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[email protected] Current Medicinal Chemistry, 2013, 20, 79-94
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Thermosensitive Polymeric Hydrogels As Drug Delivery Systems C. Gong, T. Qi, X. Wei, Y. Qu, Q. Wu, F. Luo and Z. Qian* State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China Abstract: Thermosensitive hydrogels are very important biomaterials used in drug delivery systems (DDSs), which gained increasing attention of researchers. Thermosensitive hydrogels have great potential in various applications, such as drug delivery, cell encapsulation, tissue engineering, and etc. Especially, injectable thermosensitive hydrogels with lower sol-gel transition temperature around physiological temperature have been extensively studied. By in vivo injection, the hydrogels formed non-flowing gel at body temperature. Upon incorporation of pharmaceutical agents, the hydrogel systems could act as sustained drug release depot in situ. Injectable thermosensitive hydrogel systems have a number of advantages, including simplicity of drug formulation, protective environment for drugs, prolonged and localized drug delivery, and ease of application. The objective of this review is to summarize fundamentals, applications, and recent advances of injectable thermosensitive hydrogel as DDSs, including chitosan and related derivatives, poly(N-isopropylacrylamide)-based (PNIPAAM) copolymers, poly(ethylene oxide)/poly(propylene oxide) (PEO/PPO) copolymers and its derivatives, and poly(ethylene glycol)/biodegradable polyester copolymers.
Keywords: Injectable, thermosensitive, hydrogel, phase transition, drug delivery, controlled release, chitosan, N-Isopropylacrylamide, pluronic, PEG, PLA, PLGA, PCL, PCLA, PHB. 1. INTRODUCTION Drug delivery systems (DDSs) are rapidly developing fields, which are underpinned by the progress in the fields of chemistry, pharmaceutics, biotechnology, nanotechnology, and etc [1-3]. Controlled DDSs are designed to deliver drugs at predetermined rates for desirable times or specific sites, which have been used to achieve the improved therapeutic effects and to overcome the shortcomings of conventional drug formulations [4]. Although remarkable advances have been made in recent years, more progress is yet to be performed in the field of DDSs. Hydrogels are a special class of polymeric networks, which can absorb and retain a large amount of water while maintaining their three-dimensional integrity [4-6]. In past decades, the stimuli-sensi tive hydrogels have gained increasing attention owing to their smart responsibility to the environmental stimulus, including chemical substances and changes in temperature, pH, light, pressure, electric field or etc [7-10]. Among the stimuli sensitive hydrogels, the in situ gel-forming hydrogels have been widely investigated, which were sol state before administration but formed non-flowing gels after administration [11-13]. The in situ gel-forming hydrogels can be formed by chemical crosslinking (covalent bonds) or physical junctions (hydrophobic interactions, electrostatic interactions, chain entanglements or etc) [11, 13]. Compared with the permanent networks formed by chemical crosslinking, the in situ gel-forming hydrogels formed by physical junctions show a reversible phase transition behavior by varying the environmental conditions [14]. They have several advantages, including absence of crosslinking agents, without photo irradiation, organic solvents free, and no heat released during polymerization. Especially, the thermosensitive physical crosslinked in situ gel-forming hydrogels with sol-gel transition have been extensively studied due to their potential biomedical applications, including controlled drug delivery, cell encapsulation and tissue engineering [13-24]. As advanced DDSs, the injectable thermosensitive hydrogels act as a very important role [13, 24, 25]. At or below ambient temperature, the thermosensitive hydrogels are free flowing sol. Then, by in vivo injection, the hydrogels convert into non-flowing gel at body temperature. Upon incorporation of pharmaceutical agents into the hydrogel, the systems could potentially act as sustained *Address correspondence to this author at the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China; Tel: 86-28-85164063; Fax: 86-28-85164060; E-mail:
