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

• 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
• 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

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)：从理论上讲，对上皮性卵巢癌来说，腹膜内(IP)注射抗癌药物是一种令人信服的治疗选择。然而，由于药物在腹膜滞留时间短、潜在的泛腹膜毒性以及抗癌药物在细胞内摄取/积累不足等原因，IP化疗的理论优势转化为临床益处的难度很大。我们建议开发一种新形式的聚合物纳米颗粒(NPs)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纳米抗癌药物载体，用于安全有效的卵巢癌IP化疗。本研究的目的是创建聚乳酸-羟基乙酸共聚纳米粒(PLGA)作为紫杉醇的载体，紫杉醇在正常组织中是惰性的，但在肿瘤周围区域会转化为反应性形式(瘤周可转化NPs或PTNPs)。这将使NPs与非癌症组织有最小的相互作用，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层表层，由(A)聚乙二醇(PEG)和基质金属蛋白酶(MMPs)特异性底物多肽(MMP底物)的结合物和(B)反式激活转录激活因子(TAT)蛋白的片段(TAT多肽，TATP)组成。每个成分的功能是：(I)当存在TATP和NPs时，聚乙二醇会保护TATP和NPs，防止PTNPs在通往肿瘤的途中与非肿瘤组织相互作用；(Ii)当PTNPs暴露于在卵巢上皮性肿瘤中过表达的MMPs(基质金属蛋白酶-2、基质金属蛋白酶-9)时，基质金属蛋白酶底物将允许聚乙二醇裂解；以及(Iii)暴露TATP将促进肿瘤细胞对PTNPs的摄取和滞留。基本的假设是：(I)更特异地集中在瘤周区域的MMPs可以被用来切割MMP底物，并将聚合型NPs从聚乙二醇化的形式转化为包被TATP的形式，以及(Ii)这种转化将使NPs能够以肿瘤特异性的方式与肿瘤细胞相互作用。为了证明这一假设，我们将通过以下方法来创建PTNPs：先用TATP-PLGA共轭和聚乙二醇-基质-基质-PLGA共轭制备纳米粒，或者先用TATP-PLGA共轭制备纳米粒，然后再与聚乙二醇-基质共轭(目标1)。同时，在目标2中，我们将在人卵巢癌原位异种移植模型中测定正常组织、腹水和肿瘤组织中的体内基质金属蛋白酶水平。这些信息将用于评估新的纳米粒在体外的细胞摄取、细胞内转运和紫杉醇的疗效。新型PTNPs可提供肿瘤特异性细胞内给药，减少总剂量需求，提高抗肿瘤疗效，最大限度地发挥卵巢癌IP化疗的药代动力学优势。这项拟议的研究将是朝着更有效和安全的晚期卵巢癌治疗迈出的重要一步。 公共卫生相关性：我们建议开发一种肿瘤特异性纳米抗癌药物载体，用于安全有效的卵巢癌腹膜内化疗。IP化疗在理论上是上皮性卵巢癌的一种引人注目的治疗选择，但由于IP给药的困难，将这一理论优势转化为临床益处受到阻碍。我们的目标是通过设计一种新型的纳米载体来克服这些挑战，这种载体将与非癌症组织有最小的相互作用，但通过瘤周表面转化，很容易被肿瘤细胞吸收和积聚，提供细胞内的药物储存库。