Oral delivery of PARP inhibitor via gelatin- and chitosan-based nanocarriers for refined therapy of primary and metastatic melanomas.

PARP inhibitors provide an outstanding therapeutic option for targeted therapy among patients with different forms of cancer and are generally administered orally. However, the oral delivery of PARP inhibitors significantly reduces their bioavailability and is non-optimal tumor accumulation, which can lead to poor prognosis in cancer therapy. In this study, we developed novel orally delivered dosage forms represented by the PARP inhibitor based on 2-aminothiophene (2AT) entrapped in polymer-based nanocarriers made of biological macromolecules such as gelatin (GNPs) and chitosan (ChNPs) for refined therapy of both primary and metastatic melanomas. It allows improving the bioavailability of PARP inhibitors and overcoming the existing biological barriers. The GNPs@2AT (Dh ~ 170-230 nm) and ChNPs@2AT (Dh ~ 292-350 nm) were characterized both in vitro and in vivo. The molecular docking analysis showed that 2AT binds to PARP. The in vitro dose-dependent cytotoxicity of GNPs@2AT and ChNPs@2AT was determined. In vivo bioimaging demonstrated rapid and persistent accumulation of 99mTc- and Cy5-labeled GNPs and ChNPs in GIT organs (stomach, small intestine and colon). Two syngeneic models, solid tumor model and lung metastasis model, were used to examine the antitumor efficiency of GNPs@2AT and ChNPs@2AT. Their oral administration exhibited a highly effective inhibition in melanoma models. In particular, GNPs@2AT and ChNPs@2AT resulted in ~88-95 % inhibition of solid tumors and ~76 % inhibition of metastases within the lung tissues. Notably, it did not lead to any serious side effects. Thus, these novel dosage forms of PARP inhibitors offer a very promising strategy to enhance the therapy of primary and metastatic melanomas.