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Biodegradable nanocarriers and antibodies as targeting delivery vehicles for cancer metallodrugs

可生物降解的纳米载体和抗体作为癌症金属药物的靶向递送载体

基本信息

批准号：
10153816
负责人：
Maria Contel
金额：
$ 39.25万
依托单位：
BROOKLYN COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153816
关键词：
Advanced Development Affect Antibodies Antibody-drug conjugates Arsenic Trioxide Auranofin Biological Availability Cancer cell line Carboplatin Cells Cisplatin Clinical Clinical Trials Colon Carcinoma Copper Development Drug Delivery Systems ERBB2 gene Effectiveness Eloxatin Encapsulated Enzymes FDA approved Fiber Funding Gelatinase B Goals Gold Health Human In Vitro Institution Interdisciplinary Study Ligands Malignant Neoplasms Malignant neoplasm of ovary Matrix Metalloproteinases Memorial Sloan-Kettering Cancer Center Metals Monoclonal Antibodies Neoplasm Metastasis New York Organometallic Compounds Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phosphines Platinum Pre-Clinical Model Property Public Health Renal carcinoma Research Research Personnel Resistance Resources Ruthenium Science Site Techniques Time Tissues Toxic effect Trastuzumab Up-Regulation Work Xenograft procedure anti-cancer base cancer type carbene chemotherapeutic agent college cytotoxic design erbB-2 Receptor follow-up gastric cancer cell improved in vivo leukemia malignant breast neoplasm metallicity nanocarrier neoplastic cell novel overexpression oxaliplatin refractory cancer self assembly side effect systemic toxicity targeted delivery titanocene triple-negative invasive breast carcinoma tumor tumor progression water solubility

项目摘要

PROJECT SUMMARY 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) receptors overexpressed in certain cancers. More specifically, we will be evaluating specific ovarian, breast, colon and gastric cancer cell lines and xenografts.

项目总结

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Platinum(IV)-Gold(I) Agents with Promising Anticancer Activity: Selected Studies in 2D and 3D Triple-Negative Breast Cancer Models.

具有良好抗癌活性的铂 (IV)-金 (I) 药物：2D 和 3D 三阴性乳腺癌模型的精选研究。

DOI：
10.1002/chem.202302045
发表时间：
2023
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
0
作者：
López-Hernández,JavierE;Nayeem,Nazia;Cerón-Carrasco,JoséP;Ahad,Afruja;Hafeez,Aiman;León,IgnacioE;Contel,Maria
通讯作者：
Contel,Maria

Luminescent iminophosphorane gold, palladium and platinum complexes as potential anticancer agents.

DOI：
10.1039/c4qi00003j
发表时间：
2014
期刊：
Inorganic chemistry frontiers
影响因子：
7
作者：
Frik M;Jiménez J;Vasilevski V;Carreira M;de Almeida A;Gascón E;Benoit F;Sanaú M;Casini A;Contel M
通讯作者：
Contel M

Customizing Morphology, Size, and Response Kinetics of Matrix Metalloproteinase-Responsive Nanostructures by Systematic Peptide Design.

DOI：
10.1021/acsnano.8b07401
发表时间：
2019-01
期刊：
ACS nano
影响因子：
17.1
作者：
Jiye Son;Daniela Kalafatovic;Mohit Kumar;B. Yoo;Mike A. Cornejo;M. Contel;R. Ulijn
通讯作者：
Jiye Son;Daniela Kalafatovic;Mohit Kumar;B. Yoo;Mike A. Cornejo;M. Contel;R. Ulijn

Novel enantiopure cyclopentadienyl Ti(IV) oximato compounds as potential anticancer agents.

DOI：
10.1016/j.jinorgbio.2015.12.002
发表时间：
2016-03
期刊：
Journal of inorganic biochemistry
影响因子：
3.9
作者：
de la Cueva-Alique I;Muñoz-Moreno L;Benabdelouahab Y;Elie BT;El Amrani MA;Mosquera ME;Contel M;Bajo AM;Cuenca T;Royo E
通讯作者：
Royo E

A heterometallic ruthenium-gold complex displays antiproliferative, antimigratory, and antiangiogenic properties and inhibits metastasis and angiogenesis-associated proteases in renal cancer.