Development of ß-elemene and Cisplatin Co-Loaded Liposomes for Effective Lung Cancer Therapy and Evaluation in Patient-Derived Tumor Xenografts.

PURPOSE: ß-elemene and cisplatin combined chemotherapy currently is one of the most important settings available for lung cancer therapy in China. However, the clinical outcome is limited by their pharmacokinetic drawbacks. On the other hand, most of nanomedicines have failed in clinical development due to the huge differences between heterogeneous clinical tumor tissues and homogenous cell-derived xenografts. In this work, we fabricated a ß-elemene and cisplatin co-loaded liposomal system to effectively treat lung cancer. METHOD: In vitro cytotoxicity of co-loaded liposomes was studied by MTT, trypan and Hoechst/PI staining, and western blot in A549, A549/DDP, and LCC cells. In vivo antitumor efficacy was evaluated in cell-derived and clinically relevant patient-derived xenografts. RESULTS: Co-loaded liposomes were more cytotoxic to cancer cells, especially than the combination of single-loaded liposomes, benefiting from their simultaneous drug internalization and release. As a result, they exhibited desirable therapeutic outcome in both cell-derived and patient-derived xenografts. CONCLUSION: ß-elemene and cisplatin co-loaded liposomes are a clinically promising candidate for effective lung cancer therapy.

Hypoxia-Responsive Stereocomplex Polymeric Micelles with Improved Drug Loading Inhibit Breast Cancer Metastasis in an Orthotopic Murine Model.

Tumor metastasis is a leading cause of breast cancer-related death. Taxane-loaded polymeric formulations, such as Genexol PM and Nanoxel M using poly(ethylene glycol)-poly(d,l-lactide) (PEG-PLA) micelles as drug carriers, have been approved for the treatment of metastatic breast cancer. Unfortunately, the physical instability of PEG-PLA micelles, leading to poor drug loading, premature drug leakage, and consequently limited drug delivery to tumors, largely hinders their therapeutic outcome. Inspired by the enantiomeric nature of PLA, this work developed stereocomplex PEG-PLA micelles through stereoselective interactions of enantiomeric PLA, which are further incorporated with a hypoxia-responsive moiety used as a hypoxia-cleavable linker of PEG and PLA, to maximize therapeutic outcomes. The results showed that the obtained micelles had high structural stability, showing improved drug loading for effective drug delivery to tumors as well as other tissues. Especially, they were capable of sensitively responding to the hypoxic tumor environment for drug release, reversing hypoxia-induced drug resistance and hypoxia-promoted cell migration for enhanced bioavailability under hypoxia. In vivo results further showed that the micelles, especially at a high dose, inhibited the growth of the primary tumor and improved tumor pathological conditions, consequently remarkably inhibiting its metastasis to the lungs and liver, while not causing any systemic toxicity. Hypoxia-responsive stereocomplex micelles thus emerge as a reliable drug delivery system to treat breast cancer metastasis.