http://informahealthcare.com/drt ISSN: 1061-186X (print), 1029-2330 (electronic) J Drug Target, Early Online: 1–16 ! 2015 Informa UK Ltd. DOI: 10.3109/1061186X.2015.1020426

REVIEW ARTICLE

Polybutylcyanoacrylate nanocarriers as promising targeted drug delivery systems Shiya Gao1*, Yurui Xu1*, Sajid Asghar1,2*, Minglei Chen1, Lang Zou3, Sulieman Eltayeb4, Meirong Huo1, Qineng Ping1, and Yanyu Xiao1 1

Department of Pharmacy, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, People’s Republic of China, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan, 3The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, People’s Republic of China, and 4Department of Pharmaceutics, Faculty of Pharmacy, Omdurman Islamic University, Omdurman, Sudan

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Abstract

Keywords

Among the materials for preparing the polymeric nanocarriers, poly(n-butylcyanoacrylate) (PBCA), a polymer with medium length alkyl side chain, is of lower toxicity and proper degradation time. Therefore, PBCA has recently been regarded as a kind of widely used, biocompatible, biodegradable, low-toxic drug carrier. This review highlights the use of PBCA-based nanocarriers (PBCA-NCs) as targeting drug delivery systems and presents the methods of preparation, the surface modification and the advantages and limitations of PBCA-NCs. The drugs loaded in PBCA-NCs are summarized according to the treatment of diseases, and the different therapeutic applications and the most recent developments of PBCA-NCs are also discussed, which provides useful guidance on the targeting research of PBCA-NCs.

Pharmaceutical applications, poly(butylcyanoacrylate), polymeric nanocarriers, targeted drug delivery

Introduction In recent years, there has been a considerable interest in the development of novel targeted drug delivery systems using nanotechnology. Nanoparticles are functional devices with dimensions at nanoscale, similar dimensions as some of our body components. Nanocarriers prepared from natural or synthetic polymers have been extensively investigated as targeted drug delivery strategy in the pharmaceutical research [1]. Modern synthetic chemistry has provided different and complex polymer molecules suitable for the nanocarriers formation with diverse characteristics due to the nanometer range of their molecular extension. A wide variety of drugs can be delivered using polymeric nanocarriers which have the ability to modify their pharmacokinetics, biodistribution and enhance their therapeutic efficacy. Surface modification of drug-loaded polymeric nanocarriers with specific ligands is a perfect method for controlled release and targeted delivery of therapeutic entities [2]. Among the materials for preparing the polymeric nanocarriers, n-butylcyanoacrylate (BCA), one of the most widely

*These authors contributed equally to this work. Address for correspondence: Yanyu Xiao, Department of Pharmacy, State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tong Jia Xiang, Nanjing 210009, People’s Republic of China. Tel: +86 25 83271079. Fax: +86 25 83271079. E-mail: [email protected]

History Received 5 November 2014 Revised 19 January 2015 Accepted 14 February 2015 Published online 4 March 2015

studied alkyleyanoacrylate (ACA) materials, has received extensive attention due to its non-toxicity and biodegradability and has been used clinically in Europe, Canada and USA, like IndermilÕ and liquibandÕ as tissue adhesives (glues). BCA monomer has a high activity of self-polymerization in an acid medium to form polybutylcyanoacrylate (PBCA) without an energy input, which may not affect the stability of the loaded drug [3]. In biological systems, the hydrolysis of the ester bond of PBCA is catalyzed by the esterases in lysosomes or plasma, leading to side chain removals which results in increased hydrophilicity of the polymer chains (Figure 1), which are finally eliminated by the kidney [4–6]. As a kind of drug carriers, PBCA-based nanocarriers (PBCANCs) are easy to synthesize and scale up, and are modifiable, biodegradable and biocompatible, and have been reported to show a distinct tendency for the encapsulation of various pharmacologically active agents, such as cytotoxic drugs, antibiotics, peptides and genes, leading to elevated effects of antibacterial drugs, increased efficacy of anti-cancer drugs and enhanced relative bioavailability of the peptides [3,5,7]. Therefore, this review focuses on the preparation techniques, the modification materials for different target sites, and current applications of PBCA-NCs as targeted drug delivery systems. The drugs loaded in PBCA-NCs are summarized according to the treatment of diseases, and the most recent developments of PBCA-NCs are also discussed, which provides useful guidance in the research domain of targeting of PBCA-NCs.

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Figure 1. The in vivo and in vitro degradation process of PBCA: the ester bond of PBCA are biologically hydrolyzed by enzyme resulting in poly (2cyanoacrylic acid) and alcohol in vivo; PBCA are stepwise degraded in basic medium in vitro into PBCA of lower degree, formic acid and cyanoacetate.

Figure 2. Preparation techniques for PBCANCs: according to the structural organization biodegradable nanoparticles are classified as nanocapsule and nanosphere. The drug molecules are either entrapped inside or adsorbed on the surface.

Method of preparation of PBCA-NCs Among many techniques used for the preparation of PBCANCs, the two main strategies discussed here are polymerization-based and nanoprecipitation-based methods, leading to the two main types of PBCA-NCs, namely, nanospheres and nanocapsules (Figure 2). Nanospheres are matrix systems constituted by a polymer, in which the drug is dispersed or adsorbed, whereas nanocapsules are vesicular systems, in which the drug is solubilized in a liquid core, surrounded by a polymer shell. Polymerization-based method The polymerization-based method is defined as the polymerization of BCA monomer triggered by an anion (anionic polymerization) or a radical (radical polymerization) at an ambient temperature (Figure 3), including emulsion polymerization [8,9], interfacial polymerization [10,11] and miniemulsion polymerization methods [12,13] (Figure 4). In practice, the anionic polymerization is strongly favored because it is rapidly initiated at ambient temperature. Classical initiators of anionic polymerization are anions (I–, CH3COO–, Br–, OH–, etc.), weak bases such as alcohols and water and amino acids encountered in living tissues. Emulsion polymerization method is a very popular approach used to synthesize polymeric colloids with a matrix structure (nanospheres). Briefly, BCA monomer is added dropwise under magnetic stirring to an acidic aqueous

medium (generally pH 2.0–3.0) containing the appropriate amount of a surfactant (e.g. poloxamer 188, pluronic F127, BrijÕ 78) or a stabilizing agent (e.g. dextran 70, dextran 40, dextran 10, sodium dodecyl sulfate, chitosan). Then, polymerization of BCA monomer is initiated by an anion. Afterwards, the mixture is magnetically stirred for several hours to allow further growth of the polymer chains and produce PBCA nanospheres. The resulting suspension is neutralized with 0.1 N NaOH solution to stop the polymerization, filtered, purified and finally lyophilized. For drugloaded PBCA-NCs, the drug is either dissolved in the acidic aqueous medium [14] or BCA monomer [15]. Interfacial polymerization method is a self-polymerization process of BCA monomer happening at the interface of oil phase and aqueous phase. Therefore, the reactions are performed either in water-in-oil or oil-in-water emulsion systems, leading to PBCA nanocapsules with an oil or a water core surrounded by a thin polymer envelope, respectively. In brief, the aqueous phase is prepared by adding the selected surfactant to the water, and then the pH of the aqueous phase is adjusted by HCl (generally pH 2.0–3.0). The oil phase is slowly added to the aqueous phase to obtain oil-in-water emulsion or the aqueous phase is slowly added to the oil phase to obtain water-in-oil emulsion. The emulsion is then kept under mechanical stirring to accomplish the interfacial polymerization process. In addition, after forming the emulsion, BCA monomer can be also added into the emulsion to form PBCA nanocapsules. According to the solubility of the

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DOI: 10.3109/1061186X.2015.1020426

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Figure 3. The polymerization mechanism of n-butyl cyanoacrylate used in emulsion polymerization method. (A) Anion; (B) Radical (Hansali [13]).

