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Acta Biomaterialia 2017, 50, 396–406.

Cyclic RGD peptide-functionalized reversibly core-crosslinked biodegradable poly(ethylene glycol)-bpoly(ε-caprolactone) (PEG-PCL) micelles (cRGD-RCCMs) were designed and developed for highly potent and targeted glioma chemotherapy. To achieve crosslinkable core, dithiolane-functionalized trimethylene carbonate (DTC) was incorporated into PCL block. Interestingly, cRGD-RCCMs displayed a high doxorubicin (DOX) loading content of 18 wt%, small hydrodynamic size of 50 nm, and excellent colloidal stability with minimum drug leakage under physiological conditions while fast DOX release under cytoplasmic-mimicking reductive environments. MTT, confocal microscopy and flow cytometry measurement results pointed out that cRGD-RCCMs with 30% cRGD surface density (cRGD30-RCCMs) showed an evident selectivity, efficient cytoplasmic drug release, and superior antitumor activity to clinically used pegylated liposomal doxorubicin (DOX-LPs) in avb3 integrin overexpressing U87MG glioblastoma cells. Strikingly, DOX-loaded cRGD30-RCCMs demonstrated a prolonged circulation time showing an elimination half-life of 4.7 h, three times exceeding that of the non-crosslinked counterparts, and a remarkably enhanced tumor accumulation of 7.7%ID/g. Furthermore, in vivo therapeutic studies revealed that DOX-loaded cRGD30-RCCMs effectively suppressed tumor growth, significantly prolonged survival time, and lessened side effects in subcutaneous U87MG glioblastoma-bearing nude mice. These reversibly core-crosslinked multifunctional biodegradable micelles might be developed into advanced and clinically viable targeted anticancer nanomedicines.

Y. Fang, Y. Jiang, Y. Zou, F.H. Meng*, J. Zhang, C. Deng, H.L. Sun and Z.Y. Zhong*, Targeted glioma chemotherapy by cyclic RGD peptide-functionalized reversibly core-crosslinked multifunctional poly(ethylene glycol)-b-poly(e-caprolactone) micelles, Acta Biomaterialia 2017, 50, 396–406.

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