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drug release depot in vivo [8, 24, 26, 27]. The injectable thermosensitive hydrogel systems exhibit many advantages, such as enhanced solubility of hydrophobic drugs, enhanced safety (no organic solvents, no toxic initiators, and less systemic toxicity), simple drug formulation and administration, without surgery procedure, sustained release behavior, site-specificity, and delivery of various types of drugs (hydrophilic drugs, hydrophobic drugs, peptides, proteins, nucleic acid and etc). Therefore, in situ administration of drugs assisted by injectable thermosensitive hydrogel is an interesting route for local drug delivery. This review explores recent progress addressing the synthesis, structure-property relationship, phase transition mechanisms, and biomedical applications of injectable thermosensitive hydrogels, covering chitosan and related derivatives, poly(N-isopropylacry lamide)-based (PNIPAAM) copolymers, poly(ethylene oxide)/poly (propylene oxide) (PEO/PPO) copolymers and its derivatives, and poly(ethylene glycol)/biodegradable polyester copolymers. 2. CHITOSAN AND RELATED DERIVATIVES Chitosan is a linear polysaccharide derived from the partial deacetylation of chitin, a natural component of crustacean and insects exoskeleton [28]. Chitosan is composed of randomly distributed -(1-4)-linked D-glucosamine and N-acetyl-D-glucosamine units, which is shown in Fig. (1A). Due to its non-toxicity, biodegradability, biocompatibility, stability, and bioadhesive properties, chitosan was approved by US Food and Drug Administration (FDA) and has been widely applied in biomedical fields [29]. Chenite and colleagues developed an interesting reverse thermal-responsive hydrogel composed of chitosan and -glycerolphos phate (GP) [30]. Chitosan was dissolved in hydrochloric acid solution, and a GP solution was prepared and kept in an ice bath along with the chitosan solution. Then, the chilled GP solution was added dropwisely to cold chitosan solution with stirring to form chitosan/GP solution. At neutral pH, the chitosan/GP solution was a homogeneous and clear liquid at room temperature, and became a gel rapidly at around body temperature upon heating. Molecular weight of the chitosan had no effect on the gelation temperature, but gelation temperature decreased as the degree of deacetylation increased. The gelation rate was affected by chitosan deacetylation degree, concentration of GP, pH and temperature of chitosan/GP solution [31]. Gelation of chitosan/GP solution may drive by hydrophobic association of the neutral chitosan molecules, which can be enhanced by the influence of GP on water at higher temperature © 2013 Bentham Science Publishers
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[31]. Biocompatibility of chitosan/GP hydrogel was investigated in detail. Chitosan with higher deacetylation degrees yielded a lesser inflammatory reaction in vivo by subcutaneous injection, and dexamethasone could practically abolish it [32]. Recently, Ahmadi and Bruijn found that extracts of chitosan/GP hydrogel could stimulate mesenchymal stem cell (MSC) proliferation at certain concentrations, which indicated the material is a promising vehicle for cell encapsulation and tissue engineering [33]. The morphology of the chitosan/GP was investigated by laser scanning confocal microscopy (LSCM), and the results showed that the hydrogel is quite heterogeneous with fractal-like morphology [34]. Kempe et al. found that the spin-labelled insulin incorporated into the aqueous environment of the hydrogel was released in its native form [35]. In addition, they also claimed the in vitro release behavior of the insulin was governed by diffusion of drug from the hydrogel matrix, and the amount of released drug was increased with increase of GP proportion. Chitosan/GP hydrogel prepared by the drug being added into chitosan solution showed a slower release profile than that prepared by the drug being directly added in to hydrogel. It is very interesting that release of hydrophilic drug adriamycin from chitosan/GP