potential in colorectal cancer therapy The shortcoming of these potential approaches, however, should also be evaluated carefully Information on the development of current strategies for targeted colorectal cancer summarized in this review would give the readers a general but deep understanding of practical approaches and effective carriers that can be applied in targeted colorectal cancer delivery (Fig 1) Most of colorectal cancer survivals depend on how early the stage at diagnosis is [11] Overcoming the lack of sensitive property of current devices and the nature of small colorectal neoplasia of the disease which hinder a successful treatment, a tool for observation and diagnosis of precancerous lesions would be a great *Address correspondence to this author at Institute for Frontier Materials, Deakin University, Waurn Ponds, Victoria, 3217, Australia; Tel/Fax: +61352272087, ++61352271002; E-mails: lingxue.kong@deakin.edu.au 1381-6128/16 $58.00+.00 contribution to the field Here the imaging agents encapsulated in polymer-based nanoparticles are the subjects of the discussion Furthermore, efficient delivery of the nanoparticles with surface engineering are also outlined CURRENT POLYMER STRATEGIES DEVELOPED FOR TARGETED COLORECTAL CANCER 2.1 Poly (Lactide-co-Glycolide) (PLGA)-Based Approaches Since its discovery in the 1970, PLGA has become one of the most common and feasible polymers developed for controlled drug delivery among polymeric nanoparticles [12-16] It has been approved by the U.S Food and Drug Administration as a material for use in medical applications and since then a number of drugs have been investigated to incorporate in PLGA encompassing laboratory products and commercial products with FDA approval [17-27] Typical structure of PLGA has been known as the hydrophobic synthetic and linear copolymer constructed by two different types of monomer which are glycolic acid and lactic acid [28-31] The molar ratio of these monomers and molecular weight defines the commercial form of PLGA and its physicochemical properties (Fig 2) [32-34] The crystal degree of PLGA depends on molecular weight and this molar ratio (higher 70% glycolic indicates amorphous state in nature) [35] The increase of the glycolic content in the ratio can result in less hydrophobic character and lower required degradation time of PLGA [36, 37] In the presence of water, these monomers will be released and then subjected to metabolism via the Krebs cycle easily [38], resulting in a minimal systemic toxicity associated with biocompatible and biodegradable properties of PLGA for controlled drug delivery [39-41] Therefore, PLGA has attracted many attentions and commonly used as a potential carrier for the encapsulation of anti-cancer drugs In addition, other specific characteristics of PLGA such as drug degradation protection, sustained drug release, possibility of surface engineering to modify surface properties and targeted drug delivery make it become more promising in further applications [8, 12] Despite the widespread application of PLGA and different methods that have been used in designing nanoparticles for drug delivery, there have been few reports describing PLGA-based nanoparticles for targeted drug delivery to colorectal cancer © 2016 Bentham Science Publishers Current Pharmaceutical Design, 2016, Vol 22, No 00 Tran et al Fig (1) Current strategies of polymer-based nanoparticles for targeted colorectal cancer O O HO H O n m O Fig (2) Typical structure of a PLGA n= number of units of lactic acid; m= number of units of glycolic acid For example, PLGA 50:50 identifies 50% lactic acid and 50% glycolic acid 2.1.1 Emulsion Solvent Evaporation PLGA-based nanoparticles have received tremendous attention as a powerful drug delivery system for cancer-related diseases Among various fabrication methods, the emulsion solvent evaporation has been commonly reported as a potential technique for targeted colorectal cancer In the method developed by Wang et al., [43], dichloromethane was used as organic solvent to dissolve PLGA and paclitaxel – a poorly water-soluble drug The O/W (oilin-water) emulsion was formed by adding organic phase to aqueous phase containing polyvinyl alcohol (PVA) Meanwhile, the particle size was controlled by probe sonication This kind of technique is quite simple and only allows the encapsulation of hydrophobic drugs Alternatively, the double emulsion solvent evaporation method was developed to encapsulate hydrophilic drugs instead of hydrophobic drugs In previous research of targeted colorectal cancer of 5-fluorouracil [42, 44, 45], while drug was dissolved in water to obtain an inner aqueous phase, PLGA was dissolved in an organic solvent The aqueous drug solution (W) was emulsified in the organic phase with a probe sonicator to form W/O (water-in-oil) emulsion which was then emulsified in PVA solution, resulting in W/O/W emulsion Similarly, Sureban et al [46] have utilized this technique to encapsulate DCAMKL-1 specific siRNA in PLGA nanoparticles They demonstrated that an inhibition of colorectal cancer