Biodegradable nanocarriers and antibodies as targeting delivery vehicles for cancer metallodrugs

项目摘要 几种金属基化合物对顺铂和其他耐药癌症非常有效 在过去的十年中，已经描述了具有较少副作用的化学治疗剂 包括我们布鲁克林学院的一些例子。尽管对患者或 这些新型无机化合物和FDA批准的铂衍生物的临床前模型， 在大多数情况下，存在一些困难，与药品不足有关， 溶解性差，生物利用度低，循环时间短。因此，有必要改进提供 这些药物，使他们可以有效地释放在特定的肿瘤部位，而不影响健康 组织中该提案的最终目标是开发安全和高选择性的金属基 通过掺入生物可降解的酶特异性可裂解的 纳米载体或与特异性单克隆抗体缀合。本提案的具体目标 目标1.确定“智能”可生物降解纳米载体的选择性和功效 可以通过特异性酶裂解释放金属药物。我们假设通过利用当地的 酶在某些癌症类型中的过度表达，我们可以使用可生物降解的基于肽的载体， 易于自组装并形成局部的纤维基储库。为此，我们将做好准备， 在体外和体内包封具有相关抗肿瘤特性的选定有机金属化合物， 在体内，转化为新的MMP-9-可裂解的肽-两亲物。然后我们将评估抗癌药物 所得纳米载体-金属药物缀合物（NMDC）在体外和体内细胞中的性质 和过表达MMP-9的肿瘤，MMP-9是一种与癌症进展相关的酶， 侵袭和转移。我们将重点关注特定的乳腺癌和肾癌。 目标2.确定单克隆抗体作为靶向载体的选择性和有效性， 基于金属的细胞毒性有效负载到肿瘤细胞。我们假设，在一个高度 细胞毒性金属药物与单克隆抗体的结合将选择性地将其递送到特定的肿瘤。到 产生稳定的抗体药物缀合物（ADC），我们将合成含有高浓度的合成子 基于膦和主要是N-杂环卡宾配体的细胞毒性金（I）片段， 适合与单克隆抗体曲妥珠单抗生物偶联的适当接头。我们将 评价所选基于金的ADC在癌症中的体外和体内抗肿瘤活性， 过表达HER 2/neu。已知曲妥珠单抗会干扰HER 2/neu（ERBB 2）受体 在某些癌症中过度表达。更具体地说，我们将评估特定的卵巢，乳房， 结肠癌和胃癌细胞系和异种移植物。

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.