hydrogel was slower than that of hydrophobic 6mercaptopurine [36]. Moreover, the chitosan/GP hydrogel system was examined for delivery of bone protein (BP) in vivo and encapsulation of chondrocytes for tissue engineering [30]. Chitosan/GP hydrogel system was evaluated for pharmaceutical applications, which suggested the hydrogel system could deliver macromolecules up to several days [37-39]. Hydrophilic drugs were first incorporated into liposomes and then mixed with chitosan/GP hydrogel to achieve a slow release rate [38]. Furthermore, local tumor recurrence could be prevented by the local administration of paclitaxel (PTX) loaded chitosan/GP hydrogel [39]. The chitosan/GP hydrogel system was also applied for cell delivery in cartilage repair [40]. Ellagic acid (EA) and EA loaded PLGA nanoparticles were incorporated into chitosan/GP hydrogel for sustained delivery via subcutaneous route to improve its bioavailability [41]. Han et al. reported that chitosan/GP hydrogel system exhibited synergistic antitumor effects by combining chemotherapy with a vaccinia viral vaccine [42]. More recently, EA loaded chitosan/GP hydrogel was investigated for treatment of brain cancer in vitro [43]. A novel chitosan/GP-elastin-like polymers hydrogel system was developed for bone tissue engineering with drastically improved mechanical properties at physiological conditions [44]. Bhattarai and coworkers developed an injectable and thermoreversible hydrogel based on poly(ethylene glycol)-graft-chitosan (PEG-g-chitosan, Fig. (1B)) without additional crosslinking agents [45]. PEG-g-chitosan was prepared by grafting monohydroxy PEG onto the chitosan backbone. By optimizing the content and molecular weight of PEG in the polymer, PEG-g-chitosan exhibited a thermoreversible phase transition from an injectable sol at ambient temperature to a gel at physiological temperature. The phase transition is believed to be the association of chitosan chains and reduction in the mobility of the PEG block at high temperatures. Furthermore, the same group investigated the in vitro release behavior of PEG-g-chitosan hydrogel using bovine serum albumin (BSA) as a model protein drug [46]. BSA could be steadily released for about 70 hours after an initial burst release. More recently, a novel chitosan-PEG diblock copolymer was synthesized by block copolymerization of monomethoxy PEG macromere onto chitosan chain using potassium per sulfate as a free radical initiator, and the prepared chitosan-PEG aqueous solution also showed a reversible thermogelling behavior [47]. Park and colleagues reported the synthesis and characterization of Pluronic-chitosan copolymer as thermally reversible hydrogels (Fig. (1C)) [48]. Moreover, the same group described the Pluronicchitosan hydrogel as an injectable cell delivery carrier for cartilage regeneration [49]. PNIPAAM-chitosan thermoreversible hydrogel was also investigated for cell carriers and drug delivery, which was
Gong et al.
mentioned in section 3 and was not described here in detail (Fig. (1D)) [50-54]. OH HO
HO
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Fig. (1). The chemical structure of chitosan (A) PEG-g-chitosan (B), chitosan-Pluronic (C), and chitosan-g-NIPAAM (D).
Chitosan was modified by conjugation of hydroxybutyl groups to its backbone, which rendered it water solubility and thermosensitivity, and the formed gel at body temperature is strong enough to maneuver with forceps [55]. Human MSC and cells derived from the intervertebral disk could proliferate after encapsulated in the hydrogel. Chitosan and gelatin blends hydrogel also claimed to form gels rapidly at body temperature, which have promising perspective for use in local and sustained delivery of protein drugs [56]. The thermosensitive hydrogel system based on chitosan and poly(vinyl alcohol) (PVA) was reported and applied for protein delivery [57-59]. The hydrogel was believed to be formed by hydrogen bonds between chitosan chains and PVA and hydrophobic interactions of chitosan chains [57]. Furthermore, hydroxyapatite
Thermosensitive Hydrogel As DDSs
