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Drug Delivery

Drug Delivery - Poster Session E

Poster X4 - Hydrogen sulfide-releasing polymeric micelles with Anti-Cancer Activity

Saturday, October 26, 2024
10:00 AM - 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Hydrogen sulfide (H2S) is an important gaseous signaling molecule in the human body. H2S is involved in different biological processes and has been shown to inhibit tumor growth. Despite the interesting biological activities of H2S, the lack of safe and efficient delivery systems limits its therapeutic applications. Our approach to solve this issue is using H2S-releasing polymeric micelles that enable controlled release in response to oxidative stress. Here, we present polymeric micelles with different H2S release profiles, prepared from amphiphilic block copolymers consisting of a hydrophilic PEG segment and a hydrophobic segment containing H2S-releasing anethole dithiolethione (ADT) groups. We show that oxidative stress, the hall mark of most cancers, induces H2S-release from the micelles and that release can be controlled by polymer design. We found that micelles having moderate H2S release rates exert the strongest anti-proliferative effect in human colon cancer cells in in vitro assays as well as the chick chorioallantoic membrane cancer model without affecting proliferation of non-cancerous human umbilical vein endothelial cells.

Materials and

Methods:  Amphiphilic block copolymers consisting of a PEG segment and an ADT-containing segment differing in ADT content were synthesized by reversible addition fragmentation and transfer (RAFT) polymerization and postmodification. The H2S release from the micelles in response to H2O2 and endogenous ROS in human colon cancer HT29 cells was measured using the HSip-1DA H2S detection dye. The antiproliferative activity of the micelles was evaluated in in vitro cell culture by MTT assay. The chick chorioallantoic membrane cancer model was used to evaluate the effect of the micelles by measuring the weight of tumorlike structures.

Results, Conclusions, and Discussions: Results and Discussion
Amphiphilic block copolymers with a degree of ADT modification of 50% formed spherical micelles (ADTMC1) while those of 100% formed worm-like micelles (ADTMC2). These micelles released H2S in the presence of H2O2 in phosphate buffered saline. H2S release from the micelles was also confirmed in HT29 cells. The release rates for the micelles were much slower than that of small H2S donor ADT. Furthermore, the degrees of ADT modification significantly affected H2S release kinetics where ADTMC1 showed faster release than ADTMC2. The effect of the micelles on cell proliferation was assessed in different cancer cells, HT29 and B16F10, and normal cells, human umbilical vein endothelial cells (HUVECs) and NIH3T3. The micelles inhibited proliferation of cancer cells while no obvious effect was observed in normal cells. Importantly, ADTMC1 showed the strongest antiproliferative effect followed by ADTMC2 and ADT. These results indicate that the H2S release rate has a significant effect on regulating cancer proliferation. To further evaluate the anticancer effect of the micelles, the CAM cancer model transplanted with HT29 cells was treated with the micelles. Similar to the in vitro assay, a significant reduction in tumor weight was observed for ADTMC1.
Conclusions
Polymeric micelles having a core containing H2S-releasing ADT groups showed sustained release of H2S in response to H2O2. H2S release rates could be controlled by changing the number of ADT groups in the core. The micelles inhibited cancer cell proliferation while they did not show any toxic effects in normal cells. It was also found that the release rate of H2S significantly affects antiproliferative activity. Our novel approach to control H2S release rates using ADT-containing micelles will provide safe and efficient H2S delivery system for treating pathological conditions characterized by oxidative stress such as cancer.

References:
van der Vlies et al., Advanced Healthcare Materials, (2023), 12 (6), 2201836.
Hasegawa et al., Medicinal Chemistry Communications, (2015), 6 273-276.

Acknowledgements (Optional):  This work was supported by National Science Foundation (NSF), CBET, 2102848, and Center for Molecular Analysis of Disease Pathways (CMADP), National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH), P20GM103638.