Figure 4. The process of emulsion polymerization (A) in which drug is dissolved in water phase and loaded onto PBCA nanospheres by adsorption (drug can also be dissolved in BCA monomer, resulting in being entrapped into PBCA nanospheres, figure not shown); interfacial polymerization (B) in which drug and BCA monomer are both dissolved in oil droplets, after magnetic stirring, small oil droplets dislocate from the initial ones and BCA monomer polymerizes on the surface to form nanocapsules with drug entrapped inside. The magnetic stirring also causes transportation of drug into the aqueous medium, leading to decreased EE and LE of PBCA-NPs; and miniemulsion polymerization (C), drug and BCA monomers are both dissolved in oil droplets and the droplets are broken up into tiny uniform droplets by an ultrasonication process to form drug-loaded nanocapsules.

drug, it can be dissolved in the aqueous phase or oil phase [15–17]. If the organic solvents are used as the oil phase, the residual of the organic solvents can be removed by rotary evaporation [17]. It is very important to choose suitable oil to prepare drug-loaded PBCA nanocapsules. The oil used in PBCA nanocapsules must be non-toxic and inert. Some organic solvents when used as oil phase may produce anions thus accelerating the polymerization process, and resulting in inhomogeneous particles, which must be avoided.

The commonly used oils include vegetable oil, mineral oil and organic solvents such as diethyl ether, ethanol and so on [17–19]. Miniemulsion polymerization method was first used by Limouzin et al. to prepare PBCA-NCs [20], is much like that of emulsion polymerization or interfacial polymerization, only having an additional ultrasonication process. For example, in miniemulsion interfacial polymerization, an appropriate amount of oil is added to an acidic aqueous

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Table 1. A summary of different preparation techniques of PBCA-NCs.

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Preparation technique

Nanocarrier type

Advantages

Disadvantages

Emulsion polymerization

Nanospheres

 Simple  Easily scalable

Interfacial polymerization

Nanocapsules

 Encapsulation of both hydrophilic and hydrophobic drugs  Higher EE and DL

Miniemulsion polymerization

Nanocapsules or nanospheres

Nanoprecipitation

Nanospheres

    

          

Lower quantities of Surfactants used Homogenous particle size distribution Higher EE and DL Homogenous particle size distribution No chemical interaction between drug and polymer

solution containing surfactant and other adjuncts, and then sonicated or rapidly stirred to yield a pre-emulsion. Later, BCA is added and the mixture is sonicated to produce a miniemulsion, with the polymerization of BCA taking place at the interface between aqueous phase and oil phase to form nanocapsules. The drug is either dissolved in the oil medium or BCA monomer. Huang et al. [21] found that both drug loading and encapsulation efficiencies of PBCA-NCs prepared by miniemulsion polymerization method were approximately three times higher than those obtained using interfacial polymerization method with similar paclitaxel content in the feed monomer (1%, w/w). The reason might be that the drugcontaining monomer was homogenized by high energy shear generated by ultrasonication, to obtain tiny monomer droplets and the drug dissolved in monomers can be completely encapsulated in PBCA-NCs prepared by the miniemulsion polymerization method. However, in an emulsion polymerization system, the largest fraction of BCA monomer is dispersed in the form of monomer droplets and the principle reaction sites are located in the monomer-swollen micelles. As polymerization proceeds, the monomer molecules move from the monomer droplets into the aqueous phase and subsequently into the reaction sites. The highly hydrophobic drug dissolved in the monomer droplets is almost insoluble in water which makes it difficult for the drug molecules to diffuse out of monomer droplets and therefore restricts the transport of drug from droplets to reaction sites, thus leading to lower drug loading and encapsulation efficiencies. The polymerization process of BCA can be triggered not only by anions, but also by radicals. Recently, miniemulsion polymerization and emulsion polymerization methods initiated by radicals have also been reported [13,22]. The radical polymerization process is similar to that of polymerization initiated by an anion except a much lower pH medium (below 1.0) and the addition of a radical initiator, such as 2,2azobis (2-methylpropionitrile) and cerium ions, before the addition of BCA monomer are involved. The radical polymerization is terminated by disproportionation and coupling processes (Figure 3B). Nanoprecipitation-based method Nanoprecipitation-based method is another method for the preparation of PBCA-NCs, starting from pre-synthesized polymer. Briefly, an appropriate amount of stabilizer is

Use of toxic solvents Non-homogenous particle size distribution Removal of surfactants required Use of toxic solvents Non-homogenous particle size distribution Removal of surfactants required Use of toxic solvents High energy process Removal of surfactants required Use of toxic solvents Removal of surfactants required

dissolved in water or PBS to obtain the water phase, and then the pH of the water phase is adjusted to a suitable value. Afterwards, the acetone solution containing pre-synthesized PBCA is added drop wise to the water phase, the mixture is kept under stirring, and the resulting suspension is neutralized with 0.1 N sodium hydroxide solution to complete the polymerization. The residual acetone can be removed by rotary evaporation. According to the solubility of the drug, it is added to either the water phase or the acetone solution [23,24]. In comparison with the polymerization-based method, the nanoprecipitation-based method has the advantage that the used BCA can be polymerized into PBCA with accurate molecular weight before the preparation of PBCA-NCs. This allows nanocarriers’ characteristics to be independent of the preparation conditions of PBCA-NCs as the molecular weight of PBCA can be easily controlled. Nevertheless, no chemical reaction (such as polymerization) takes place during the formation of PBCA-NCs prepared by nanoprecipitation as the contact between drug molecules and BCA monomers is avoided, which is sometimes important for the preservation of biological activity of the loaded drug. Table 1 summarizes the main advantages and drawbacks of each method.

Physicochemical characteristics and release mechanisms of PBCA-NCs In 2001, Behan et al. [12] explained the process of PBCANCs’ formation: first, oligomeric species are produced in the monomer droplets and are then terminated by the acid inhibiting agents present in the monomer, which is the step that may lead to batch to batch variation in oligomer molecular weight and particle size; second, aggregation of the oligomeric units and their swelling with monomer; finally, in situ re-initiation of terminated oligomeric units by live chains followed by further polymerization until reaching molecular weight equilibration (Figure 5). The physicochemical properties of PBCA-NCs are evaluated by four indexes: the particle size, the zeta potential, the encapsulation efficiency (EE) and loading efficiency (LE). Particle size is one of the main factors influencing the biodistribution and bioavailability of PBCA-NCs. It has been reported that common NCs in the size range of 300 nm4d 4150 nm would be taken up by mononuclear phagocyte system (MPS) and transported to macrophage rich organs,

Polybutylcyanoacrylate nanocarriers

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Figure 5. The mechanism of PBCA-NCs’ formation (Behan et al. [12]).