was added into chitosan/PVA system to form a composite hydrogel, and the composite hydrogel showed a notably enhanced strength [58]. N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) was synthesized by the reaction of chitosan and glycidyltrimethylammonium chloride (GTMAC). Thermo- and pHsensitive hydrogel composed of HTCC and GP was described by Wu et al., and release behavior of doxorubicin hydrochloride (Dox) from the hydrogel system at different pH values was investigated [60]. Latter, the same group prepared a HTCC/PEG/GP thermosensitive hydrogel system for nasal drug delivery [61]. The insulin loaded hydrogel decreased the blood glucose by 40-50% for at least 4-5 h after administration. In another contribution, an N-trimethyl chitosan/GP (TMC/GP) thermogelling hydrogel was prepared for protein delivery [62]. Besides, biocompatibility of chitosanHTCC/GP hydrogel was investigated, and the hydrogel showed excellent biocompatibility and may had potential as injectable DDS and tissue-engineering scaffold [63]. Recently, a new chitosan-dibasic orthophosphate hydrogel with thermoreversible gelation behavior was developed by Ta and colleagues [64-66]. They found the hydrogel could gel at physiological conditions and release incorporated agents in a sustained manner. In addition, they suggested that the chitosan/dipotassium hydrogen orthophosphate (chitosan/DHO) hydrogel is potential controlled delivery systems for different therapeutic agents [66]. Dox loaded chitosan/DHO hydrogel system was used to evaluate the therapeutic effect on a clinically relevant orthotopic osteosarcoma (OS) model. A significant reduction of both primary and secondary OS was observed, and the hydrogel system also reduced cardiac and dermal toxicity of Dox in mice [64]. The same group investigated the OS gene therapy with pigment epithelium-derived factor (PEDF) combined with chemotherapy [65]. The results showed that the combination of plasmid treatment and chemotherapy together with the use of chitosan/DHO hydrogel led to the highest suppression of tumor growth without side effects. Another chitosan-dibasic orthophosphate hydrogel system, chitosan/dibasic sodium phosphate (chitosna/DSP), was described by Li et al. [67, 68]. The hydrogel system exhibited two phase transition points corresponding to 30oC to 43 oC as temperature increases, which is gel state at 4 oC, sol state at 30 oC, and gel again at 37 oC [67]. Moreover, the hydrogel system was used for local delivery of camptothecin (CPT) nanoocolloids [68]. 3. N-ISOPROPYLACRYLAMIDE COPOLYMERS Of the many thermo-responsive polymers, PNIPAAM and its copolymers are one class of most intensively investigated. The structure of PNIPAAM is shown in Fig. (2A). PNIPAAM-based hydrogels are often studied for the structure-property relationship [69, 70], drug delivery [71-74], cell encapsulation [75], and tissue engineering [76]. It is well known that PNIPAAM exhibits the phenomenon of lower critical solution temperature (LCST) phase transition in water. PNIPAAM is soluble below 32oC and precipitates at or above 32 oC in aqueous solution. Below the LCST, hydrogen bonding between polar amide groups in PNIPAAM and water molecules results in the dissolution of the polymer. At or above the LCST, PNIPAAM becomes hydrophobic due to the coil-to-globule transition, which leads to precipitation [77, 78]. The LCST of PNIPAAM can be controlled by grafting with other monomers. Copolymerization of PNIPAAM with a more hydrophobic monomer results in a reduced LCST. Likewise, incorporating PNIPAAM with a more hydrophilic monomer leads to an elevated LCST [79, 80]. Furthermore, pH and salts also have effect on LCST of aqueous PNIPAAM solution to some extent [81, 82]. By addition of polymers with different hydrophobicity into PNIPAAM backbone, the obtained copolymer hydrogels may undergo sol-gel phase transition, instead of volume phase (swelling-