tumor growth could be achieved by targeting DCAMKL-1 Detailed illustration of this method is shown in Fig (3) 2.1.2 Combination of Salting-Out and Emulsion Evaporation This modification method was developed using water-miscible solvents and salting-out agents in the process of emulsion evaporation method For example, to explore the inhibition of adenocarcinoma cells (HT-29) using meloxicam in PLGA nanoparticles, acetone (AC) was mixed with dichloromethane to dissolve PLGA and the model drug before pouring the mixture into an aqueous solution containing salting-out agent [47] AC was used as a water-miscible solvent to induce the formation of PLGA nanoparticles through the diffusion of AC into the aqueous phase [48-59] In addition to AC, MgCl2 was used as a salting-out agent which could cause the salting-out effect by a sudden change in the salt concentration in the continuous phase of the emulsion under the dilution process [57, 59-61] Consequently, a stable O/W emulsion was expected to be obtained due to the prevention of phenomena commonly observed when an organic solvent is mixed with water [62] The most frequently used salting-out agents are MgCl2, magnesium acetate, NaCl Nanoparticulate Drug Delivery to Colorectal Cancer Current Pharmaceutical Design, 2016, Vol 22, No 00 Probe sonicator Probe sonicator Drug PVA solution Fig (3) Illustration of double emulsion solvent evaporation [42] and CaCl2 [62, 63] Although this method can be useful for encapsulation of heat sensitive drugs and proteins that are agents introduced in a process without temperature and with minimizing tension to protein encapsulants, respectively, the main disadvantage of this method is the requirement of severe purification [8, 64, 65] 2.1.3 Nanoprecipitation Usually, the nanoprecipitation method has been developed by dropwising a polymer in an organic solvent into an aqueous phase (anti-solvent) [66-69] It is also called the solvent displacement method with one-step process In the effort of functionalizing aptamer on PLGA containing curcumin nanoparticles as delivery system to colorectal cancer cells [70], acetonitrile, an organic solution containing PLGA and curcumin, was added in the lipid aqueous phase containing lecithin and Pegylated phospholipid (DSPEPEG2000-COOH) for self-assembled formation of nanoparticles Ethanol, methanol and AC instead of acetonitrile could be considered as alternative solvents of polymers in the nanoprecipitaion method In addition, a surfactant could be added in the aqueous phase for stabilization OH OH OH HO O HO NH2 O HO O NH2 O HO n O OH NH2 Fig (4) Chemical structure of chitosan 2.2 Chitosan (CS)-Based Systems There has been a wide trend of using CS in drug delivery systems recently, especially for gastrointestinal delivery due to exhibition of good mucoadhesive features, prolonged residence time in the intestine and, subsequently, enhancing the bioavailability of the drugs [71-76] Furthermore, it is a nontoxic and biocompatible polysaccharide [77-80] With regards to a specific structure of a weak base having pKa value of about 6.2 - 7.0 (Fig 4), pure CS can be easily dissolved in an acidic environment with pH in the range within stomach due to the protonation of amino groups [81-83] CS, therefore, usually needs a modification or nanoparticulate formulation in targeting oral delivery for colorectal cancer in spite of the well-known advantage of chitosan that can release therapeutic agents specifically at the colon by colonic microflora (glycosidic linkages degradation) [84-86] 2.2.1 Ionic Gelation In this method, the electrostatic interaction between positive charged CS solution and negative charged salt solution was used in preparation of CS nanoparticles [87-89] According to Li et al [90] and Jain et al [91, 92], this method was successfully applied in preparation of CS nanoparticles for delivery of 5-fluorouracil and oxaliplatin in colorectal cancer therapy using sodium tripolyphosphate solution as the negative charged solution Furthermore, the loading combination of 5-fluorouracil and leucovorin in CS nanoparticles by this method has resulted in a promising and effective multiple anticancer drugs delivery system in the chemotherapy of colorectal cancer [93] In addition to the therapeutic purpose in colonic delivery, another research used CS to develop a safe livertargeting cytokine delivery system that exploited liver immunity to prevent colorectal liver metastasis [94] Using similar ionic gelation method, Xu et al [94] demonstrated that the system where interluekin-12 encapsulated in CS nanoparticles could trigger antitumor immunity in the liver by the interleukin-12 accumulation Fig (5) briefly illustrates the ionic gelation method in which CS was firstly dissolved in an aqueous solution and then, a solution of negatively charged drug(s) was dropped into CS solution under magnetic stirring at room temperature for the formation of CS nanoparticles The greatest advantage of this method is its simplicity and mild generation which would be applied to most CS nanoparticle preparation