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.

本研究旨在探讨智能病毒纳米凝胶（VM-nanogels）治疗卵巢上皮性癌（OEC）的可行性。VM纳米凝胶具有核-壳型胶束结构。核心由ph敏感聚合物块构成，并装载抗癌药物，如阿霉素（DOX）和紫杉醇（PTX）。vm纳米凝胶的亲水聚乙二醇（PEG）外壳与大分子（如白蛋白）部分交联，以保持其结构完整性。表面用细胞穿透肽（如本提案中的TAT）进一步修饰，以使活性细胞进入，产生VM（TAT）纳米凝胶。VM（TAT）纳米凝胶的表面TAT被有效地屏蔽在血管空间(pH