such as liver and spleen [32,33]. However, NCs with particle size less than 100 nm can escape MPS resulting in non-liver targeting [34,35] and those between 20 and 30 nm would suffer from a renal clearance process [36]. In addition, NCs with particle size between 85 and 150 nm have been reported as targeted systems for bone marrow [37] and those of extreme small particle size (no more than 10 nm) may have the ability to permeate the skin barrier [38]. Zeta potential is another important property of PBCA-NCs. With higher zeta potential, NCs tend to separate from each other due to electrostatic repulsion, thus enhancing the stability of the nanoparticle system. In addition, it is closely related to the endocytosis of the NCs. The positive charge facilitates the cellular uptake of NCs by electrostatic interaction with negatively charged cell membrane. The amount of the drug loaded in PBCA-NCs can be evaluated by measuring the EE and the LE. The EE is defined as the percentage of the amount of drug entrapped in PBCA-NCs relative to the total drug amount of drug used for the formulation, and the LE is defined as the percentage of the drug entrapped in NCs relative to the total weight of NCs (w/w). Precise determination of the drug content is not easy because NCs are colloidal systems, thus a separation process of NCs from nonencapsulated or non-adsorbed drug is needed firstly. The most effective methods to do the separation are ultracentrifugation and gel filtration. A successful nanoparticle system should have higher EE and LE so as to reduce the quantity of the carrier required for administration. The EE and LE are mainly governed by (1) the solubility of drugs in the medium; (2) the pH value of the polymerization medium because the polymerization of BCA would be too fast to encapsulate drugs under the condition of higher pH value [9]; (3) the affinity of drugs to PBCA-NCs and the oil phase. Factors affecting physicochemical properties of PBCANCs are also important to be considered for better tuning of

the desired features of carriers. First, the polymerization method has a great effect on the polymerization of BCA. For example, PBCA-NCs obtained by radicals were of higher molecular mass and yet harder to be degraded in vivo compared with that initiated by anions [13]. Second, the pH of the aqueous medium affects the polymerization velocity of BCA, thus affecting the particle size, zeta potential and EE of PBCA-NCs [39]. Acid solution of high concentration is necessary to limit the BCA reaction speed and make the polymerization process of BCA controllable. Third, the surfactants or the stabilizers would influence the particle size and zeta potential of PBCA-NCs due to being adsorbed on the nanoparticle surface. For example, with the addition of 1% of different surfactants (dextran70, cholesterol, lecithin, polyvinyl alcohol and their mixture), the diameter of PBCANCs was dramatically decreased from 800 nm to 200–300 nm [25]. In addition, the amount and time of drug added in PBCA-NCs also influence the properties of PBCA-NCs (Table 2). The drug release mechanisms are equally important for the application of NCs in sustained release drug delivery. In general, there are five kinds of drug release behaviors from PBCA-NCs: (1) desorption of the drug bound to the surface, (2) drug diffusion through the polymer matrix, (3) drug diffusion through the polymer wall of nanocapsules, (4) erosion or degradation of NPs matrix and (5) a combination of erosion and diffusion processes [40]. The release mechanism of a drug from PBCA-NCs depends on its loading pattern in PBCA-NCs. Drugs would be dispersed in the polymer matrix of PBCA-NCs, or adsorbed or chemically bound to the surface of PBCA-NCs [26,41–43]. The state of the loaded drug in PBCA-NCs can be judged by the adsorption isotherm. A linear adsorption isotherm illustrates that the drug is dispersed in PBCA-NCs in the form of a solid solution, and Langmuir or S-type isotherm demonstrates that the drug is

24.7 to 40.4 – – 1.21 to + 20.82 +15.6 +33.4 – +6.8 19.3 2.1 – 32.58 119.1–144.0 222 220 182.2–844.4 106 259 – 140–150 99.7 345–365 178 325

Interfacial polymerization Interfacial polymerization Interfacial polymerization Anion emulsion polymerization Anion emulsion polymerization Anion emulsion polymerization Anion emulsion polymerization Miniemulsion polymerization Miniemulsion polymerization Nanoprecipitation Nanoprecipitation Nanoprecipitation

Zeta potential (mv) Average particle size (nm)

adsorbed on the surface of PBCA-NCs [44]. Besides, only few drugs can react with BCA or PBCA so as to be chemically linked to the surface of PBCA-NCs. Drugs that are adsorbed on the surface of PBCA-NCs are released by desorption. Entrapped drugs, which are weakly bounded to the PBCA, are released by diffusion. Drugs, which have high affinity to the PBCA are released very slowly by diffusion and can be released during the bioerosion of the PBCA. It has been shown that enzymes, which enhance the rate of PBCA-NCs erosion by enhancing the hydrolysis of ester bonds, also accelerate the drug release from PBCA-NCs [40]. The bioerosion of PBCA-NCs actually happens in three ways: hydrolysis of the ester bond of PBCA by enzyme or base, unzipping de-polymerization of the old polymers and the repolymerization of new smaller polymers triggered by base [13,21], and the famous inverse Knoevenagel reaction catalyzed by enzymes, which produces formaldehyde and cyanoacetic ester, a toxic substance to the body. However, the last degradation pathway of PBCA is too slow to cause any influence on drug release from PBCA-NCs compared with other mechanisms [45].

Where EE% is the entrapment efficiency of PBCA-NCs and LE% is the drug loading efficiency of PBCA-NCs. ‘‘–’’ not mentioned.

39.9–51.5 64.0–77.3 99.23 46.0–68.0 – 19.3–22.5 – 7.3 56.6 – 92.2 82.8–90.2 – Dextran 70/Poloxamer 188/Tween 80 Lecithin/dextran 70 Dextran 70/Lecithin/Cholesterol Tween 80/Cetyltrime-thylammonium bromide Chitosan Pluronic F127 Tween 80/Dextran 70 Pluronic F127 Dextran 40/Tween 80 Pluronic F68 Hyaluronic acid D-Cycloserine

– – 1.07 – 90 – 0.0254 – 0.56 35 – –

EE (%) Additive used

LE (%)

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Surface modification of PBCA-NCs

Drugs

Table 2. Physicochemical properties of PBCA-NCs prepared by different methods.

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Preparation method

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[17] Oleanolic acid [18] Paclitaxel [19] Paclitaxel [25] pAFP-TK/GCV suicide gene [26] Thymopentin [27] Hydroxycamptothecin [28] Doxorubicin [29] Paclitaxel [30] Epirubicin [31] Thymopentin [23] Paclitaxel [22]

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The process of opsonization is one of the most important biological barriers to targeted drug delivery, by which conventional unprotected NCs become covered with opsonin proteins within seconds after intravenous administration, thereby making them more visible to phagocytic cells. After opsonization, phagocytosis occurs to engulf and eventually destruct or remove the NCs from the bloodstream before they can perform their designated therapeutic functions. In general, hydrophobic NCs are rapidly cleared from the systemic circulation by the MPS, ending in the liver or spleen, which is called passive targeting. However, if the NCs need to be targeted to non-liver or spleen tissues, i.e. active targeting, taking advantage of the high degree of specificity of receptors distributed in most of tissues, the modification of the ligand on the surface of NCs can lead to their accumulation in the targeted tissues via ligand-receptor mediated transport. Recently, several modification strategies have been developed to mask or camouflage NCs from the MPS. PBCA-based NCs offer various possibilities for surface modification to realize active targeting due to the presence of functional groups (i.e. plenty of –COOH and –CN) on the surface of the NCs. For example, conjugation of ligands to the surface of PBCA-NCs is usually achieved through covalent bond formation between the ligands and the functional groups on PBCA surface. However, surface coating or electrostatic adsorption techniques may be also utilized for surface modification of NCs. In the PBCA-ligand combinations, the PBCA acts as a biodegradable carrier for drug delivery whereas the ligand is used for modifying the pharmacokinetic parameters such as enhancing the nanosystem stability and slowing the drug release (e.g. PVP), prolonging its circulation half-life (e.g. PEG), improving gene transfection efficiency (e.g. CTAB), enhancing the relative bioavailability of peptides (e.g. chitosan and its derivatives) or as a targeting agent (e.g. CRM197, NR1 antibodies, ApoE and hyaluronic acid; Figure 6).

