Preparation And Characterization Of Paclitaxel-loaded PEG-block-P(CL-co-LLA) Polymeric Micelles

Paclitaxel(PTX) is a naturally occurring lipophilic drug that wasorignally extracted from the pacific yew tree Taxus brevifolia. PTX hasgreat antitumor efficacy. However, its poor solubility in water drasticallylimits its use in the natural form. There are two kinds of formulaion in theclinical: Taxol and Abraxane. Taxol is composed of paclitaxel,Cremophor EL, and ethanol. Because of the addition of Cremophor EL andethanol, it has many side effects such as hypersensitivity reactions,neurotoxicity, and nephrotoxicity. Abraxane causes many notable sideeffects as well such as hair loss, infection, fatigue and weakness, low redblood cell count, mouth or lip sores, joint and muscle pain, stomach upset,diarrhea, and cardiovascular effects. So it is urgent to develop a convenientand safe delivery system for PTX to minimize the side effects is urgent.copolymeric micelles have drawn much attention due to their greatflexibility in tuning drug solubility, micelle size, targeted delivery andstability. However, there are only a few reports about micellar carriers withhigh drug loading capacity. With the purpose of obtaining micellar carrierswith high drug loading capacity, we synthesized six kinds of biodegradable polyesters as follows: methoxypoly(ethyleneglycol)-poly(-caprolactone-co-l-lactide), methoxypoly(ethylene glycol)-poly(-caprolactone-co-trimethylene carbonate) and methoxypoly(ethyleneglycol)-poly(l-lactide-co-trimethylene carbonate) with two kinds ofmolecular weight of methoxypoly(ethylene glycol)(2K and5K),respectively. They were characterized by1H NMR and gel permeationchromatography(GPC). Their solubility in water was evaluated by nakedeyes.Then, the corresponding paclitaxel-loaded micellar formulations wereprepared，followed by investigating their stability, particle diameter so asto screen out better drug carriers with higher stability and higher drugloading capability. The MPEG2K-P(CL-co-LLA) andMPEG5K-P(CL-co-LLA) were the needed ones and their correspondingmicelles were selected as the paclitaxel carriers for the following research.Their drug loading content were as high as36wt.%.Thirdly, their release behavior in vitro and antitumor activitiy both invitro and in vivo were evaluated. The in vitro release data showed asustained drug release from PTX-loaded polymeric micelles for350hourswith only a little burst release. We evaluated the antitumor effects ofpaclitaxel-loaded MPEG5K-P(CL-co-LLA) micelle in vivo and in vitro. Inthe MTT assay, blank MPEG5K-P(CL-co-LLA)(10mg/mL) showed nocytotoxity to MGC80-3cell while the tumor inhibition was up to80%ofpaclitaxel-loaded MPEG5K-P(CL-co-LLA)(PTX concentration:20ng/mL).In Pharmacodynamics study, paclitaxel-loaded MPEG5K-P(CL-co-LLA)micelle showed high antitumor efficacy with low cytotoxity and sustainedrelease. Therefore, six biodegradable micellar carriers were synthesized, two of which were selected. Their corresponding micelles had high drugloading capability and sustained release, and showed good antitumor effect.The results showed that paclitaxel-loaded MPEG-P(CL-co-LLA) micelleshad the potential to be promising paclitaxle deliver systems.