On September 6, 2019, Science Advances published the latest work of Prof. Chunying Chen's team in the field of nanomedicine research, titled with "New power of self-assembling carbonic anhydrase inhibitor: Short peptide-constructed nanofibers inspire hypoxic cancer therapy". A self-assembled nanomaterial based on short peptides modification of carbonic anhydrase inhibitor (CAI) was reported for the first time, with marked selectivity and interesting mode of action, offering strategic therapy for hypoxic tumors.
Hypoxia areas perform profound clinical significance in carcinoma progression and metastatic dissemination. Carbonic Anhydrase IX (CA IX), as a hypoxia-induced transmembrane enzyme, are considered as important target for hypoxic tumor theranostic. They exclusively overexpress on the surface of many kinds of hypoxic tumors, regulating acidic tumor microenvironment, metastasis, and drug-resistant phenotypes. More interestingly, current investigations have recognized that hypoxia inhibits endocytosis of tumor cells in caveolin-1 dependent pathway. Only hypoxia-induced overexpression of CA IX override this problem and further allow intracellular uptakes of cytotoxins in certain hypoxic cancer cells. Considering the pivotal role of CA IX enzyme in hypoxic tumor, its inhibition has been validated as a diagnostic and therapeutic target for anti-proliferation, anti-metastasis and anti-angiogenesis treatments in hypoxic tumors.
Prof. Chunying Chen's research team and her collaborators have already made a series of progress in the research and development of high-efficiency and low-toxicity nanomedicines for tumor therapy (Nano Letters, 2019, 19, 4692; Nature Communications, 2018, 9, 4861; Advanced Materials, 2017, 29, 1701268; Advanced Materials, 2016, 28, 8950; Nature Communications, 2015, 6, 5988). Recently, they utilized the advantages of extracellular active site in CA IX enzyme, to construct CA IX targeted self-assembly on cell surface. They have developed a new class of multifunctional supramolecular hydrogelators, made of D-amino acids and traditional inhibitor of CA IX. Performing a new mechanism of enzyme inhibition, small molecules of CA inhibitor present new power in hypoxic cancer therapy via self-assembly. Due to their stronger extracellular retention and ligand-receptor binding, these novel pericellular self-assembled nanofibers of CA inhibitor exhibit enhancing inhibition efficacies towards CA IX. More importantly, the CA IX targeted self-assembly imprisons cancer cell and subsequently interrupts the normal activities of hypoxic cancer cells. Impressively, CA IX-related endocytosis promotes the intracellular uptakes of these self-assembled nanofibers under hypoxia, by which the morphology and features of nanofibers will be upgraded with decreasing pH values, subsequently causing intracellular damage and protective autophagy blockage inside hypoxic cancer cells. The versatility of their cell milieu stimulated tunable nanostructures provides novel mechanism and strategic therapy for hypoxic cancer cells, benefiting in vivo applications on anti-proliferation, anti-metastasis, and anti-angiogenesis of breast cancer tumor. Accomplished a remarkable enhancement of antitumor efficacies in Doxorubicin administration, this hydrogel formulation of self-assembled CA inhibitors present potent possibility for their application in cancer interventional therapy.
Benefiting from its biocompatible components and distinguished hypoxia therapies, this novel self-assembled CA inhibitor could be a safe and convenient material that advances current chemotherapy, providing a completely new direction for hypoxic cancer therapy.