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Figure 6. PBCA-NCs modified with different materials: (A) surfactants such as Tween 80, the materials are adsorbed onto the surface of PBCA-NCs; (B) long chain molecules such as PEG or CTAB, one terminal of the molecule is inserted into PBCA-NCs and the other is free in the medium; (C) large nonlinear molecules such as targeting ligands or DNA, a linear molecule is needed to serve as a linker to connect the target and NCs.

Modification by polyethylene glycol (PEG) Reliable multifunctional effects of NCs in vitro and preclinical studies have been reported, however, few formulations have successfully filled the demands in clinical assessment. Uptake of NCs by MPS and subsequent removal from the systemic circulation could be the major factor. To avoid uptake of NCs by MPS, several methods have been developed to mask or camouflage NCs. PEG, a hydrophilic polymer, can absorb or graft to the surface of NCs to create a hydrophilic protective layer around NCs, thus repelling the adsorption of opsonin proteins to the surface of NCs via steric repulsion forces, hence prolonging NCs’ circulation time in blood [46,47] and also increasing the probability of targeting the NCs to the non-liver tissues [48]. Therefore, modification by PEG improves the biodistribution of the drug loaded in NCs to the non-liver tissues. PEG has also been used to protect peptide loaded in PBCA-NCs after oral administration from the destructive gastrointestinal tract enzymes as PEG can form a ‘‘brush’’ and prevent the docking of gastrointestinal enzymes on hydrophobic surface of PBCA-NCs [49]. At present, there are three methods used for the preparation of PEG-modified PBCA-NCs. The first method is to first fabricate PBCA-NCs by any of the above-mentioned methods and then drop wise addition of the PEG in the solution containing PBCA-NCs under continuous magnetic stirring. After centrifugation and discarding excess PEG, PEGmodified PBCA-NCs are obtained [49]. The other two methods are based on the idea of self-polymerization of the BCA monomers in the presence of some molecules having basic groups, such as –OH, –NH2, which work as nucleophile initiators for BCA polymerization. Zhang et al. prepared PEG-coated paclitaxel-loaded PBCA nanocapsules with an oil core by the miniemulsion polymerization method [46]. Methoxy-polyethylene glycol (mPEG), as a nucleophile initiator of the polymerization of BCA through its hydroxyl terminal group, was dissolved in acid aqueous solution. After adding BCA monomer, PEG-PBCA chains were formed that surrounded the surface of oil cores by hydrophobic interaction. With the prolongation of the PEG chain length, mPEG 5000 acted as a stronger stabilizer compared to mPEG 2000. Furthermore, mPEG 5000-modified PBCA-NCs showed smaller particle size than those modified by mPEG 2000.

With an increased amount of mPEG 5000 (from 2% to 10%, w/v) in the suspension, the LE of PBCA nanocapsules was improved, while the particle size decreased from 560 to 268 nm. In addition, mPEG-modified PBCA nanocapsules could decrease the hemolysis of the red blood cells compared with PBCA nanocapsules. However, mPEG-OH has low reactivity of –OH group, which hinders the reaction progress between mPEG. Therefore, amino-PEG (amine group can work as a stronger initiator of polymerization reaction) has also been tried to solve this question. Chaudhari et al. prepared PEG-modified docetaxel-loaded PBCA-NCs by adding mPEG amine or PEG bisamine in the acid aqueous solution [50]. Salt-induced aggregation and serum-induced aggregation studies showed PEG-modified PBCA-NCs with the addition of 20 mol% mPEG could most effectively prevent phagocytosis in comparison to the other formulations tested. Overall, mPEG has a comprehensive application in nanocarrier modification field. It is safe and multifunctional and easy to be linked onto the surface of nano-carriers. For PBCA-NPs, PEGlaytion can effectively cut down particle size, stabilize the nanoparticles and prolong their circulation time in blood. However, mild chemical structural transformation such as amination is needed to make mPEG as a viable initiator of BCA polymerization, which is not an easy task considering high polymerization degree of mPEG. Modification by Tween 80 (Polysorbate 80) Drugs that are effective against diseases in the central nervous system (CNS), must pass through the blood–brain barrier (BBB) to reach the brain via the blood compartment. BBB is formed by the capillary endothelial cells lining the microvessels, which are coupled by much tighter junctions (zonulae occludentes) than found in peripheral vessels, prevents the entry of 498% of small molecules and 100% of large molecules into the brain, and thus has been called ‘‘the problem behind the problem’’ of CNS drug development. As early as 1990, Troster et al. [51] observed that coating poly (methyl methacrylate) NCs with Tween 80 led to a significantly higher total brain concentration after intravenous injection to rats. The first attempt of PBCA-NCs coated with Tween 80 was done by Alyautdin et al. [52]. So far, there have been a lot of researches published on the Tween 80-coated PBCA-NCs [52,53]. According to previous studies,

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Tween 80 was identified as a potential ‘‘lead substance’’ for brain targeting, however, the precise mechanism is still unclear. Some mechanisms have been proposed: (1) endocytotic uptake (phagocytosis and not pinocytosis) by endothelial cells lining brain blood vessels [54]; (2) degradation of the polymer to disrupt the BBB so as to enhance the permeability of the BBB and (3) inhibition of the P-glycoprotein [55,56]. In addition, after intravenous administration, Tween 80-coated PBCA-NCs could adsorb apolipoprotein B-100, A-I and/or E in the blood stream and then mimic low-density lipoprotein particles to interact with the low-density lipoprotein receptors on the BBB, thus leading to their uptake by the brain capillary endothelial cells via receptor-mediated endocytosis. Finally, the drug could be delivered by passive diffusion from endothelial cells to the brain and generate therapeutic effects [52,56–58]. In general, Tween 80-coated PBCA-NCs are obtained by incubating the mixture of Tween 80 (1% v/v) and PBCA-NCs. In addition, Tween 80-coated oil-core PBCA nanocapsules can be prepared by interfacial polymerization in o/w microemulsions formed using Tween 80 as a surface active agent [59]. The transendothelial electrical resistance (TEER) measurements and the 14 C-sucrose and TITC-BSA permeability studies were applied to investigate the effects of Tween 80-coated PBCA-NCs on the in vitro BBB integrity model [60]. The results showed that Tween 80-coated PBCA-NCs caused a reversible disruption of the BBB in a dose-dependent manner. At a concentration of 13.31 g/mL of NCs, Tween 80coated PBCA-NCs could induce a complete disruption of BBB in 4 h and reconstitution in the following 24 h. However, a higher concentration of 26.62 g/mL of NCs would lead to an irreversible disruption of BBB. The maximum concentration of drug in brain was achieved within 45 min to 1 h after intravenous administration of drug-loaded Tween 80-coated PBCA-NCs. Rempe et al. also explained the theory of the temporary open up of BBB: the decline in cell organization, the change in morphology and the areas of serrated cell borders after Tween 80 treatment [52,60,61]. This theory broadens the scope of application of Tween 80-modified PBCA-NPs because they might not only be employed as drug carriers but also offer the possibility to be used as specific openers of the BBB. In other words, Tween 80-modified PBCA-NPs might also bring drugs into the brain which could not be loaded by PBCA-NPs. Intravenous administration of tacrine encapsulating Tween 80-coated PBCA-NCs in rats led to the reduced accumulation of tacrine in the liver and spleen, while the drug concentration in the brain was 4.07-fold more than that of the drug solution [56]. The antitumor activity in vitro and in vivo of Tween 80-coated PBCA-NCs has also been evaluated. One percentage Tween 80-coated gemcitabine-loaded PBCA-NCs enhanced in vivo antitumor activity in C6 brain tumor model [9]. However, the C6 tumor model is not a good model for assessing BBB penetration (due to the lack of intact BBB in the engrafted tumors). Tween 80-coated nerve growth factor-loaded PBCA-NCs enabled a significant reduction of the basic Parkinson symptoms in vivo [62]. Ambruosi et al. reported significantly reduced uptake of doxorubicin by heart tissues after administration of doxorubicin-loaded PBCA-NCs coated with Tween 80 as compared to the doxorubicin solution, resulting in drastically

