Several metal-based compounds highly effective in cancers resistant to cisplatin and other chemotherapeutic agents but with fewer side effects, have been described over the past decade including some examples from our group at Brooklyn College. Despite the efficacy in patients or in pre-clinical models of these novel inorganic compounds and FDA approved platinum derivatives, there are some difficulties in most cases, related to pharmaceutical deficiencies such as poor water solubility, low bioavailability and short circulating time. Thus, there is a need to improve the delivery of these drugs so that they can be efficiently released at the specific tumor site without affecting healthy tissues. The ultimate goal of this proposal is to develop safe and highly selective metal-based anticancer chemotherapeutics by either incorporation into biodegradable enzyme-specific cleavable nanocarriers or by conjugation to specific monoclonal antibodies.
The specific aims of this proposal are the following:
Aim 1. Determine the selectivity and efficacy of ?smart? biodegradable nanocarriers that can release metallodrugs by specific enzyme cleavage. We hypothesize that by exploiting local enzyme overexpression in certain cancer types, we can use biodegradable peptide-based carriers that are prone to self-assembly and form localized fiber-based depots. To do this, we will prepare and encapsulate selected organometallic compounds with relevant antitumor properties in vitro and in vivo, into novel MMP-9-cleavable peptide-amphiphiles. We will then evaluate the anticancer properties of the resulting nanocarrier-metallodrug conjugates (NMDCs) in vitro and in vivo in cells and tumors which overexpress MMP-9, an enzyme associated with cancer progression, cancer invasion and metastasis. We will focus on specific breast and renal cancers.
Aim 2. Determine the selectivity and efficacy of monoclonal antibodies as targeting vehicles to deliver metal-based cytotoxic payload to tumor cells. We hypothesize that that the incorporation of a highly cytotoxic metallodrug to monoclonal antibodies will selectively deliver it to the specific tumor. To generate stable antibody drug conjugates (ADCs), we will synthesize synthons containing highly cytotoxic gold(I)-fragments based on phosphane and mainly N-heterocyclic carbene ligands and appropriate linkers amenable for bioconjugation to the monoclonal antibody trastuzumab. We will evaluate the in vitro and in vivo anti-tumor activity of selected gold-based ADC in cancers that overexpress HER2/neu. Trastuzumab is known to interfere with HER2/neu (ERBB2) receptor s overexpressed in certain cancers. More specifically, we will be evaluating specific ovarian, breast, colon and gastric cancer cell lines and xenografts.
The work proposed is relevant to public health, since it will help based cancer chemotherapeutics with improved pharmacological and clinical profiles than drugs advance the development of metal- currently used. Thus, the findings are ultimately expected to be applicable to the health of human beings.
