Nanoplatform Overcomes Kidney Cancer Drug Resistance

Drug resistance is one of the significant clinical burdens in renal cell carcinoma (RCC). The development of drug resistance has been attributed to many factors, including impairment of apoptosis, elevation of the enzyme carbonic anhydrase IX (CA IX, a marker of tumor hypoxia), and infiltration of tumorigenic immune cells. Everolimus, a derivative of rapamycin, is currently used as an immunosuppressant to prevent rejection of organ transplants and in the treatment of renal cell cancer and other tumors.

To overcome the Everolimus-resistance (Evr-res) that appears in this type of cancer, investigators at Wayne State University (Detroit, MI, USA) used Sorafenib (Sor) - a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced RCC) - in combination with a novel tumor hypoxia directed nanoparticle (NP) loaded with a new class of apoptosis inducer, CA IX-C4.16. Copper-free "click" chemistry was utilized to conjugate SMA-TPGS (styrene-maleic acid -- D-alpha-tocopheryl polyethylene glycol succinate) with Acetazolamide (ATZ, a CA IX-specific targeting ligand).

The CA IX-SMA-TPGS labeled NPs were designed to selectively deliver their payload to the hypoxic tumor core. The NPs were further tagged with a clinically approved dye for evaluating hypoxic tumor core penetration and organ distribution.

The investigators reported in the August 30, 2018, online edition of the journal Biomaterials that imaging of a tumor spheroid treated with dye-labeled CA IX-SMA-TPGS revealed remarkable tumor core penetration that was modulated by CA IX-mediated targeting in hypoxic-A498 RCC cells. The significant cell killing effect with the synergistic combination of CA IX-C4.16 and Sor treatment suggested efficient reversal of Evr-resistance in A498 cells. Furthermore, treatment with the nanoplatform did not cause liver or kidney toxicity in mice.

“Our tumor hypoxia directed nanoparticle used in conjunction with the FDA-approved renal cell carcinoma treatment, Sorafenib, has had positive outcomes in our animal trials,” said senior author Dr Arun Iyer, assistant professor of pharmaceutical sciences at Wayne State University. “The nanoparticles can deliver the payload selectively to tumor tissue and penetrate deep into the tumor core and provoke significant tumor inhibition with marked safety. This new approach of using our nanoplatform will reopen doors that were once closed because drugs that had become ineffective to cancer treatment are now once again usable and effective. It is our hope that this research will one day soon be used in clinics for treating patients.”

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