Synthesis Of Polyethylene Glycol-polylactide-β-cyclodextrins For Drug Delivery

Most of the peptide and protein drugs are hydrophilic macromolecules. They are wellknown for their therapeutic potential in various diseases.However, considerable hurdles needto be overcome before practical use can be made of therapeutic peptides and proteins, i.e.,their chemical and enzymatic instability, poor absorption through biological membranes, rapidplasma clearance, peculiar dose-response curves, and immunogenicity. Additionally,doxorubicin (DOX) hashighcytotoxicityin spite ofit’santicancer activity. Therefor, it isextremelyimportant to reseach controlled-release formulation of these drugs.In the present study, a series of-CD-conjugated linear and star-shaped PEG-PLApolymers were synthesized with MPEG8K (Mn=8,000),4armPEG (Mn=10000&20000) asthe macromolecular initiator and stannous octoate(Sn-oct) as the catalyst. ThePEG-PLA-COOH was synthesized with PEG-PLA and succinicanhydride (SA). Then, CDenwas synthesized through the reaction of ethanediamine (EDA) andmono[6-O-(p-toluenesulfonyl)]-β-CD (mono-6-OTs-β-CD). Finally, the PEG-PLA-β-CDcopolymers were synthesized via coupling reactions betweenCDen and PEG-PLA-COOH.The synthetic copolymers were characterized with FT-IR spectra,1H NMR spectra, Gelpermeation chromatography (GPC), DSC instrument and the carboxyl content ofPEG-PLA-COOHs was determined by non-aqueous titrations using sodium hydroxide as abase.The Reverse micelle (RMs) were prepared as follows: The polymers (4mg) weredissolved in DCM (4mL), and BSA aqueous solution (40μL,50mgmL-1) was added to thesolution. The mixture was sonicated at100W for4min in an ice bath, and agitated untilvisibly clear solutions.The Particle size (200nm-300nm) and morphology were determined bydynamic light scattering (DLS) and scanning electron microscrope (SEM). The core-shellstructure of the RMs from the amphiphilic copolymers was verified by comparing the1HNMR spectra of the MPEG8K-PLA8K-CD in DMSO-d6with that in deuterated chloroform.The encapsulation efficiency (EE) ofBSA in the RMs fabricated from the PEG-PLA-β-CDcopolymers was much improved in comparison with the counterpart(PEG-PLA-OH). Releaseof BSA was studied in double distilled water. Finally, the RMs weredispersed into ethyl oleate.Stability of BSA released from the RMs was determined by circular dichroism spectroscopy(CD).DOX loaded micelles were prepared by dialysis. The particle size of the micelles wasdetermined by DLS. The controlled release ability of DOX from micelles at pH=4was betterthan that at pH=7.Because the pH value of cancer cells is lower than that of normal cells, it is potentially usefulfor delivery of anticancer drugs.