processes for colorectal cancer delivery [95-97] 2.2.2 Nanogels More recently, a modified ionic gelation method has been developed to prepare the chitosan-based nanogels According to studies of Feng et al [98, 99] with the purpose of improving oral bioavailability of doxorubicin and mucoadhesive properties, Current Pharmaceutical Design, 2016, Vol 22, No 00 Tran et al in the aqueous medium and act as a polymer backbone for carrying drug, was introduced via a grafting reaction between the amino groups and carboxyl group [107] The results of this research demonstrated that the drug-encapsulated micelles inhibited colorectal cancer stem cells effectively [106] In another research, the amphiphilic doxifluridine-chitosan copolymer was synthesized by grafting a prodrug of 5-fluorouacil (doxifluridine) and hydrophilic chitosan [108] The self-assembled micellar nanoparticles demonstrated the synergistic anticancer activity due to the sustained release of 5-fluorouracil via the slow conversion of doxifluridine 2.3 Albumin and Other Polymers Recently, albumin (AL) has been another promising material that has drawn a tremendous attention in nanoparticle preparation due to its versatile applications, mild condition preparation and loading capacity of various molecules [109, 110] Moreover, given a wide range of carrier types in drug delivery systems, albumin nanoparticles have been considered as a preferable delivery due to the capability of being easily adaptable to human body [110, 111] A simple and well-known method to produce albumin nanoparticles is coacervation that would be applied in preparation of albumin nanoparticles for targeted colorectal cancer [112, 113] For instance, 5-urouracil and cetuximab were successfully loaded in albumin nanoparticles and delivered to colon carcinoma cells in some recent reports [101, 114] Briefly, two basic consecutive steps including a desolvation agent addition for phase separation and rigidization of the coating are involved in the coacevation method (Fig 6) In the first step, albumin is dissolved and incubated in a suitable aqueous solution with or without drug Nanoparticles are formed by continuous dropwise of desolvation agent like ethanol under stirring at specific or room temperature In the second step, an aqueous solution of a crosslinking agent, for instance, glutaraldehyde, is added to the above solution to stabilize the resulting nanoparticles Although popular polymers such as PLGA, CS and AL are most commonly used in a number of colorectal cancer therapeutics research, difficulties in the development of polymer-based nanomaterials for biomedical applications still remain, which hinder the contribution of these polymers to the full potential benefit of therapeutic nanoparticles Chemical modification/synthesis is a current strategy that could modulate the particle size, shape or state of these polymer-based systems The synthesis of halloysite-nanocomposite hydrogel was proposed to be more efficient for colon cancer delivery [115] Sodium hyaluronate and poly (hydroxyethyl methacrylate) were chosen as biocompatible and biodegradable materials for hydrogel formation Subsequently, the encapsulation of 5fluorouracil in the halloysite-nanocomposite hydrogel showed the pH-dependent drug release profile Another approach was addressed to utilize the amphiphilic structure facilitating the selfassembly process to form the corresponding nanoparticles [10] It has been demonstrated that these 7-ethyl-10-hydroxy camptothecin micelle formulations were preferentially accumulated in tumors Higher anti-tumor efficacy and longer circulation time of the mi- Fig (5) Illustration of the ionic gelation method [93] chitosan-based nanogels were prepared by mixing CS solution containing drug and tripolyphosphate under constant stirring The designed formulation could be promising for the treatment of colorectal cancer by prolonging and improving local drug concentration 2.2.3 Solvent Emulsication Evaporation Similar to the solvent emulsification evaporation method in preparing PLGA nanoparticles (Section 2,1), an organic solvent was used for emulsification in addition to the aqueous CS solution Commonly AC, dichloromethane [100], or even acetic acid [4] with or without surfactant and stabilizer can be used as the organic phase It has been noted that a high speed mixer emulsifier or a high-speed homogenizer had to be used to emulsify the mixture in a few hours for promoting particle formation Udompornmongkol et al [100] was successful in encapsulating curcumin for targeted human colorectal adenocarcinoma cell line (HT29) and human colon carcinoma cell line (HCT116) using this method Tummala et al [4] also successfully loaded 5-Fluorouracil to CS-based systems for sustained release and localized drug in treatment of colorectal cancer However, enteric-coating of CS nanoparticles should be conducted as discussed in the surface engineering section below 2.2.4 Chitosan-Based Micelles Hydrophobically modified chitosan by grafting or conjugation with hydrophobic groups is an ideal strategy of