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shrinking) transition. Ham and Bea found that aqueous solution of high molecular weight poly(N-Isopropylacrylamide-co-acrylic acid) (P(NIPAAM-AA), (Fig. (2B)) copolymer exhibited reversible solgel phase transition at approximately 32oC above the CGC of about 4 wt% [83]. Aqueous P(NIPAAM-AA) solution did not precipitate at LCST like PNIPPAM in water, but it showed a clear sol-opaque sol-opaque gel-shrunken gel phase transition instead as temperature increased. Besides, upon cooling, P(NIPAAM-AA) hydrogel reverted to sol state without showing hydteresis between phase transition temperatures. An interesting phenomenon of the P(NIPAAMAA) hydrogel is that it did not dissolve or swell in water. The solgel transition may results from the copolymer chain entanglements and the formation of hydrophobic physical junctions by collapsed copolymer globules with expanded copolymer coils. A refillable biohybrid artificial pancreas was reported by entrapping islets of Langerhans into P(NIPAAM-AA) hydrogel [84-88]. The isolated islets of Langerhans was suspended in the P(NIPAAM-AA) solution, and then was incorporated in the hydrogel when the temperature increased to physiological temperature. Besides, P (NIPAAMAA) hydrogel could efficiently immobilize rat islets of Langerhans with higher permeability of insulin and showed prolonged insulin secretion. Recently, P(NIPAAM-AA) hydrogel was found to be a promising cell and drug delivery matrix [75], and articular chondrocytes incorporated in the P(NIPAAM-AA) hydrogel could keep the phenotype with a round shape [89]. A series of PNIPAAM/PEG copolymers have been studied. The formation of thermoreversible micelles by PEG-PNIPAAM-PEG [90] or PEG-PNIPAAM [91] in water was investigated, respectively (Fig. (2C)). A family of linear and star-shaped copolymers with a central hydrophilic PEG block and terminal thermosensitive PNIPAAM block have been synthesized [92]. The aqueous copolymer solutions were a sol state at lower temperature, and formed a gel at body temperature, when the copolymer concentration was higher than 20 wt%. Moreover, the formed gel exhibited no syneresis, and the sol-gel transition process was reversible without hysteresis. The gelation mechanism of star-shaped hydrogel was claimed to be the formation of a strong associative network owing to the aggregation of PNIPAAM blocks above LCST, while the diblock copolymer gelation was contributed to micellar aggregation. The application of similar copolymers as immobilization and culturing of chondrocytes was reported [93]. More recently, a novel PEG diacrylate (PEG-DA) crosslinked PNIPAAM hydrogel was prepared and applied as ocular drug delivery platform [94]. Upon injection of PEG-DA crosslinked PNIPAAM hydrogel, only a small transient effect on retinal function was found, without any longterm effects. The synthesis of a family of macromers based on NIPAAM, pentaerythritol diacrylate monostearate (PEDAS), acrylamide (AAm), and hydroxyethyl acrylate (HEA) were reported [95, 96]. By varying the relative concentrations of comonomers, aqueous macromer solution underwent thermally induced physical gelation. Monomers containing NIPAAM, PEDAS, HEA, and vinylphosphonic acid were also synthesized by the same group. Aqueous solution of the synthesized monomer underwent thermogelation around body temperature (36.2 to 40.5oC). By adding calcium ions in solution, the sol-gel transition temperature decreased in some extent (27.6 to 34.4 oC) [97]. PNIPAAM-poly(2-methacryloy loxyethyl phosphorylcholine)-PNIPAAM (PNIPAAM-PMPC-PNI PAAM) copolymers were achieved using atom transfer radical polymerization (ATRP), and the triblock copolymer aqueous solution at concentration of 6-7% wt. formed freestanding physical gels at 37oC owing to hydrophobic interactions between PNIPAAM segments [98]. The same group also reported the synthesis of PPOPMPC-PNIPAAM triblock copolymers [99]. When temperature increased, aqueous solution of the copolymer exhibited unimersmicelles and micelles-gel transitions at about 15oC and 37oC, respectively. Aqueous solution of poly(methyl methacrylate)-PNI
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H2 C
H C
H2 C
H C
O
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C
NH
OH
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n C
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Y O
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B: P(NIPAAM-co-AA)
CH3 CH3O
CH2CH2O
C
C
O
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CH2
CH
m
n O
CH3 C
NH
CH CH3
C: PEG-b-PNIPAAM
Fig. (2). The chemical structure of PNIPAM (A), P(NIPAAM-AA) (B), and PEG-b-PNIPAAM) (C) copolymers.
