Injectable block copolymer hydrogels for sustained release of a PEGylated drug
Introduction
Over the past few decades, polymeric drug delivery systems have been an issue of intensive research (Csaba et al., 2006, Hoffman, 2002, Langer, 1998, Park et al., 2006, Sadzuka et al., 2006, Yamagata et al., 2006, Zhang et al., 2005a). Among various sorts of sustained release carriers, in situ-formed polymeric hydrogels have recently been paid much attention as an injectable topical carrier due to the advantages of easy formulation, high loading and free of any organic solvent etc. (Itoh et al., 2006, Jeong et al., 1997, Kang et al., 2006, Kissel et al., 2002, Ricardo et al., 2005, Shim et al., 2007, van de Wetering et al., 2005). Compared to chemically crosslinked hydrogels (van de Wetering et al., 2005, Wang et al., 2006), physical thermogelling of some polymer aqueous solutions is especially attractive due to free of initiator and unreacted agents, and also due to convenience of formulation (Jeong et al., 1997, Kang et al., 2006, Zentner et al., 2001). Such a system makes drugs or bioactive molecules easily entrapped in situ by a simple syringe injection of their aqueous solutions at target sites. It is not hard to understand that as an ideal drug vehicle, the favorite thermogelling material might exhibit lower critical solution temperature (LCST) behaviors, namely, the underlying polymer aqueous solution is in a sol state below room temperature or body temperature while gelling at body temperature. The mixing of drug with polymer at low temperatures is beneficial for protecting drug away from denaturing, aggregation and any undesired chemical reaction.
So far, several temperature responsive polymers have been tried in drug delivery (Coughlan and Corrigan, 2006, Ruel-Gariepy and Leroux, 2004, Wu et al., 2006, Zhang et al., 2005a, Zhang et al., 2005b). Poloxamer or pluronic hydrogels composed of poly(ethylene glycol-b-propylene glycol-b-ethylene glycol) perhaps represent the most extensively researched LCST thermogelling drug delivery system. For example, poloxamer hydrogel displayed a zero-order release profile for urease and interleukin-2 over 8 h (Fults and Johnston, 1989, Johnston et al., 1992). However, poloxamer is not considered an optimal drug delivery system due to its non-biodegradability and relatively fast dissolvability at the injection site. A kind of novel thermogelling triblock copolymers has thus been reported as controlled release drug carriers (Chen et al., 2005, Qiao et al., 2005, Tyagi et al., 2004, Zentner et al., 2001). These polymers are composed of hydrophilic poly(ethylene glycol) (PEG) (A) and biodegradable hydrophobic polyester (B), for instance, poly(lactic acid-co-glycolic acid) (PLGA), usually in the form of a symmetric triblock copolymer with an architecture of BAB or ABA type, with some appropriate compositions leading to also LCST behaviors (Jeong et al., 1999a, Shim et al., 2002, Yu et al., 2007, Yu et al., 2006). The integrity of the gel remains in rats over 4 weeks and the final degradation products are no toxic and can be obviated (Jeong et al., 2000). The degradation rate, burst release rate, sol–gel transition temperature and permeability of hydrogel matrix can be modified by molecular weight (MW) of polymers, PLGA/PEG ratio, lactide/glycolide (LA/GA) ratio, concentration, and even the end group, etc. (Chen et al., 2005, Qiao et al., 2005, Shim et al., 2002, Yu et al., 2007, Yu et al., 2006).
On the other hand, PEG has been approved by the Food and Drug Administration (FDA) and many authority bureaus for internal consumption and injection in a variety of foods, cosmetics, personal care products, and pharmaceuticals. The attachment of a PEG chain to a protein, an organic drug, or a liposome, so-called PEGylation, has so far been well known to prolong circulating time of many drugs in body. PEGylation can lead to a stealthy liposome (Sadzuka et al., 2006). This stealthy property is beneficial for alleviating protease degradation and immunogenicity. PEGylation has indeed been a fashion in the field of controlled release during the past few decades (Greenwald et al., 2003, Sadzuka and Hirota, 1997, Vyas et al., 2006).
