Intelligent Polymeric Nanogel Technology Overcoming Drug Resistance in Ovarian Ca

智能聚合物纳米凝胶技术克服卵巢钙耐药性

• 批准号: 7696849
• 负责人: You Han Bae
• 金额: $ 31.23万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7696849
• 关键词: Albumins; Animals; Antigens; Antineoplastic Agents; Behavior; Biological; Blood Vessels; C57BL/6 Mouse; Carcinoma; Cell surface; Cells; Clinical; Combination Drug Therapy; Cytosol; Diagnosis; Disease; Doxorubicin; Drug Carriers; Drug resistance; Engineering; Epithelial ovarian cancer; Ethylene Glycols; Evaluation; Folate; Generations; Goals; Heterogeneity; Immunocompetent; In Vitro; Injection of therapeutic agent; Malignant Epithelial Cell; Malignant neoplasm of ovary; Membrane; Micelles; Modeling; Molecular; Monitor; Multi-Drug Resistance; Mus; NanoGel; Operative Surgical Procedures; Osmotic Pressure; Ovarian; Paclitaxel; Patients; Peptides; Pharmaceutical Preparations; Polymers; Resistance; Sampling; Specificity; Staging; Structure; Structure-Activity Relationship; Surface; Survival Rate; System; Tail; Technology; Testing; Therapeutic Effect; Time; Tissues; Tumor Debulking; Veins; Virus; biological systems; cancer cell; capsule; cell killing; cell motility; crosslink; cytotoxic; design; ethylene glycol; extracellular; folate-binding protein; human disease; in vivo; mimetics; mouse model; nanocarrier; nanosized; neoplastic cell; receptor; receptor mediated endocytosis; research study; tool; tumor

The goal of this proposal is to investigate the feasibility of treating ovarian epithelial carcinoma (OEC) with intelligent virus-mimetic nanogels (VM-nanogels). The VM nanogel has a core-shell type micelle-like structure. The core is constructed with pH-sensitive polymer blocks and loaded with anticancer drugs such as doxorubicin (DOX) and paclitaxel (PTX). The hydrophilic poly(ethylene glycol) (PEG) shell of the VM-nanogel is partially cross-linked with macomolecules, such as albumin, to sustain its structural integrity. The surface is further modified with a cell penetrating peptide (such as TAT in this proposal) for active cell entry, yielding VM(TAT)-nanogel. The surface TAT of VM(TAT)-nanogel is then effectively shielded in the vascular space (pH 7.4) by counter ionic polymers, such as PEG-b-polysulfonamide, which will minimize interactions with normal healthy tissues but expose the tumor cells/tissue by deshielding within the tumor’s extracellular pH. Preliminary results demonstrate that DOX-loaded VM(F)-nanogels, conjugated with folate (F), are highly cytotoxic to both sensitive and multidrug resistant (MDR) cancer cells and migration/reentry into neighboring intact cancer cells. Major functions documented were: 1) folate receptor mediated endocytosis, 2) triggered release of DOX by endosomal pH, 3) endosomal membrane disruption by the volume transition/osmotic pressure of VM(F)-nanogels, 4) minimal release of DOX in the cytosol, and 5) escape from dead cancer cells and re-entry into neighboring cells. The VM(F)-nanogels are eventually disintegrated and eliminated. The preliminary results also demonstrate the feasibility of a tumor pH-specific deshielding mechanism for TAT. This unique approach will maximize therapeutic effects with minimal amounts of a selected drug and carrier materials and is expected to overcome drug resistance. The VM(TAT) nanogel will avoid concerns of micelle stability in biological systems and the heterogeneity issue of cell surface markers including folate receptor in the clinical setting. Four specific aims to achieve the stated goal are outlined in this application.

该提案的目的是研究具有智能病毒模拟的卵巢卵巢癌（OEC）的盛宴（VM纳米凝胶）。 - 敏感的聚合物块和抗癌药物阿霉素（DOX）和紫杉醇（ptx）的壳壳。用细胞穿透肽（例如此提案中的TAT）产生VM（TAT） - 纳叶凝胶。 7.4）通过反离子聚合物（例如多硫酰胺），这将最大程度地减少与正常组织的相互作用，但通过在肿瘤的细胞外ph中取消持久而暴露了细胞/组织的相互作用。初步结果表明，Dox负载的VM（F） - 纳米凝胶（F） - 纳米凝胶，尼米凝胶，尼米凝胶，糖（nanogels conjuged），与糖结合了。 ），癌细胞和迁移/重新进入尼尔堡完整的癌细胞。 OSOL和5）从死癌细胞中逃脱并重新进入邻近细胞，VM（F） - 纳叶凝胶最终被解散并消除。 这种独特的方法将最大程度地提高一些选定的药物和载体材料，以克服纳米凝胶的VM（TAT）将避免对生物学系统的关注以及在临床环境中ding叶酸受体的异质性问题。在本应用程序中概述了实现既定目标的四个具体目标。