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.
Chloroquine, initially used to treat malaria, has been discovered as a sensitizer to augment antitumor activity of other clinically used chemotherapeutics. In this work, chloroquine and doxorubicin were co-loaded into hypoxia-responsive liposomes to synergistically treat solid tumor.
In vitro drug release profiles demonstrated that the liposomes were of not only good stability under normoxic condition but also high sensitivity under hypoxic condition. In vitro cell experiments demonstrated that chloroquine augmented doxorubicin cytotoxicity, and co-loaded
liposomes were thus more toxic than single-loaded liposomes, especially under hypoxic condition, as a result of hypoxia-responsive drug release. These findings highlighted the potential for chloroquine and doxorubicin co-loaded hypoxia-responsive liposomes in treating solid tumors.
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