forming CS nanoparticles for tumor targeting With regards to amphiphilic structure consisting of hydrophobic grafts on hydrophilic backbone, micelle structure in aqueous medium with outer shell of hydrophilic segments via hydrophobic interactions could be obtained through the self-assembly process [9, 102-105] Hydrophobic drugs such as curcumin and paclitaxel hence could be encapsulated in the core of micelles which is hydrophobic Aiming at enhancing solubility and stability of curcumin for improvement of antitumor activity and inhibition of colorectal cancer stem cells, a formulation containing curcumin in stearic acid-g-chitosan oligosaccharide polymeric micelles has recently been developed [106] Stearic acid-g-chitosan oligosaccharide, an amphiphilic polymer that could form micelles Fig (6) Illustration of coacevation method [101] Nanoparticulate Drug Delivery to Colorectal Cancer celles were observed as compared to that of a prodrug of 7-ethyl10-hydroxy camptothecin (irinotecan) at an equivalent dose Very recently, Le et al [116] reported that a hydrophilic methoxypoly(ethylene glycol)-b- poly[-(carbamic acid benzyl ester)-caprolactone-co-amino--caprolactone] iblock copolymer was synthesized via ring-opening polymerization This approach was believed to increase accumulation of nanocarriers with prolonged release of 5-fluorouracil in vitro and in vivo THERANOSTICS AND IMAGING AGENTS The use of theranostic polymer-based nanoparticles is not quite new in fabrication of drug delivery systems for biomedical applications In general there are three strategies in detection of colorectal cancers 3.1 Iron oxide Nanoparticles (IONPs) Among the imaging agents used, iron oxide nanoparticles (IONPs) show their promising applications in biomedical nanotechnology [117] IONPs have be incorporated in the PLGA nanoparticles by a proper method with the aims of developing multifunctional nanoparticles for simultaneous targeted drug delivery, molecular imaging and therapeutic response monitoring or the thermosensitivity of colorectal cancer (Fig 7) Generally, IONPs were dispersed in an organic solution with or without PLGA before encapsulation For instance, in the study by Schleich et al [118], PLGA was dissolved in dichloromethane containing IONPs and using emulsion solvent evaporation method for encapsulation of doxorubicin or paclitaxel This research suggested that these nanoparticles with high uptake and magnetic characteristics not only inhibited the CT26 cells growth but also supported the MRI imaging In another research developed by Esmaelbeygi et al [1], dichloromethane was also used to disperse IONPs However, IONPs were encapsulated in PLGA nanoparticles by multiple emulsions–solvent evaporation methods Consequently, this drug delivery system was effective for the treatment of colorectal cancer due to the assistance of harmful hyperthermia Fig (7) Example of iron oxide-based multifunctional nanoparticles for theranostics of colorectal cancer 3.2 5-Aminolaevulinic Acid 5-aminolaevulinic acid is known as a precursor during heme group synthesis [119] In human body, it is totally degraded in the cells and converted to protoporphyrin IX which is excited by optima light to generate fluorescence in cancer lesions [120, 121] Therefore, 5-aminolaevulinic acid is a promising material in detecting malignant or premalignant tissue [122] Recent articles addressed this issue by encapsulation of 5-aminolaevulinic acid in chitosan nanoparticles showed that these nanoparticles played a significant role in fluorescent endoscopic detection [122-125] Current Pharmaceutical Design, 2016, Vol 22, No 00 3.3 Near-Infrared Fluorescence (NIRF) Imaging Dye Like other imaging agents, NIFR imaging dye is encapsulated in nanoparticles to improve photostability, biocompatibility and fluorescent signal NIRF imaging has multi-detection capability and high sensitivity in cancer imaging and therapy [126] Still, new NIR fluorescence imaging dyes have been developed to observe tumors with the enhanced fluorescent signal (IR-783) [127] The targeting theranostic system using NIRF imaging dye (Cy5.5) and anticancer drug (irinotecan) was also evaluated by Choi et al [128] for therapy and early diagnosis of colorectal cancer SURFACE ENGINEERING With a possibility of surface modification, nanoparticles, therefore, could target and accumulate in a specific tissue [101] Several approaches have been investigated for targeting the colonic cancer region 4.1 Chitosan-Coated Microspheres The most promising process of surface modification in targeted colorectal cancer is the CS coating on surface of PLGA nanoparticles An original PLGA, which has shortage of functional groups on surface, has been suggested to be coated by chitosan for specialized targeting and biomimetic purposes [129] The CS outer shell also facilitated a sustained drug release and an increased stability of macromolecules like proteins, as well as the promotion of cellular adhesion and the retention of the delivery system at the target site [130-132] Generally, CS could be coated on the surface