Peritumorally transformable nanoparticles for intraperitoneal chemotherapy of ova

用于卵子腹腔化疗的瘤周可转化纳米粒子

基本信息

批准号：
7659971
负责人：
Yoon Yeo
金额：
$ 16.61万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7659971
关键词：
Adenocarcinoma Cell Antineoplastic Agents Ascites Blood Circulation Cancer cell line Cancerous Carcinoma Cell Line Cleaved cell Clinical Dose Drug Carriers Drug Delivery Systems Drug Kinetics Drug resistance Drug-sensitive Engineering Enzyme-Linked Immunosorbent Assay Epithelial ovarian cancer Evaluation Female Figs - dietary Future Gelatinase A Gelatinase B Glycolates Goals Gold Human Immunohistochemistry Implant In Vitro Intervention Malignant neoplasm of ovary Matrix Metalloproteinases Methods Normal tissue morphology Nude Mice Ovarian Adenocarcinoma Ovarian Surface Epithelial-Stromal Tumor Ovary Ovum Paclitaxel Pan Genus Peptides Peritoneal Peritoneum Pharmaceutical Preparations Polyethylene Glycols Proteins Research Reverse Transcriptase Polymerase Chain Reaction Route Surface Testing Therapeutic Time Tissues Toxic effect Transcription Coactivator Translating Translations Tumor Tissue Uterus Xenograft Model cancer cell cancer therapy cytotoxic density improved in vitro testing in vivo intraperitoneal intraperitoneal therapy nanocarrier nanoparticle neoplastic cell novel ovarian neoplasm overexpression prevent public health relevance residence sensor trafficking tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Intraperitoneal (IP) administration of anti-cancer drugs is a theoretically compelling therapeutic option for epithelial ovarian cancer. However, translation of the theoretical advantage to clinical benefits is hampered by difficulties in IP chemotherapy due to several reasons including short residence time of drugs in the peritoneum, potential of pan-peritoneal toxicity, and insufficient intracellular uptake/accumulation of the anti-cancer drugs. We propose to develop a new form of polymeric nanoparticles (NPs) that will overcome these problems. The LONG TERM GOAL of our research is to develop a tumor-specific nanocarrier of anti-cancer drugs for safe and efficient IP chemotherapy of ovarian cancer. The OBJECTIVE of this study is to create poly(lactic-co- glycolic acid) (PLGA) NPs as a carrier of paclitaxel, which are inert in normal tissues but transform to a reactive form in the peritumoral region (Peritumorally Transformable NPs or PTNPs). This will allow the NPs to have a minimal interaction with non-cancerous tissues, yet be readily taken up and accumulate in ovarian tumor cells providing an intracellular drug reservoir. To this end, we will engineer a surface layer on the PLGA NP drug carrier core, consisting of (a) a conjugate of polyethylene glycol (PEG) and matrix metalloproteinase (MMP) specific substrate peptide (MMP substrate), and (b) a fragment of trans- activating transcriptional activator (TAT) protein (TAT peptide, TATp). The function of each component is that (i) PEG will shield the TATp and NPs when present, preventing interactions between PTNPs and non- cancerous tissues en route to the tumors; (ii) MMP substrate will allow the PEG to cleave off when the PTNPs are exposed to MMPs (MMP-2, MMP-9), which are overexpressed in the epithelial ovarian tumors; and (iii) then exposed TATp will promote cellular uptake and retention of the PTNPs in the tumor cells. The underlying HYPOTHESES are that (i) MMPs that are more specifically concentrated in the peritumoral region can be utilized to cleave MMP substrate and transform polymeric NPs from a PEGylated form to one coated with TATp, and (ii) this transformation will enable the NPs to interact with tumor cells in a tumor-specific manner. To prove this hypothesis, we will create PTNPs by preparing NPs with TATp-PLGA conjugate and PEG-MMP substrate-PLGA conjugate or preparing NPs with TATp-PLGA conjugate first and then conjugating PEG-MMP substrate (Aim 1). Simultaneously, in Aim 2, we will determine in-vivo MMP levels in normal tissues, ascites, and tumor tissues in an orthotopic xenograft model of human ovarian cancer. This information will be used in evaluating the new NPs in vitro with respect to cellular uptake, intracellular trafficking, and the efficacy of paclitaxel delivered by the PTNPs. The novel PTNPs should provide tumor-specific intracellular drug delivery, which would reduce the total dose requirement, improve the anti-tumor efficacy, and maximize the pharmacokinetic advantage of IP chemotherapy of ovarian cancers. The proposed study will be a significant step toward more effective and safe management of advanced ovarian cancers. PUBLIC HEALTH RELEVANCE: We propose to develop a tumor-specific nanocarrier of anti-cancer drugs for safe and efficient intraperitoneal (IP) chemotherapy of ovarian cancer. IP chemotherapy is a theoretically compelling therapeutic option for epithelial ovarian cancer, but translation of this theoretical advantage to clinical benefits is hampered by difficulties in IP drug delivery. We aim to overcome these challenges by engineering a novel nanocarrier that will have a minimal interaction with non-cancerous tissues, yet be readily taken up and accumulate in the tumor cells providing an intracellular drug reservoir, through peritumoral surface transformation.