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reduced cardiotoxicity of the cytostatic drug, which is a commonly observed side effect of doxorubicin [63]. Modification by cross-reacting material 197 Cross-reacting material 197 (CRM197), a ligand of diphtheria toxin receptor (DTR), derived from a single missense mutation in the fragment A of diphtheria toxin shows an effective anticancer ability in pre-clinical trials. Since brain endothelia overexpresses DTR, NCs grafted with CRM197 could be a promising drug delivery system for treating the CNS diseases. Kuo and Chung [64] prepared the zidovudine-loaded PBCA-NCs by the emulsion polymerization method, and then modified them with CRM197 using the crosslinking agent, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N[carboxy (polyethylene glycol)-2000] (DSPE-PEG(2000)carboxylic acid) to get CRM197-grafted PBCA-NCs (zidovudine-CRM197-PBCA-NCs). The permeability of zidovudineCRM197-PBCA-NCs across the BBB was reported to be particle size- and CRM197 concentration-dependent. The particle size of zidovudine-CRM197-PBCA-NCs decreased with the increase in the density of CRM197 on the surface of NPs which facilitated the uptake of the NCs by BMECs and their permeation across the BBB. Modification by NR1 antibodies Glutamate-N-methyl-D-aspartate receptor 1 (NR1), a kind of important excitatory amino acid receptor that handles the storage of associative memories, is distributed in most ganglion cells and preferentially located in some neurons of the CNS [65]. Therefore, NCs binding with the ligands of NR1 would easily be assimilated by nerve cells. Vladimir et al. [66] connected superoxide dismutase (SOD) and the antibodies targeting NR1 onto the surface of PBCA-NCs and determined their anti-oxidation ability in vitro. Briefly, SOD, NR1 antibodies and the cross-linker (n-hydroxysulfosuccinimidyl-4-azidobenzoate), at a ratio of 2500:40:1, were mixed with the blank PBCA-NCs to obtain the SOD–NR1–PBCANCs. The enzyme activity of SOD–NR1–PBCA-NCs was similar to that of SOD. However, SOD–NR1–PBCA-NCs were more easily taken in by rat cerebellar neurons than SOD, which significantly reduced the oxidative stress of the neurons challenged by superoxide. No dead neurons were found in cell cultures pre-treated by SOD–NR1–PBCA-NCs, while no live cells were presented in the untreated controls after being challenged by superoxide, which confirmed the superiority of NR1–PBCA-NCs to deliver drugs to neurons. Modification by apolipoprotein-E Apolipoprotein-E (ApoE), a component of triglyceride-rich lipoproteins, has been studied as a ligand of low-density lipoprotein receptors widely located on the BBB. ApoE has three major isoforms, such as E2, E3 and E4 co-dominant alleles, which are encoded by ApoE2, ApoE3 and ApoE4, respectively. An association between ApoE and plasma concentrations of total-cholesterol, LDL-C and ApoB has been demonstrated. ApoE4 allele tends to improve the plasma cholesterol levels. In contrast, ApoE2 allele can decrease the

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plasma concentrations of cholesterol. Both of them are closely related to the risk of coronary heart disease [67]. ApoE3 is a ligand of low-density lipoproteins receptor expressed in brain vessels. In a study by Mulik et al. [68], ApoE3 was used to mediate the transportation of curcumin-loaded PBCA-NCs across the BBB. Curcumin-loaded PBCA-NCs prepared by the emulsion polymerization method were incubated with ApoE3 for 1 h to obtain ApoE3-modified PBCA-NCs. After incubation with 2 lM of curcumin solution, curcumin–PBCANCs and curcumin–ApoE3–PBCA-NCs, the percentage of cells containing caspase-3 (the main effecter caspase inducing cell apoptosis) were 24.3, 38.9 and 60.2%, respectively, and the cell viability of SH-SY5Y cells were 98.7, 86.2 and 31.5%, respectively, thus confirming the ability of ApoE3 to drive NCs into SH-SY5Y human neuroblastoma cells. Though, demonstrating cell entry and cell viability in neuroblastoma cells do not necessarily predict BBB penetration and efficacy in vivo. Further, in vivo biodistribution studies and tumor control studies are required to confirm the ability of the ApoE-coated NCs to traverse the BBB. Modification by hyaluronic acid Hyaluronic acid (HA) is a linear glycosaminoglycan containing two alternating units of D-glucuronic acid and N-acetyl-Dglucosamine linked together through b-(1,4)-glycosidic bonds. Studies has revealed that HA is one of the highly efficient targeting molecules for cancer therapy that can bind to the HA receptors like trans-membrane glycoprotein CD44 overexpressed in many types of cancer cells. Therefore, HA modified delivery systems can increase drug accumulation specifically in CD44 over-expressing cancer cells via a CD44 receptor mediated endocytosis pathway [69,70]. He et al. [22] prepared HA-modified paclitaxel-loaded PBCA-NCs by the radical emulsion polymerization method and investigated their antitumor effects in vivo. In brief, HA was added into the water phase before the radical initiator and BCA monomers were added. As the HA/BCA ratio increased from 1:1 to 1:4, the particle size of the NCs decreased from 432 to 219 nm, while the particle size of NCs increased from 291 to 1010 nm with the increase of HA molecular weight from 18 KDa to 1 MDa. The in vitro release experiment showed that a larger HA component in the NCs corresponded to slower drug release and restriction of the initial burst. The tumor inhibition rate of paclitaxel after intravenous administration of HA-modified paclitaxel-loaded PBCA-NCs in S180-inoculated mice model was 1.44- and 2.54-fold higher than after intravenous administration of paclitaxel-loaded PBCA-NCs and paclitaxel solution, respectively. However, He et al. did not provide enough evidences about the interaction of HA with PBCA-NPs at molecular level to confirm the surface modification of NPs by HA. Furthermore, S180 tumor model is not a suitable model to study the HA mediated targeting as S180 sarcoma cells do not overexpress the receptors for HA. Modification by cetyltrimethyl ammonium bromide In recent years, gene therapy has attracted much attention in the field of the treatment of cancer and hereditary diseases. Traditional gene transport vectors are classified into two