of PLGA nanoparticles by two basic methods so-called physical adsorption and chemical binding [133] (Fig 8) According to the results of this research, pH values of CS solution could be modified to regulate the surface charges of nanoparticles and would benefit more affinity to cancer cells Besides, controlled drug release would be achieved through this system In addition to the coating process of PLGA nanoparticles, chitosan-coated alginate microparticles containing oxaliplatin were investigated for oral administration for colorectal cancer [134] This research proposed that mucoadhesive microspheres, and particularly pH sensitive character could prevent drug release at an acidic environment and deliver the chemotherapeutics to the intestinal site specifically In vivo data demonstrated that efficient therapeutic effects in an orthotopic mouse model of colorectal cancer were observed by substantially reduced the tumor burden and reduced mortality 4.2 Enteric Coating Enteric coating are usually applied for solid dosage forms like tablets and capsules for delayed release formulations [135, 136] In these applications, enteric coating materials should be efficient and safe for controlled drug delivery [137] Various types of aqueous coating suspensions are currently available such as Aquacoat®, Surelease®, Kollicoat®, Eudragit®, Advantia® and Acryl-Eze® with advantages for toxicology and environment [138] For targeting colorectal cancer by polymer-based nanoparticles, Eudragit® S100 is a preferred selection due to its ability of dissolving at pH or higher only [4, 42, 92] Conventional coating pan is generally applied in the coating process [4, 92] or oil-in-oil solvent evaporation method [42] 4.3 Ligand Conjugation Although ligand conjugation has been reported in various types of nanoparticles for targeting purposes [139-141], there have been only a few reports about targeting colon cancer cells using ligand conjugation in polymer-based nanoparticles Folic acid [44, 90] and hyaluronic acid [91, 92] are the most common targeting ligand in recent research Folate receptors are highly expressed in colorectal and numerous tumors [142-144] Consequently, the utility of folic acid in conjugated nanoparticles as a recognition moiety has been Current Pharmaceutical Design, 2016, Vol 22, No 00 Tran et al Fig (8) Examples of two basic methods of chitosan-coated microspheres [133] investigated extensively due to its ease of conjugation, high affinity for the folate receptor and the limited distribution of its receptor in normal tissues [145, 146] Hyaluronic acid, another ligand conjugation, possesses a high binding affinity to various cancer cells (overexpressed CD44) specifically [147-149] Given excellent properties including nontoxic, nonimmunogenic and particularly versatile modifications, hyaluronic acid-decorated nanoparticles have been extensively investigated in cancer therapy [150-152] CONCLUSION AND FUTURE PERSPECTIVES Recent advances in polymer-based nanoparticles have indicated the potential use of polymers in both therapy and diagnosis of colorectal cancer PLGA and CS are popular polymers which have been most frequently explored Moreover, an increasing number of investigations on albumin or discovery of new materials demonstrates the importance of relevant studies in the field Surface engineering techniques which provide more versatile methods for cell-specific targeting of nanoparticles have been exploited in an effort to reach a successful treatment of the cancer In parallel to studies of optimized drug carriers, research towards imaging agents for diagnosis of precancerous colonic lesions using polymer-based nanoparticles leads to new key tools for theranostics Although in the past most research focused on several carrier types loaded with approved pharmaceutical ingredients for colorectal cancer therapy, an increasing number of studies on smart nano-based systems with new nanomaterials and potential surface engineering for theranostics brings an expectation of important beneficiaries of these inventions in near future ACKNOWLEDEGMENTS We would like to thank Institute for Frontier Materials (Deakin University, Waurn Ponds, Victoria, Australia) and Australian Government for their supports and offering the Endeavour Fellowships program to Dr Thao Truong-Dinh Tran to undertake study, research and professional development in Australia We also thank International University, Vietnam National 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MgCl2, magnesium acetate, NaCl Nanoparticulate Drug Delivery to Colorectal Cancer Current Pharmaceutical Design, 2016, Vol 22, No 00 Probe sonicator Probe sonicator Drug PVA solution Fig (3) Illustration... Nanoparticulate Drug Delivery to Colorectal Cancer celles were observed as compared to that of a prodrug of 7-ethyl10-hydroxy camptothecin (irinotecan) at an equivalent... range within stomach due to the protonation of amino groups [81-83] CS, therefore, usually needs a modification or nanoparticulate formulation in targeting oral delivery for colorectal cancer in