描述（由申请人提供）：腹膜内（IP）施用抗癌药物是理论上令人信服的上皮性卵巢癌治疗选择。然而，由于腹膜内药物停留时间短、潜在的全腹膜毒性以及抗癌药物细胞内摄取/积累不足等多种原因，IP化疗中的困难阻碍了理论优势向临床效益的转化。。我们建议开发一种新型聚合物纳米颗粒（NP）来克服这些问题。我们研究的长期目标是开发一种肿瘤特异性抗癌药物纳米载体，用于安全有效的卵巢癌腹膜内化疗。本研究的目的是创建聚乳酸-乙醇酸 (PLGA) 纳米粒子作为紫杉醇的载体，其在正常组织中呈惰性，但在瘤周区域转化为反应形式（瘤周可转化纳米粒子或 PTNP）。这将使纳米粒子与非癌组织的相互作用最小化，但很容易被卵巢肿瘤细胞吸收和积累，提供细胞内药物储存库。为此，我们将在 PLGA NP 药物载体核心上设计一个表面层，该表面层由 (a) 聚乙二醇 (PEG) 和基质金属蛋白酶 (MMP) 特异性底物肽（MMP 底物）的缀合物组成，以及 (b)反式激活转录激活因子（TAT）蛋白（TAT肽，TATp）的片段。每个成分的功能是：(i) PEG 将屏蔽 TATp 和 NP（当存在时），防止 PTNP 与非癌组织在通往肿瘤的途中相互作用； (ii) 当 PTNP 暴露于在上皮性卵巢肿瘤中过度表达的 MMP（MMP-2、MMP-9）时，MMP 底物将使 PEG 裂解； (iii) 然后暴露的 TATp 将促进肿瘤细胞中 PTNP 的细胞摄取和保留。潜在的假设是 (i) 更具体地集中在肿瘤周围区域的 MMP 可用于裂解 MMP 底物并将聚合纳米颗粒从聚乙二醇化形式转化为涂有 TATp 的纳米颗粒，并且 (ii) 这种转化将使纳米颗粒能够以肿瘤特异性方式与肿瘤细胞相互作用。为了证明这一假设，我们将通过用 TATp-PLGA 缀合物和 PEG-MMP 底物-PLGA 缀合物制备 NP，或先用 TATp-PLGA 缀合物制备 NP，然后缀合 PEG-MMP 底物来创建 PTNP（目标 1）。同时，在目标 2 中，我们将测定人卵巢癌原位异种移植模型中正常组织、腹水和肿瘤组织的体内 MMP 水平。该信息将用于在体外评估新 NP 的细胞摄取、细胞内运输以及 PTNP 递送的紫杉醇的功效。新型PTNPs应提供肿瘤特异性的细胞内药物递送，这将减少总剂量需求，提高抗肿瘤功效，并最大限度地发挥卵巢癌IP化疗的药代动力学优势。拟议的研究将是朝着更有效和安全地治疗晚期卵巢癌迈出的重要一步。公共健康相关性：我们建议开发一种肿瘤特异性抗癌药物纳米载体，用于安全有效的卵巢癌腹膜内（IP）化疗。 IP 化疗在理论上是一种引人注目的上皮性卵巢癌治疗选择，但这种理论优势向临床效益的转化受到 IP 药物输送困难的阻碍。我们的目标是通过设计一种新型纳米载体来克服这些挑战，该纳米载体与非癌组织的相互作用最小，但很容易被肿瘤细胞吸收和积累，通过瘤周表面转化提供细胞内药物储存库。