We here suggest the combination of the PEGylation technique of drug and the in situ implant technique of release carriers based upon the above thermogelling material. Such a combination might be with significant progress and striking advantages: the topically formulated drug could be sustained released from the hydrogel for a quite long time, meanwhile the released drug could be circulated for a long time, and thus the efficacy might be greatly enhanced. To our best knowledge, there is so far no report about encapsulation of a PEGylated drug into the thermogelling PLGA–PEG–PLGA block copolymers. Will this physical gel system be valid to encapsulate and deliver a PEGylated drug? Will the gel formation be influenced by loading of a PEGylated drug into the material? These fundamental problems are still open, and thus the methodology studies are highly called for at this stage.
Camptothecin (CPT) is an anti-tumor Chinese medicine which can kill cells by converting DNA topoisomerase I into a DNA-damaging agent. However, both the low water solubility of the drug and the opening of its active lactone ring at physiological pH (and higher pH) limit its clinical application. It has been reported that modifying CPT at the 20th position as a PEG ester not only achieves the soluble transport form of CPT but also stabilizes the active lactone ring under physiological conditions (Greenwald et al., 1996). In the present paper, PEGylated CPT was prepared and it was employed as the model drug to examine the validity of the carrier system of PLGA–PEG–PLGA materials for a PEGylated drug. The PEGylated drug was found to alter the gelling points of such a polymeric biomaterial. Both in vitro and in vivo experiments were performed. A successful controlled release lasting for 1 month was achieved. The release mechanism was also discussed.
Section snippets
Materials
Poly(ethylene glycol)s with two MW (PEG 1000 and PEG 1500; Sigma), monomethoxy-poly(ethylene glycol) (MPEG 5000; Sigma), dl-lactide (Purac), glycolide (Purac), stannous octoate (Aldrich), N,N′-dicyclohexyl carbodiimide (DCC; Aldrich), 4-dimethylamiopryidine (DMAP; Acros) were used as received. 20(S)-camptothecin (CPT, 95% purity) was purchased from Shanghai Junjie Biotechnology Co., Ltd. All other chemicals used were reagent grade and used as purchased without further purification.
Animals
S-180 sarcoma
Characterization of synthesized products
PLGA–PEG–PLGA triblock copolymers were obtained in an about 85% yield. The NMR peaks at 4.80, 3.60, 1.55 ppm were used to calculate the number average MW of the PLGA–PEG–PLGA triblock copolymer (Jeong et al., 1999b). The MW and their polydispersity indexes of the triblock copolymers and composition ratios of LA/GA or PEG/PLGA were determined via both GPC and 1H NMR. The results are shown in Table 1.
MPEG-CPT was synthesized by two steps as shown in Scheme 1. FT-IR spectra of MPEG, MPEG-acid,
Conclusion
The biodegradable thermogelling PLGA–PEG–PLGA copolymers with the different compositions were synthesized as a sustained drug carrier, along with MPEG-CPT as a model of a PEGylated drug. By formation of a nano-particle, the PEGylation of CPT enhanced the solubility of the hydrophobic CPT in water to several orders of magnitude. The sustained release of MPEG-CPT from PLGA–PEG–PLGA hydrogels was confirmed, which lasted for 1 month. The early release was sensitive to polymer concentration but less
Acknowledgements
We are grateful for the financial support from NSF of China (Nos. 20574013 and 50533010), the Key Grant of Chinese Ministry of Education (No. 305004), 973 project (No. 2005CB522700), Science and Technology Developing Foundation of Shanghai (No. 055207082), and 863 project from Chinese Ministry of Science and Technology. The helps from Dr. Bin Shi and Dr. Xinyi Sha of School of Pharmacy, Fudan University are also appreciated.
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