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types: the viral vectors and the non-viral vectors. Viral vectors always provide higher transfection efficiency but have serious drawbacks such as immune response, virulence and so on; while non-viral vectors face the difficulty of improving transfection efficiency. Lately, some researches demonstrated that the transfection efficiency of non-viral vectors was inversely proportional to their particle size [71–73]. Therefore, the usage of small sized NCs as gene carriers is receiving great attention. PBCA-NCs are stable, non-toxic, biodegradable, biocompatible and easy to be modified, fulfilling the basic requirement of a non-viral gene vector. Yet, PBCA-NCs take on negative charge and for wrapping DNA into PBCA-NCs, cetyltrimethyl ammonium bromide (CTAB), the cationic surface-active agent, has been used to modify the surface of PBCA-NCs to make the surface take on positive charge, which is beneficial for the electrostatic adsorption between NCs and genes [74]. CTAB-modified PBCA-NCs could be achieved by incubating the mixture of CTAB and PBCA-NCs for 1 h [26]. The highest pDNA loading efficiencies of NCs (over 90%) were achieved when the mass ratio of CTABmodified PBCA-NCs to DNA was 10:1. The average diameters of CTAB-modified PBCA-NCs were between 80 and 200 nm, and zeta potential of NCs was +15.6 mV. Moreover, CTAB-modified PBCA-NCs could protect DNA from degradation by nuclease, and the transfection efficiency of CTAB-modified PBCA-NCs was a little higher than that of SuperFect Transfection Reagent. The change of zeta potential brought by CTAB modification would impart PBCA-NPs with enhanced features and functionalities since surface charge is an important characteristic of nanoparticles. Some researchers showed that positively charged nanoparticles would facilitate cell uptake and oral bioavailability of some drugs compared to the negative ones [75,76]. Positively charged nanoparticles with suitable particle size and terminal group also serve as nonviral gene vectors and have excellent properties [26,77]. On the other hand, too much positive charge also increases uptake by immune system and other organs leading to nonspecific toxicities. Therefore, a balance is required for the coating purpose. Modification by chitosan and its derivatives In an attempt to provide a positive charge to PBCA-NCs, chitosan has been used in the preparation of PBCA-NCs to raise the zeta potential of PBCA-NCs to a positive value, resulting in higher internalization by cells [27,78]. Chitosan is a high molecular weight cationic heteropolysaccharide composed mainly of b-(1,4)-2-deoxy-2-amino-D-glucopytanose units and partially of b-(1,4)-2-deoxy-2-acetamidoD-glucopyranose. Due to favorable biological properties such as biodegradability, biocompatibility and non-toxicity, chitosan has attracted great attention in pharmaceutical and biomedical fields. Chitosan also increases the transcellular and paracellular transport across epithelium [79]. In addition, chitosan contains amino and hydroxyl groups, which might act as nucleophilic agent to initiate the BCA monomer polymerization via an anionic mechanism, a zwitterionic mechanism or both of them [27]. At the same time, chitosan is

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also used as a stabilizer to prepare chitosan-modified PBCANCs [78,80]. Chitosan and its derivatives with high bioadhesive ability, such as thiolated trimethyl chitosan, are applied to construct bioadhesive nanocarriers for oral delivery of proteins and peptides, which can protect drugs against premature degradation, increase their absorption by intestinal epithelium and Peyer’s patches, and prolong the gastrointestinal residence time through either non-specific or specific interactions between carriers and mucosal surface of the gastrointestinal tract due to the formation of disulfide bonds between the thiolated polymer and cysteine-rich subdomains of the mucus gel layer [7,81]. Chitosan-modified PBCA-NCs could be obtained by adding chitosan into the acidic polymerization solution or by adding chitosan or its derivatives’ solution to lyophilized power of PBCA-NCs. Yang et al. investigated the effect of the concentration, volume and molecular weight of chitosan (as a stabilizer) on the size of PBCA-NCs [80]. Results showed the highest grafting percentage of chitosan occurred at pH 2.0. When the chitosan concentration was lower than 0.2% w/v, PBCA-NCs were unstable due to the insufficient amount of stabilizer to effectively cover the available surface. However, when the chitosan concentration was higher than 1.0% w/v, the system was easy to form a gel in the polymerization process. An increase in the chitosan volume from 10 to 40 mL might not only produce smaller and more narrowly distributed nanoparticles, but may also simultaneously avoid the formation of a gel caused by the increasing chitosan concentration. For the same chitosan concentration (0.5% w/v), the mean particle diameter of PBCA nanoparticles decreased with increasing chitosan molecular weight, which could be explained by considering particle formation and theoretical aspects of electrostatic and steric stabilization [82]. PBCA-NCs coated by chitosan or chitosan-glutathione conjugate (chitosan-GSH) were prepared by Jin et al. for oral administration of thymopentin [7]. Compared with chitosan, Chitosan-GSHcoated PBCA-NCs offered a more effective and promising oral delivery system to improve absorption of peptides and proteins. It is worth mentioning that due to the presence of a good number of amino groups, chitosan could be a good initiator of BCA polymerization reaction thus can be chemical linked onto PBCA-NPs. This advantaged property makes chitosan and its derivatives’ modification on the PBCA-NPs easier than other available ligands. Modification by polyvinyl pyrrolidone Since the aggregation of PBCA-NCs and burst release of drugs from PBCA-NCs are two big pitfalls, scientists are taking efforts to seek new modified materials to overcome these disadvantages. To improve the physical stability of PBCA-NCs, efforts have been made to disperse NCs in the solution with high viscosity such as polyvinyl pyrrolidone (PVP), carboxymethylcellulose sodium (CMC-Na) and hydroxoy-propyl methyl cellulose (HPMC) solutions [46]. The conductance rate of NCs colloid was used to predict the stability of PBCA-NCs, and results showed that 4% PVP was the most suitable material among those materials. In addition,

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it was reported that the addition of PVP into NCs could decrease the release rate of drug from PBCA-NCs. Hydroxycamptothecin (HCPT)-loaded PBCA-NCs coated with PVP were prepared by sonication (5 min) and shaking (12 h) the mixture of PVPK30 and HCPT-loaded PBCA-NCs [83,84]. The results on in vitro release showed that the addition of PVP into PBCA-NCs could retard the drug release. At 37  C in saline medium, PBCA-NCs coated with PVP released 35 and 75% of the loaded drugs at 10 and 48 h, respectively, while the uncoated ones released almost 70% of the loaded drugs within the first 10 h. The release data of HCPT-loaded PBCA-NCs associated with PVP fitted the Higuchi Equation. Albendazole-loaded PBCA-NCs modified by PVP have also been reported [85]. Results showed that the addition of PVP had no effect on particle size, EE and DL of NCs. The release data of albendazole-loaded PBCA-NCs modified by PVP also fitted the Higuchi Equation. The use of PVP has only been reported to stabilize PBCANPs and avoid the burst release of PBCA-NPs caused by the adsorption of drug molecules. There is lack of in vivo characterization as the presence of PVP could be tested for the increased biocompatibility, biodistribution and prolonged circulation due to the hydrophilic nature of PVP.

Magnetic PBCA-NCs Recently, magnetic nanoparticles have attracted lots of attention for their usefulness as contrast agents in magnetic resonance imaging (MRI) or as colloidal mediators for cancer magnetic hyperthermia [86]. In addition to the above discussed modification strategies, magnetically targeted PBCA-NCs are also used to improve the therapeutic efficiency of drugs with the help of an external magnetic field in a target region, which results in a preferential drug distribution to the target site [87,88]. At present, there are two methods to prepare magnetic PBCA-NCs. First method requires PBCA-NCs preparation by the emulsion polymerization method with the addition of Fe3O4 magnetic fluid into water phase [89]. Another method involves the synthesis of superparamagetic iron oxide PBCA-NCs. Gao et al. [11] prepared magnetic aclacinomycin-loaded PBCA-NCs (aclacinomycin-MPNS-PBCA-NCs). The effect of aclacinomycinMPNS-PBCA-NCs on the gastric cancer cell line in vitro presented less difference compared with that of the physical mixture of aclacinomycin solution with blank MPNs-NPs in the absence of a magnetic field. However, after implanting the magnetic field with surface field strength of 2.5 T into the center of the tumor, the inhibitory rate of aclacinomycinMPNS-PBCA-NCs on human gastric carcinoma (52.55%) was almost two times higher than that of the aclacinomycin solution (22.63%). Despite the excellent targeting function of magnetic NCs in animal experiments, some difficulties still exist in its application to humans, such as poor targeting at a deep site within the body (42 cm), poor retention of the magnetic carriers when the magnet is removed and poor drug binding and release characteristics of the carriers [87]. Magnetic nanoparticles were also reported to be excellent genetic vectors due to their rapid transfection and excellent overall transfection levels [90]. Since PBCA-NCs can be prepared to be magnetic nanoparticles, they may possess all

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the abilities of magnetic nanoparticles. Nevertheless, magnetic PBCA-NCs were rarely reported thus leaving behind lots of space for the subsequent researchers.

