| PTCA (Percutaneous Transluminal Coronary Angioplasty) has become one of the most important strategies to treat coronary artery diseases. However, restenosis has been observed in pathological and clinical studies, and poses a formidable problem (15-60%). Currently, there are mainly two local drug delivery syetems are employed to prevent restensis after balloon angioplasty including drug-eluting stent/radioactive stent and catheter-based drug delivery system. The proliferation of VSMC, the cause of restenosis development, could be inhibited by the application of radioactive and drug eluting stents. However, their efficacy and safety have not been confirmed in all clinical settings. It should be also noted that 30-40% of critical lesions cannot be stented, largely because they occur at branch sites or in small arteries. Important safety issues such as thrombosis, late stent malapposition, aneurysm formation, edge effect, late inflammation due to choice of polymer used to bind the drug, the release of toxins, and potential interaction with brachytherapy have not been completely addressed. Thus, non-stent-based local delivery of antiproliferative drugs may offer additional flexibility and efficacy in the entire range of applications. It may also deliver drugs to vessel areas not directly covered by the stent, which could be of special interest for small and tortuous vessels. However, the delivery efficiency and intramural retention time of infused drug solution remains rather low. Nanoparticles modified with a cationic surfactant, didodecyldimethylammonium bromide (DMAB) can greatly enhance arterial retention in animal angioplasty models. Paclitaxel can inhibit neointimal formation in vivo with plasma paclitaxel levels about 100 to 1000 times lower than the concentrations to treat neoplasms. Thus, paclitaxel was selected as a better pharmacologic component to be formulated into nanoparticles.In chapter 1, the recent progress of the research topic was reviewed.The major contents of this paper are shown as follows:Chapter 2. This study tested the possibility of localized intravascular infusion of positive charged paclitaxel-loaded nanoparticles (NPs) to better prevent neointimal formation in a rabbit carotid artery injury model. Paclitaxel-loaded NPs were prepared by oil/water emulsion/solvent evaporation technique using biodegradable poly (lactide-co-glycolide) (PLGA). Urokinase-loaded PLGA NPs were prepared by w/o/w emulsion/solvent evaporation technique. A cationic surfactant, didodecyldimethylammonium bromide (DMAB), was absorbed on the NP surface by electrostatic attraction between positive and negative charges. NPs were characterized in such aspects as size, surface morphology, surface charges as well as in vitro drug release profile. Balloon-injured rabbit carotid arteries were treated with single infusion of paclitaxel-loaded NP suspension and observed for 28 days. The inhibitory effects of NPs on neointima formation were evaluated as end-point. NPs showed spherical shape with a diameter ranging from 200 to 500 nm. Negatively charged PLGA NPs shifted to positive after the DMAB modification. The in vitro drug release profile showed a biphasic release pattern. After 48 hours, the specific activity of released urokinase droped dramatically, indicating that urokinase cann't be used to prepare nanoparticles for a prolonged release. Morphometric analyses on the retrieved artery samples revealed that the inhibitory effect of intima proliferation was dose-dependent. At a concentration of 30 mg ml-1, NP infusion completely inhibited intima proliferation in a rabbit vascular injury model. Paclitaxel-loaded NPs with DMAB modification were proven an effective means of inhibiting proliferative response to vascular injury in a rabbit model.Chapter 3. PCL/F68 was synthesized by bulk polymerization as described previously. Paclitaxel-loaded nanoparticles(NPs) were prepared by solvent displacement method using biodegradable PCL/F68. A cationic surfactant, didodecyldimethylammonium bromide (DMAB), was absorbed on the NP surface by electrostatic attraction between positive and negative charges. NPs were characterized in such aspects as size, surface morphology, surface charges as well as in vitro drug release profile. Balloon-injured rabbit carotid arteries were treated with single infusion of paclitaxel-loaded NP suspension and observed for 90 days. The inhibitory effects of NPs on neointima formation were evaluated as end-point. The obtained PCL/F68 compound has a viscosity average molecular weight of 44,000. PCL/F68 NPs showed porous surface and spherical shape with a mean diameter around 300nm. Negatively charged PLGA NPs shifted to positive after the DMAB modification. The in vitro drug release profile showed a biphasic release pattern. Morphometric analyses on the retrieved artery samples revealed that PCL/F68 NP infusion completely inhibited intima proliferation in a rabbit vascular injury model. Compared with PLGA NPs, the paclitaxel-loaded PCL/F68 has a better effect of inhibiting intima proliferation in animal model (P＜0.05). Paclitaxel-loaded PCL/F68 NPs with DMAB modification represents a longer delay and an effective means of inhibiting proliferative response to vascular injury in a rabbit model.In conclusion, the modified paclitaxel-loaded nanoparticles as local delivery system provide an effective means of inhibting proliferative response to vascular injury in the rabbits.
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