Peritumorally transformable nanoparticles for intraperitoneal chemotherapy of ova

描述（由申请方提供）：抗癌药物的腹膜内（IP）给药在理论上是上皮性卵巢癌的一种令人信服的治疗选择。然而，将理论优势转化为临床益处受到IP化疗困难的阻碍，这是由于几个原因，包括药物在腹膜中的停留时间短、潜在的全腹膜毒性和抗癌药物的细胞内摄取/积累不足。我们建议开发一种新形式的聚合物纳米颗粒（NPs），将克服这些问题。本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IP化疗。本研究的目的是创建聚（乳酸-共-乙醇酸）（PLGA）NP作为紫杉醇的载体，其在正常组织中是惰性的，但在肿瘤周围区域转化为反应形式（肿瘤周围可转化NP或PTNP）。这将允许NP与非癌组织具有最小的相互作用，但容易在卵巢肿瘤细胞中被吸收和积累，提供细胞内药物储库。为此，我们将在PLGA NP药物载体核心上设计表面层，其由（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，和（B）反式激活转录激活因子（达特）蛋白的片段（达特肽，TATp）组成。每种组分的功能是（i）PEG将在存在时屏蔽TATp和NP，防止PTNP与通向肿瘤的非癌组织之间的相互作用;（ii）当PTNP暴露于MMP时，MMP底物将允许PEG裂解MMP-2、MMP-9在卵巢上皮性肿瘤中高表达;和（iii）然后暴露的TATp将促进PTNP在肿瘤细胞中的细胞摄取和保留。潜在的假设是（i）更特异性地集中在肿瘤周围区域的MMP可用于切割MMP底物并将聚合物NP从PEG化形式转化为用TATp包被的形式，和（ii）这种转化将使NP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，我们将通过制备具有TATp-PLGA缀合物和PEG-MMP底物-PLGA缀合物的NP或首先制备具有TATp-PLGA缀合物的NP然后缀合PEG-MMP底物来产生PTNP（目的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MMP水平。该信息将用于在体外评价新NP的细胞摄取、细胞内运输和PTNP递送紫杉醇的功效。新型PTNPs可提供肿瘤特异性的细胞内药物递送，这将降低总剂量需求，提高抗肿瘤疗效，并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地管理晚期卵巢癌迈出的重要一步。 公共卫生相关性：我们建议开发一种肿瘤特异性抗癌药物纳米载体，用于安全有效的卵巢癌腹腔内（IP）化疗。IP化疗是上皮性卵巢癌的一种理论上令人信服的治疗选择，但这种理论优势转化为临床益处受到IP药物递送困难的阻碍。我们的目标是通过工程设计一种新型纳米载体来克服这些挑战，该纳米载体将与非癌组织具有最小的相互作用，但通过瘤周表面转化，易于在肿瘤细胞中吸收和积累，提供细胞内药物储库。

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.