Pharmaceutical applications of PBCA-NCs

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Use of different preparation methods, allows PBCA-NCs to encapsulate diversity of drugs. As targeted drug delivery system, PBCA-NCs can accumulate in the target tissues after administration, resulting in a high local concentration of the drug. This characteristic provides a specific advantage for PBCA-NCs in the therapy of cancer, CNS disease and bacterial infection in which the therapeutic efficiency is positively related to the drug concentration in the nidus. Here, the applications of PBCA-NCs as a drug delivery system are discussed. Cancer Cancer chemotherapy is suffering from their non-selective damage to both normal and tumor cells. In addition, the overexpressed P-glycoprotein in tumor cell membrane would pump anticancer drugs out, leading to a lower intracellular drug concentration than the effective drug concentration, which is called multi-drug resistance (MDR). For these reasons, scientists have begun to draw great attention on nanodrug delivery systems for tumor targeted delivery. In a Phase II clinical trial, an increase in the median survival time with decreased intensity of drug-related toxicity was reported in Chinese patients with hepatocellular carcinoma patients by intravenous administration of mitoxantrone encapsulating PBCA nanoparticles [91]. In general, targeting of tumor by PBCA-NCs is achieved via two ways: a passive targeting way and an active targeting way. Passively targeted PBCA-NCs tend to be retained and accumulated in tumor tissues due to unique anatomical characteristics of the tumor vasculature. In addition, the lymphatic vessels, known as the efflux system, are ineffective in tumors, resulting in inefficient drainage of drugs in the tumor. The phenomena was first proposed in 1986 and was later named as EPR effect [92]. For achieving active targeting, ligands are connected to the surface of NCs to target cancer cells or tumor endothelial cells that provide oxygen and nutrients to the tumor. The targeting ligands for cancer cells include: the transferrin receptor, the folate receptor, the epidermal growth factor receptor (EGFR) and glycoproteins; and for tumoral endothelial cells include the vascular endothelial growth factor receptors (VEGFR-1 and VEGFR-2), the integrins, the vascular cell adhesion molecule1 (VCAM-1) and the matrix metalloproteinases (MMPs). However, only a fraction has been studied in the field of PBCA-NCs till today. Cerebral diseases For many years, the treatment of cerebral diseases was a difficult issue for scientists due to the existence of the BBB. This physical barrier of the brain causes a great challenge for the development of drug delivery systems to the brain tissues. Moreover, the challenge is further amplified by the BBB associated enzymes, such as g-glutamyl transpeptidase, which may degrade the drug [48]. Functionlized PBCA-NCs were demonstrated to have the ability to deliver drugs into CNS as

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well as protect them from enzymatic degradation [93]. For brain targeting, PBCA-NCs are usually modified with PEG to escape from macrophages’ uptake, or Tween-80 to enhance the permeability of the BBB and inhibit the function of ABC efflux protein on the BBB. Moreover, specific ligands such as ApoE would help PBCA-NCs to pass through BBB. Acquired immunodeficiency syndrome Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus-1 (HIV-1) infection, and results in low levels of CD4 + T cells. The virus naturally targets only a few cell types including CD4 + T cells, CD4 + monocytes/macrophages (MM), dendritic cells (DCs), microglial cells and other cells such as macrophages which serve as reservoir sites for virus reproduction [94]. Hence, the common method for AIDS therapy is to kill the HIVs in cellular and tissue reservoirs. However, targeting HIV-infected cells is not an easy issue due to the very short life of CD4 + T cells and the lack of infection markers on latently infected CD4 + cells. Fortunately, these cells have a common feature of a higher concentration in lymph nodes (LNs). Thus, greater therapeutic efficacy can be achieved by delivering anti-HIV drugs to LNs. NCs of small size can be internalized by lymphocytes and work as intracellular drug reservoirs [95]. Nevertheless, to target LNs, NCs should be prevented from the opsonization by MPS, this problem can be solved by minimizing the particle size of PBCA-NCs below 200 nm, or modifying the particle surface with hydrophilic substances. Besides, the ligands of the pattern recognition receptors (PRRs), which are involved in the process of immune response, are good choices for PBCA-NCs modification to deliver drugs into the immune system. The PRRs such as Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors, scavenger receptors, retinoic-acid inducible gene-like receptors (RLR) and C-type lectin receptors (CLRs), recognize some conservative elements exclusively expressed on pathogens, known as pathogen-associated molecular patterns (PAMPs) [1]. For this reason, compounds with the conservative elements could be used to modify PBCA-NCs for immune system targeting. Bacterial and viral infections The therapeutic efficacy of antimicrobial agents is directly decided by the local drug concentration at infected sites. This dose-dependent phenomenon leads to large dose and high frequency of administration of common formulations to achieve the effective drug concentration at infected sites, which usually causes serious side effects and drug resistance. PBCA-NCs are capable of targeting drugs into infected tissues and releasing the encapsulated drug in a controlled release manner. Other than ensuring the effective concentration, they alleviate the side effects and shorten the duration of administration, thus being studied for the delivery of antimicrobial agents. Others Aside from the above-mentioned diseases, PBCA-NCs as the drug delivery system have also been studied for analgesia [96], anabasis [97], hepatitis B [98] and diabetes [6].

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Table 3. Performance of anti-cancer drug-loaded PBCA-NCs. Drug

Target sites

In vitro investigation

Gemcitabine [9]

Brain

Aclacinomycin [11]

Stomach

Diallyl trisulfide [39]

Liver

Poor growth with lesser cell density and increased detachment were observed for C6 glioma cells treated with 1% Tween 80 coated NPs. 1% Tween 80-coated NPs showed increase in G0/G1 phase and decreased in the S phase (p50.01) of treated cells compared with the blank control. IC50 on MKN-45 cells of drug solution, blank magnetic NPs and drug-loaded magnetic NPs were 0.09, 97.78 and 1.07 lg/mL, respectively. The toxicity of drug solution on MKN-45 cells was similar to drug-loaded magnetic NPs without magnetic field. –

Hydroxycamptothecin [84]

Liver



Mitoxantrone [99]

Liver



Docetaxel [100]

Bone metastatic tumor

Vinblastine [101]

Brain

Interferon-alpha [102]

Liver

Curcumin [103]

Brain

Temozolomide [104]

Brain

Enhanced therapeutic efficacy of ApoE3-NPs against beta amyloid-induced cytotoxicity in SH-SY5Y neuroblastoma cells compared to plain drug. –

Mitomycin C [105]

Liver



Doxorubicin [106]

Brain



NPs showed enhanced cytotoxicity in both BO2 as well as MCF-7 cell lines due to higher uptake following zoledronic acid-mediated endocytosis. NPs significantly inhibited growth of BT325 glioma cells than drug solution. –

In vivo investigation 1% Tween 80-coated NPs could significantly extend the survival time compared with the saline control (p50.05).

The tumor mass and volume were decreased in drug-loaded magnetic NPs group than those in drug solution group.