PAAM (PMMA-PNIPAAM) copolymer formed a gel at the concentration above 10% wt., and showed a significant syneresis at 31oC [100]. Incorporation of methylcellulose (MC) in PNIPAAM prevented the synersis of copolymer hydrogel [101]. Sol-gel transition of PNIPAAM-g-MC copolymer solution with a certain range of MC content occurred reversibly within 1 min near body temperature. A family of injectable, rapid gelling and highly flexible hydrogel composites based on poly(NIPAAM-AAc-NAS-HEMAP TMC) were synthesized [102]. The hydrogel composites were capable of releasing insulin-like growth factor and delivery mesenchymal stromal cell, and for application in chronic infracted myocardium [103]. Bea et al. described the PNIPAAM-g-chitosan thermoreversible hydrogel, which was used to the sustained release of 5-fluorouracil (5-Fu) [54]. Furthermore, PNIPAAM-g-chitosang-hyaluronic acid (PNIPAAM-g-chitosan-g-HA) hydrogel exhibited reversible sol-gel phase transition at 30oC above concentration of 5% [52]. In vitro cell culture in PNIPAAM-g-chitosan-g-HA hydrogel demonstrated beneficial effects on the cell phenotypic morphology, proliferation, and differentiation. Otherwise, PNIPAAM-g-chitosan and PNIPAAM-g-chitosan-HA hydrogels were investigated as injectable carriers for drug delivery and cell carriers [50, 51, 53]. PNIPAAM-g-HA copolymer solution formed a gel state at around 30-33oC, and the gel could sustained release of riboflavin [104]. Recently, thermosensitive injectable aminated hyaluronic acid-g-PNIPAAM (AHA-NIPAAM) hydrogel with solgel transition was developed for adipose tissue engineering [105]. NIPAAM homopolymer and copolymers may have great potential in biomedical applications, however, it should be noted that clinical applications of PNIPAAM and its copolymers have limitations. PNIPAAM and its copolymers are not biodegradable [106]. Furthermore, upon contact with blood, the acrylamide-based polymers activate platelets [26]. In addition, metabolism of PNIPAAM is far from fully clear. All the above mentioned problems make them difficult to win FDA approval. 4. PEO/PPO BLOCK COPOLYMERS The poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers, known as Pluronics
(BASF) or Poloxamers (ICI), were widely used as non-ionic surfactants, solubilizers and DDSs [107]. The aqueous solutions of some Pluronics demonstrated phase transitions from sol to gel at the lower critical gelation temperature (LCGT) and from gel to sol at the upper critical gelation temperature (UCGT) with the temperature increasing when the copolymer concentration was above critical gelation concentration (CGC) [24, 29, 108]. The commercial Pluronics were the most widely used reverse thermal gelation copolymers, and the chemical structure of the Pluronic is shown in Fig. (3A). The gelation mechanism of aqueous Pluronic solutions has been extensively investigated, but is still a controversy. Intrinsic changes in micellar properties as temperature increases was claimed to cause the gelation process, including micellar symmetry and aggregation number [109]. Later, 13C-NMR study on Pluronic aqueous solution indicated that the gelation was attributed to the dehydration of PPO segment [110]. The following studies suggested that gelation was driven by the entropy change caused by micellar association and interactions [111]. Based on the static and dynamic light scattering (SLS and DLS) of Poloxamer 188 aqueous solution, the unimer, transition, and micelle were claimed to be the three temperature regions of the Poloxamer aqueous solutions [112]. After that, various instrumental techniques were used to study the gelation mechanism of Pluronic aqueous solutions, including SLS, DLS, rheology, small angel neutron scattering (SANS), small angel X-ray scattering (SAXS), and etc [113-116]. Mortensen and Pedersen reported that at lower temperature, Pluronic unimers equilibrated with micelles in aqueous solutions. As the temperature increased, equilibrium shifted from unimers to micelles, which led to an increase in micelle volume fraction (m). When the m reached a critical value about 0.53 for hard-sphere crystal formation, gelation occurs due to micelle packing [117]. For the upper gel-sol phase transition, it is believed to be temperature-induced dehydration of PEO blocks, which caused the shrinkage of PEO shell of the micelles [118]. More recently, Yang and Ding designed a macromonomer composed of Pluronic F127 with end-capped by acryloyl groups, and the macromers could form micelles in aqueous solution. By polymerzing macromers in a micelle, a nanogel composed of Pluronic F127 was prepared. They found even the crosslinked micelles
Thermosensitive Hydrogel As DDSs
(nanogel) could form a physical hydrogel, therefore, they unambiguously indicated the micelle restructure is not necessary for the physical gelation of thermosensitive hydrogel [119]. Because of the lower CGC and the least toxicity in the commercially available Pluronics series, F127 (Poloxamer 407) has been studied most extensively as DDS [120]. At a concentration of 20 wt%, the aqueous solution of Pluronic F127 is a viscous sol at or below room temperature (
