R&D Profile: Treatment of Breast Cancer with Silver Antitumor Drugs Encapsulated in Biodegradable Polymeric Nanoparticles WJ Youngs, University of Akron, US
Our research in cancer focuses on the development of silver carbene complexes (SCCs), for use as antitumor agents.
Research Overview Courtesy of WJ Youngs, PhD, University of Akron, US
The Youngs’ groups research in cancer focuses on the development of silver N-heterocyclic carbene complexes (SCCs) for use as antitumor agents. They have found that SCCs have significant activity against a variety of cancers in vitro, such as ovarian, breast, melanoma, colon, renal, bladder, and prostate human cancer cell lines. Furthermore SCCs are as active as cisplatin against the MB157 (breast) human cancer cell line in vitro and SCCs are much less toxic than cisplatin.
Dr. Daniel Lindner's research group at the Cleveland Clinic studied the antiproliferative effects of SCCs in comparison to cisplatin using the Sulforhodamine B (SRB) assay in WM164 (melanoma), WM9 (melanoma), A375 (melanoma), HT29 (colon), ACHN (renal), HT1376 (bladder), SKOV3 (ovarian) and PC3 (prostate) human cancer cell lines. Although cisplatin is the most effective agent across all cell lines it is also the most toxic to normal cells. Whereas the SCC used is much less toxic and exhibits similar activity and comparable effectiveness to cisplatin. This indicates that the SCC used has reactivity within a reasonable dosing range for a chemotherapeutic agent.
An in vivo study used a silver carbene complex on an ovarian cancer (OVCAR-3) xenograft model in athymic nude mice. The administration of the silver complex subcutaneously into the tumor site resulted in necrosis of the tumors with no adverse effects to surrounding tissues or internal organs. However, there are two concerns with the systemic use of SCCs: they degrade in the presence of chloride and they also interact with sulfur groups on the proteins in the blood making the systemic delivery of SCCs very difficult.
The research group has addressed the limited stability of SCCs in the bloodstream by encapsulating them in biodegradable poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles. This provides a platform for receptor targeting of specific cancer cells and improves the stability of the complexes for systemic injection. Material currently being investigated include poly(lactic-co-glycolic acid) coupled with polyethylene glycol and utilize folic acid receptors to provide targeted delivery. Targeting should result in lower dosages of SCCs and minimize the interactions with healthy mammalian tissue thereby lowering the already low toxicity of SCCs relative to the platinum antitumor drugs.
To date, the group has produced PLGA-PEG-fol nanoparticles in the range of 150-200 nm as well as encapsulating SCCs using L-tyrosine polyphosphate nanoparticles (LTP NPs). Ongoing studies are utilizing both types of nanoparticles for in vitro and in vivo testing.