Intravenous administration of drug-loaded NPs significantly retarded the growth of orthotopically transplanted hepatoma in BALB/c nude mice. 64.5% of the drug was concentrated in the liver at 15 min after i.v. administration of drug-loaded NPs associated with PVP. The tumor growth inhibition rate on mice tumor model was higher for drug-loaded NPs (90.62%) than the drug solution (63.27%). NPs distribution in tumor affected bone was also significantly higher than the normal bone at any time point. – The distribution ratio of drug after i.v. administration in mice liver increased from 13.1% (for drug) to 50.6% (for drug-loaded NPs), and the mean retention time increased from 1.41 h (for drug) to 8.35 h (for drug-loaded NPs). –

2.29-fold higher drug accumulation in the brain at 1 h than that of drug solution after i.v. administration of Tween 80 NPs. When injected into mice, NPs accumulated more in the liver than did free drug. The antiproliferative effects on the tumor cells after administered of NPs and free drug, respectively, to rabbits bearing VX2 cells implanted into the liver were similar. After 2 h, doxorubicin concentration doubled in brain parenchyma as compared to blood vessels and cell debris, upon treatment with Tween 80-coated NPS.

‘‘–’’ not mentioned.

However, these studies only discussed in vitro characteristics of the preparations. Further in vivo investigations are needed to evaluate the final curative efficiency and draw a complete picture. So far, the drugs loaded into PBCA-NCs include anti-tumor drugs, anti-bacterial drugs, anti-viral drugs, central nervous system drugs, gene drugs and the drugs with low oral bioavailability (most of them are summarized in Tables 3 and 4).

Challenges and prospect Unfortunately, despite many advantages they possess, PBCANCs are still not put into clinical use. One of the major

shortcomings of PBCA-NCs relates to the poor drug loading, especially for hydrophobic drugs. Indeed, PBCA-NCs often present the high EE, while their LE is generally low (around 1%, mg/mg). The miniemulsion polymerization method could improve the LE of hydrophobic drugs, while the electrostatic interaction between drugs and carriers might more easily improve the affinity. In addition, surfactants or other modified materials with the opposite charge to the drug could be added into the polymerization medium to improve the affinity between the drugs with PBCA-NCs [9]. A second important drawback is the burst release of the drug from PBCA-NCs, which has been reported in most of the in vitro release studies of PBCA-NCs. The drug-loaded

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Table 4. Performance of drug-loaded PBCA-NCs against bacterial/viral infections and Alzheimer’s disease.

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Drug

Diseases

Target sites

In vitro investigation

In vivo investigation Targeting index in liver, blood, spleen and brain after oral administration of drugloaded NPs were 11.4, 3.3, 3.9 and 1.37, respectively (versus drug suspension). –

Albendazole [85]

Echinococcus granulosus infection

Liver



Moxifloxacin [107]

Tuberculosis

Lung

Allicin [108]

Fungal infections

Amphotericin B [109]

Cryptococcal meningitis

Brain

The accumulation of drug entrapped in NPs in THP-1 cells was about 3-fold times more efficiently than that of the free drug. Drug-loaded NPs were distributed throughout the macrophage cytoplasm. The MIC of NPs to C. albicans, T. rubum and E. floccosum were significantly lower than that of pure allicin; accordingly, the MFC of NPs to C. albicans, T. rubum, E. floccosum and M. canis also decreased dramatically. –

Valaciclovir [110]

Hepatitis B

Liver

The accumulation of drug entrapped in NPs in hepatocytes was more than that of the free drug.

Rivastigmine [16]

Alzheimer’s disease

Brain







NPs were detected in the brain 30 min after i.v. administration into BALB/c mice and had a higher concentration than liposome; Drug from the solution was not detected in the brain. Following infection for 24 h and then 7 days of treatment, the survival rate of mice in the NPs group (80%) was significantly higher than that of the drug (0%) or liposome (60%) treatment groups. Compared with the drug solution, NPs showed distinct characteristic of sustained release in vivo and 74.49% of the drug was found to localize in the liver 15 min after i.v. administration of NPs in the mice. Morris Water Maze Test demonstrated faster regain of memory loss in amnesic mice with NPs when compared to drug solution.

‘‘–’’ not mentioned.

PBCA-NCs undergo a rapid release of 40–70% of the whole loaded drug in less than 1 h [15,27,29]. Consequently, major portion of the drug is released before the NCs reach the targeting tissue or cells, leading to loss of drug efficacy accompanied with increased side effects. In general, the rapid initial release is attributed to the drugs adsorbed onto the surface of PBCA-NCs. Therefore, encapsulating drugs inside PBCA-NCs or binding them chemically onto the surface of PBCA-NCs might avoid burst release. Dispersing PBCA-NCs in the solution with high viscosity has been another good method. Recently, 1–5 lm-sized gas-filled microbubbles (MBs) have attracted significant attention for drug delivery purposes, e.g. ultrasound-mediated drug delivery across biological barriers and ultrasound triggered drug release from the MBs shell. Polymer-based hard-shell MBs are superior to phospholipids-based soft-shell MBs due to their better stability and ability to encapsulate high amounts of drug within their shell. PBCA-based MBs have also been studied as drug delivery systems [111–113]. In addition, PBCA nanocapsules as a potential system for photosensitizer delivery have been used in photodynamic therapy, accompanied with fewer adverse effects and higher selectivity in contrast to the chemo- and radiation therapies [111]. Delivery of NCs from the injection site to the final antitumor targets consists of various transport steps with multiple physiological and biological barriers, including transport via blood to the tumor extracellular matrix

(organ level), binding to the cell membrane (tissue level), internalization (cellular level) and intracellular delivery (cellular level and subcellular level) [114]. Significant progress has been made in PBCA-NCs during the past few years. However, limited targeting sites such as liver, brain, lungs and lymph nodes have been studied for the application of PBCA-NCs, and most of these targeting effects are realized through passive targeting or a simple modification of the surfactant on the surface of PBCA-NCs. Nonetheless, the most effective and promising targeting technique, such as the specific receptor interaction method, has been seldom investigated. Normally, the drug’s therapeutic effect is produced when a drug finally reaches the exact target point. Therefore, to promote the internalization of PBCA-NCs into target cells, regulation of zeta potential such as a positive zeta potential value and specific receptor-ligand binding mode could be effective. In addition, multifunctional NCs are the ideal system to deliver the drugs across various physiological barriers. For example, NCs targeting a beta protein to treat Alzheimer’s disease are first modified with Tween 80 to pass the BBB, and then grafted with beta antibodies to transport NCs to beta sites. However, after being uptaken into specific cells by endocytosis, PBCA-NCs often enter the lysosome, an organelle with different kinds of hydrolysis enzymes, thus leading to the destruction of the drug. The challenge of targeting subcellular organelles is to escape from the degradation of the lysosome and to bind the targeting organelles.

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For this purpose, scientists have designed pH or temperatureresponsive drug delivery systems according to the different microenvironment of each organelle. Materials owning lysosome escaping properties and intracellular receptor specificity can transport PBCA-NCs into subcellular organelles. A mass of efforts should be made to investigate these areas.

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Conclusion In conclusion, PBCA-NCs are biocompatible, biodegradable and easily prepared. After being modified with various materials, they are able to target to different sites or load protein drugs for oral administration, thus being used as drug carriers for the treatment of various diseases such as cancer, AIDS, CNS disorders and so on. However, to utilize them in clinical facilities and exploit their full potential as a drug delivery system, various shortcomings of the PBCA-NCs should be addressed in the future research.

Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper. This work was supported by the Natural Science Foundation of Jiangsu Province (Program No. BK20130655, No. BK2012761), and College Students Innovation Project for the R&D of Novel Drugs (Program No. J1030830) and the National College Students’ innovation entrepreneurial training program (Program No. G12097).

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DOI: 10.3109/1061186X.2015.1020426

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Polybutylcyanoacrylate nanocarriers as promising targeted drug delivery systems.

Among the materials for preparing the polymeric nanocarriers, poly(n-butylcyanoacrylate) (PBCA), a polymer with medium length alkyl side chain, is of ...
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