[Show abstract][Hide abstract] ABSTRACT: Postsurgical peritoneal adhesion is a major concern in clinical practice which causes significant morbidity and mortality. In this study, we investigated the efficacy of biodegradable and injectable thermosensitive poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG) micelles in preventing postsurgical cauterization-induced peritoneal adhesion. The biodegradable PEG-PCL-PEG copolymer could form nano-sized micelles in water, which instantly turned into a non-flowing gel at body temperature due to micellar aggregation. Moreover, a novel sidewall and cecum cauterization rat model was developed and the micelles were assigned for adhesion prevention tests. The PEG-PCL-PEG micelles could be administered by an ordinary syringe and provided unrestricted coverage of the cauterized peritoneum. The micelles instantly formed a gel in situ at body temperature and the formed gel could adhere to the cauterized sites as a durable barrier during critical time of adhesion formation. All rats from the control group (n = 10) developed score 5 adhesion, whereas, eight out of ten rats in the micelle-treated group showed no adhesion at all. Besides, cauterization-induced adhesion formation, adhesiveness and degradation of micelles, remesothelization of peritoneum, and restoration of cauterized tissue were investigated in detail. Our results thus indicated that, it was feasible to use biodegradable and injectable thermosensitive PEG-PCL-PEG micelles for prevention of peritoneal adhesions after surgery.
[Show abstract][Hide abstract] 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.
Current Medicinal Chemistry 10/2012; 20(1). DOI:10.2174/0929867311302010079 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis plays an important role in tumor growth and metastasis, therefore antiangiogenic therapy was widely investigated as a promising approach for cancer therapy. Recently, pigment epithelium-derived factor (PEDF) has been shown to be the most potent inhibitor of angiogenesis. Adeno-associated virus (AAV) vectors have been intensively studied due to their wide tropisms, nonpathogenicity, and long-term transgene expression in vivo. The objective of this work was to evaluate the ability of AAV-mediated human PEDF (hPEDF) as a potent tumor suppressor and a potential candidate for cancer gene therapy.
Recombinant AAV2 encoding hPEDF (rAAV2-hPEDF) was constructed and produced, and then was assigned for in vitro and in vivo experiments. Conditioned medium from cells infected with rAAV2-hPEDF was used for cell proliferation and tube formation tests of human umbilical vein endothelial cells (HUVECs). Subsequently, colorectal peritoneal carcinomatosis (CRPC) mouse model was established and treated with rAAV2-hPEDF. Therapeutic efficacy of rAAV2-hPEDF were investigated, including tumor growth and metastasis, survival time, microvessel density (MVD) and apoptosis index of tumor tissues, and hPEDF levels in serum and ascites.
rAAV2-hPEDF was successfully constructed, and transmission electron microscope (TEM) showed that rAAV2-hPEDF particles were non-enveloped icosahedral shape with a diameter of approximately 20 nm. rAAV2-hPEDF-infected cells expressed hPEDF protein, and the conditioned medium from infected cells inhibited proliferation and tube-formation of HUVECs in vitro. Furthermore, in CRPC mouse model, rAAV2-hPEDF significantly suppressed tumor growth and metastasis, and prolonged survival time of treated mice. Immunofluorescence studies indicated that rAAV2-hPEDF could inhibit angiogenesis and induce apoptosis in tumor tissues. Besides, hPEDF levels in serum and ascites of rAAV2-hPEDF-treated mice were significant higher than those in rAAV2-null or normal saline (NS) groups.
Thus, our results suggest that rAAV2-hPEDF may be a potential candidate as an antiangiogenic therapy agent.
BMC Cancer 03/2012; 12(1):129. DOI:10.1186/1471-2407-12-129 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this work, a novel vaccine delivery system, biodegradable nanoparticles (NPs) in thermosensitive hydrogel, was investigated. Human basic fibroblast growth factor (bFGF)-loaded NPs (bFGF-NPs) were prepared, and then bFGF-NPs were incorporated into thermosensitive hydrogel to form bFGF-NPs in a hydrogel composite (bFGF-NPs/hydrogel). bFGF-NPs/hydrogel was an injectable sol at ambient temperature, but was converted into a non-flowing gel at body temperature. The in vitro release profile showed that bFGF could be released from bFGF-NPs or bFGF-NPs/hydrogel at an extended period, but the release rate of bFGF-NPs/hydrogel was much lower. In vivo experiments suggested that immunogenicity of bFGF improved significantly after being incorporated into the NPs/hydrogel composite, and strong humoral immunity was maintained for longer than 12 weeks. Furthermore, an in vivo protective anti-tumor immunity assay indicated that immunization with bFGF-NPs/hydrogel could induce significant suppression of the growth and metastases of tumors. Thus, the NPs/hydrogel composite may have great potential application as a novel vaccine delivery system.
[Show abstract][Hide abstract] ABSTRACT: In this work, a biodegradable poly(ethylene glycol)-poly(epsilon-caprolactone)-poly (ethylene glycol) (PEG-PCL-PEG, PECE) triblock copolymer was successfully synthesized. The aqueous solution of such PECE copolymer displayed special sol-gel-sol transition as temperature increase, which is a flowing sol at low-temperature and turns into a nonflowing gel at body temperature. The cytotoxicity of PECE copolymer was evaluated by cell viability assay using HEK 293 cells. In vivo gel formation and degradation test based on intraperitoneal and subcutaneous administration was conducted, respectively. The acute toxicity test and histopathological study were performed in BALB/c mice by intrapleural, intraperitoneal, or subcutaneous administration of PECE hydrogel (30 Wt %), respectively. The dose of intrapleural, intraperitoneal, or subcutaneous administration was up to 10 g/kg body weight (b.w.), 25 g/kg b.w., and 25 g/kg b.w., respectively, and the mice were observed continuously for 14 days. For histopathologic study, samples including heart, liver, lung, kidneys, spleen, stomach, intestine, and tissue of injection site were prepared for histochemical analysis and were stained with hematoxylin-eosin. No mortality or significant signs of acute toxicity was observed during the whole observation period and there is no significant lesion to be shown in histopathologic study of major organs. Therefore, the maximum tolerance dose of PECE hydrogel by intrapleural, intraperitoneal, or subcutaneous administration was calculated to be higher than 10 g/kg b.w., 25 g/kg b.w., and 25 g/kg b.w., respectively. The results indicated that the prepared PECE hydrogel was nontoxic after intrapleural, intraperitoneal, or subcutaneous administration, and it could be a safe candidate for in situ gel-forming controlled drug delivery system.
Journal of Biomedical Materials Research Part B Applied Biomaterials 10/2009; 91(1):26-36. DOI:10.1002/jbm.b.31370 · 2.33 Impact Factor