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Zoledronic acid (ZA), a third-generation bisphosphonate, has been extensively used to treat osteoporosis and cancer bone metastasis and demonstrated to suppress proliferation of varied cancer cells and selectively kill tumor-associated microphages (TAMs). However, the clinical applications of ZA in extraskeletal tumor treatment are largely restricted due to its rapid renal clearance and binding to bones. In this study, to promote intracellular delivery of ZA for amplified antitumor efficacy, tumor acidity-responsive polymeric nanoparticles with high ZA payload ( ca. 12.3 wt%) and low premature ZA leakage were designed. As a pivotal material for surface coating, the acidity-sensitive and amphiphilic methoxy poly(ethylene glycol) (mPEG)-benzoic imine-octadecane (C18) (mPEG- b -C18) was synthesized by conjugation of mPEG-CHO with 1-octadecylamine upon Schiff base reaction. Through tailor-made co-assembly of the hydrophobic poly(lactic- co -glycolic acid) (PLGA), amphiphilic tocopheryl polyethylene glycol succinate (TPGS) and mPEG- b -C18 to encapsulate ionic complexes composed of ZA molecules and branched poly(ethylenimine) (PEI) segments, the attained therapeutic polymeric nanoparticles, characterized to have a hydrophobic PLGA/ZA/PEI-constituted core covered with mPEG- b -C18 and TPGS, were able to not only detach mPEG shielding upon acidity-triggered hydrolysis of benzoic imine bonds but also expose surface positive charges of protonated PEI segments. The in vitro cellular uptake and cytotoxicity studies demonstrated that the internalization of acidity-sensitive ZA-encapsulated nanoparticles by TRAMP-C1 mouse prostate cancer cells and murine macrophages RAW 264.7 was considerably promoted upon acidity-elicited PEG detachment and surface charge conversion, thus remarkably boosting intracellular ZA delivery and anticancer potency. Compared to PEG non-detachable ZA-loaded nanoparticles with poor tumor deposition and antitumor effect, the PEG-detachable ZA-carrying nanoparticles markedly accumulated in TRAMP-C1 solid tumors in vivo and inhibited tumor growth, thereby increasing the survival rate of the treated mice. The collective data suggest the great promise of tumor acidity-sensitive ZA-carrying hybrid nanoparticles in the treatment of extraskeletal solid tumors.

Tissue engineering is a promising approach to repair osteochondral defects, yet successful reconstruction of different layers in an integrated graft, especially the interface remains challenging. The multiphasic, functionally integrated tissue engineering graft described herein mimics the entire osteochondral tissue in terms of structure and composition at the cartilage, bone and cartilage-bone interface layer to repair osteochondral defects. In this manuscript, we report the fabrication of a multiphasic graft via bonding of a cartilaginous hydrogel and a sintered poly(lactic-co-glycolic acid) microsphere scaffold by an endogenous fibrotic cartilaginous extracellular matrix. We demonstrated that culturing chondrocytes within the alginate hydrogel conjugated to the poly(lactic-co-glycolic acid) scaffold allows for (i) gradient transition and integration from the cartilage layer to the subchondral bone layer as assessed by scanning electron microscopy, histology and biochemistry, and (ii) superior tissue repair efficacy in a rabbit knee defect model. Industrialization of the graft remains an unsolved challenge as after decellularization the tissue repair efficacy of the graft decreased. Taken together, the multiphasic osteochondral graft repaired the osteochondral defects successfully and has the potential to be applied clinically as an implant in orthopaedic surgery.