Camptothecin-Conjugated Poly(Ethyleneglycol)-Poly(ε-Caprol Actone) Micelles With Tumor-Targeting Moieties For Reduction-Sensitive Drug Release

In order to solve adverse effects and multi-drug resistance of commonly used antitumor drugs, biodegradable amphiphilic polymers have been investigated to form micelles in recent years. Micelles are nano-sized carriers to make the drug to accumulate in the target spots. If target molecules are introduced to the micelle, active-targeting can be achieved. The conjugation of drugs on polymer carriers can lower the solubility of hydrophobic drug and improve the bioavailability of drugs. The current work aims to introduce targeting molecules folate and disulfide bond to micelle to provide highly efficient and few toxic carriers for poorly soluble antitumor agents.Amphiphilic Boc-poly(ethylene glycol)-poly(caprolactone) block copolymer (Boc-PEG-PCL) was synthesized from Boc-PEG-NH2as initiator via the ring-opening polymerization of caprolactone. The reduction-sensitive prodrug of camptothecin was grafted to the backbone. The acylation reaction between folic acid (FA) and NH2-PEG-PCL, which was obtained from de-protection of Boc-PEG-PCL-SS-CPT, achieved FA-PEG-PCL-SS-CPT (FSC). The polymers obtained were characterized by proton nuclear magnetic resonance (’HNMR), Fourier transform infrared spectroscopy (FTIR) and gel permeation chromatography (GPC) to confirm the chemical structure.The FSC carriers were formulated into micelles though solvent evaporation method. Spherical micelles with the size ranging from100nm to200run were obtained by self-assembly in water solutions. The impacts of different dithiothreitol (DTT) concentration on the structure and morphology of micelles were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and fluorescene spectroscopy (FL) with pyrene molecular probe. Micelles with large size and highly aggregation were determined, and accelerated release of CPT was identified from micelles after incubation in dithiothreitol-containing media, indicating a good reduction-sentivity.In vitro cellular uptake and growth inhibition were evaluated on SKOV-3and A549cells using MTT assay and flow cytometry. Enhanced cellular uptake and inhibition effect of cell growth were indicated for FSC micelles compared with micelles without FA moieties and disulfide bond in the backbone.