Targeted glioma chemotherapy by cyclic RGD peptide-functionalized reversibly core-crosslinked multifunctional poly(ethylene glycol)-b-poly(ε-caprolactone) micelles.

Cyclic RGD peptide-functionalized reversibly core-crosslinked biodegradable poly(ethylene glycol)-b-poly(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 ∼18wt%, small hydrodynamic size of ∼50nm, 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 αvβ3 integrin overexpressing U87MG glioblastoma cells. Strikingly, DOX-loaded cRGD30-RCCMs demonstrated a prolonged circulation time showing an elimination half-life of ∼4.7h, 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. STATEMENT OF SIGNIFICANCE: Nanomedicines based on biodegradable micelles and nanoparticles offer a most promising treatment for malignant tumors. The therapeutic outcomes of current nanomedicines are, however, trimmed by their instability, low tumor retention, inefficient tumor cell uptake, and inferior drug release control. We report herein that cRGD-functionalized, rapidly glutathione-responsive, and reversibly core-crosslinked biodegradable micellar doxorubicin based on PEG-PCL block copolymer mediates potent and targeted glioma chemotherapy, affording significantly better treatment efficacy and lower systemic toxicity than the non-crosslinked micellar doxorubicin and clinically used pegylated liposomal doxorubicin controls. These reversibly core-crosslinked multifunctional biodegradable micelles have emerged as a robust, simple, versatile, and safe nanoplatform that might elegantly bridge the gap between the scientific and translational anticancer nanomedicine research.