Advance In Functional Polycaprolactone As5-fluorouracil Delivery And Controlled Release Material

The toxic side effects of5-fluorouracil (5-FU) decreased significantly after5-FU was encapsulated in drug carrier. However, as a typical hydrophilic drug, it is difficult for5-FU to enter into the hydrophobic micellar core. Polycaprolactone (PCL) is highlighted because of its excellent biocompatibility and biodegradability, drug delivery materials based onamphiphlic poly(ethylene glycol)-b-poly(ε-caprolactone)(PEG-b-PCL) have been extensively studied. Nonetheless, PCL degrades extremely slow both in vitro and in vivo due to its high hydrophobicity and crystallinity, and its immiscibility with a wide range of drugs limited its further application in drug delivery. The performance of PCL, including hydrophobicity, crystallinity, and miscibility with drugs, could be adjusted by introducing different chemical groups on PCL chain. In this study, a PEG-b-PCL based material with carbamic acid benzyl easter (CAB) groups pending on PCL chain (a100%substitution level) was synthesized, by increasing the non-covalent bonding force through CAB groups and5-FU, the performance of micelles would enhanced. Afterwards, active targeting ligand folic acid (FA) was conjugated to the copolymer material.The main points of the article were summer ized as follows:Firstly, Flory-Huggins Interaction Parameter (Xpd) was introduced to qualitatively evaluate the drug-polymer compatibility between hydrophilic5-fluorouracil (5-FU) and hydrophobic core block, which was formed by poly[γ-(carbamic acid benzyl easter)-ε-caprolactone](PCABCL) and poly(ε-caprolactone)(PCL). The calculation results indicated that PCABCL had better affinity with5-FU than PCL. Thus, a series of diblock polymers monomethoxy poly(ethylene glycol)-b-poly[y-(carbamic acid benzyl easter)-s-caprolactone](mPEG45-b-PCABCLn) was synthesized through ROP. The chemical structure, thermodynamic property and crystallinity of the diblock polymers were studied through NMR, GPC, WAXD and DSC. The results indicated that the introduction of CAB groups would destruct the crystallinity of PCL, moreover when the polymerization degree of PCABCL reached19, mPEG45-b-PCABCLn copolymer displayed amorphous state.5-FU loaded micelles were prepared by dialysis method. These micelles had high stability and spherical morphology. The hydrophilicity of the micellar core increased significantly with the attachment of the CAB groups on PCL chaia The release behavior could be tuned by the length of core-forming block. Moreover, micelles prepared by mPEG45-b-PCABCL19displayed the highest5-FU loading content and the most controlled release behavior. These blank micelles showed very low toxicity against HCTl16cancer cells. Meanwhile5-FU loaded micelles exhibited a concentration dependent increase in HCTl16cell death by inducing cell apoptosis in vitro.Furthermore, in order to promote the active targeting performance of the carrier, we obtained monomethoxy-poly(ethylene glycol)-b-poly[γ-(carbamic acid benzyl ester)-co-y-(amino-ε-caprolactone)](mPEG-b-P(CABCL-co-ACL)) copolymer through deprotection of CBZ groups on mPEG-b-PCABCL. The fo late-coup led mPEG-b-P(CABCL-co-ACL) was prepared by the reaction of FA with the amine group on the polymer. The degree of deprotection, chemical structure of polymers were characterized by NMR, GPC, DSC. The quantity of FA molucule was characterized by UV-Vis. It can be expected that the FA conjugated mPEG-b-P(CABCL-co-ACL) may have great potential in active targeting cancer therapy.