Biodegradable nanocarriers and antibodies as targeting delivery vehicles for cancer metallodrugs

项目总结 几种金属基化合物对耐顺铂和其他药物的癌症非常有效 在过去的十年里，已经描述了副作用较少的化疗药物 包括我们在布鲁克林学院的一些例子。尽管对患者或在 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，与药品缺乏有关，如缺水 溶解性差，生物利用度低，循环时间短。因此，有必要改进 这些药物可以有效地在特定的肿瘤部位释放，而不会影响健康 纸巾。这项建议的最终目标是开发安全和高度选择性的金属基材 通过掺入可生物降解酶特异性裂解物中的任一种的抗癌化疗药物 纳米载体或通过与特定的单抗偶联。这项建议的具体目的 目标1.测定“智能”可生物降解纳米载体的选择性和有效性 可以通过特定的酶裂解来释放金属药物。我们假设，通过利用当地的 在某些癌症类型中，我们可以使用可生物降解的多肽载体 容易自组装并形成基于光纤的局部仓库。为了做到这一点，我们将准备和 体外和体内包裹具有相关抗肿瘤特性的有机金属化合物 体内，形成新型的可切割的基质金属蛋白酶-9多肽-两亲分子。然后我们将对抗癌药物进行评估 纳米载体-金属药物结合物(NMDCs)的体内外性质 以及过度表达基质金属蛋白酶-9的肿瘤，这种酶与癌症的进展有关 侵袭和转移。我们将重点关注特定的乳腺癌和肾癌。 目的2.确定作为靶向载体的单抗的选择性和有效性 以金属为基础的对肿瘤细胞的细胞毒性有效载荷。我们假设，成立一个高度 细胞毒性金属药物以单抗为靶标，选择性地将其输送至特定肿瘤。至 产生稳定的抗体药物结合物(ADC)，我们将合成含有高度 细胞毒性金(I)-基于磷烷和主要是N-杂环卡宾配体的片段和 适合与单抗曲妥珠单抗生物偶联的连接物。我们会 评价精选金基ADC的体内外抗肿瘤活性 过度表达HER2/neu。曲妥珠单抗可干扰HER2/neu(ERBB2)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及异种移植瘤。

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.