Targeted Polymer Micelles for Treatment of Metastatic Melanoma

用于治疗转移性黑色素瘤的靶向聚合物胶束

• 批准号: 8524462
• 负责人: Kevin N Sill
• 金额: $ 13.96万
• 依托单位: INTEZYNE TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2014-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8524462
• 关键词: Address; Adult; Affinity; American Cancer Society; Animal Model; Area; Avidity; Behavior; Binding; Biodistribution; Biological; Biological Assay; Blood; Cancer Patient; Catheters; Cause of Death; Cells; Chemistry; Clinical; Contrast Media; Cutaneous; Data; Development; Diagnosis; Dialysis procedure; Disease; Distant Metastasis; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Encapsulated; Endosomes; Environment; Exposure to; Family; Fluorescence; Fluorochrome; Goals; High Pressure Liquid Chromatography; Image; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Investments; Kidney; Lead; Life; Ligands; Liver; Luciferases; Lung; Lung Neoplasms; Lung nodule; Magnetic Resonance Imaging; Malignant Neoplasms; Maximum Tolerated Dose; Melanocortin 1 Receptor; Melanoma Cell; Metastatic Melanoma; Micelles; Modeling; Mus; Neoplasm Metastasis; Nodule; Paclitaxel; Particle Size; Patients; Peptides; Pharmaceutical Preparations; Phase; Physiological; Plasma; Polymers; Preparation; Progression-Free Survivals; Property; Quality of life; Rattus; Relapse; Research; Resistance; Reticuloendothelial System; Rodent; Sampling; Site; Skin; Solid Neoplasm; Specificity; Spleen; Stimulus; Structure of jugular vein; Surface; Survival Rate; System; Tail; Taxane Compound; Technology; Therapeutic; Therapeutic Index; Time; Tissue Sample; Tissues; Toxic effect; United States; Veins; Weight; Woman; base; bioluminescence imaging; cancer cell; chemotherapeutic agent; chemotherapy; copolymer; cost; crosslink; cytotoxicity; dosage; effective therapy; improved; in vivo; inhibitor/antagonist; innovation; light scattering; melanoma; men; nanocarrier; nanoparticle; neoplastic cell; novel; peptidomimetics; phase 1 study; phase 2 study; pre-clinical; public health relevance; research study; response; success; targeted delivery; taxane; therapeutic effectiveness; time use; tumor; uptake; water solubility

DESCRIPTION (provided by applicant): According to the American Cancer Society, half of all men and one-third of all women in the United States will develop cancer in their lifetime. While chemotherapy has dramatically improved the survival rate of cancer patients, it comes at the cost of severe toxicities and in some cases poor response rates. In order to address these shortcomings, equal investments in drug delivery innovations are necessary to improve the success rate of these treatments and improve the quality of life for these patients. In order to accomplish these goals, drug delivery vehicles are needed which are stable to post-administration dilution, can avoid biological barriers (e.g. reticuloendothelial system (RES) uptake), and deliver drugs in response to a physiological stimuli encountered in solid tumor environment, i.e. change in the pH level. Furthermore, drug delivery systems that employ active targeting strategies will gain an additional advantage in the ability to target tumor cells in vivo and in turn increase the exposure of the chemotherapeutic locally at the tumor site. Polymer micelles formed by the assembly of amphiphilic block copolymers are a particular type of nanocarrier that are attractive due to their ability to confer water solubility to hydrophobic drug by encapsulating them within the core of the micelle. While the use of polymer micelles equipped with cancer-specific targeting groups is particularly promising for chemotherapy, their current clinical utility is limited due to their instability in biologically relevant environments.In an effort to address this instability problem, a polymer micelle-based drug delivery system was developed that utilizes novel stabilizing technology. This stabilizing technology utilizes reversible, pH-dependent crosslinking chemistry that stabilizes the micelle at physiological pH, but releases the drug in response to lower pH environments, such as areas surrounding a tumor or within endosomes. Taxanes are a widely prescribed family of chemotherapeutic agents, but their efficacy is limited by systemic toxicity. Herein, we propose the encapsulation of taxanes in a stabilized micelle delivery system with the goal of widening the therapeutic index of taxanes by increasing the amount of drug delivered to the tumor and reducing exposure to healthy cells. Melanoma is an example of a specific indication that has shown a preclinical response to taxanes. Because there is no effective treatment for metastatic melanoma, patients diagnosed with this lethal disease would benefit from a taxane loaded drug delivery system equipped with melanoma specific targeting group. Accordingly, we have attached a MC1R specific targeting peptide to the surface of the micelle to enhance tumor uptake and retention. MC1R is a bona fide melanoma marker with high and broad expression among metastases. Specific aim 1 will investigate the physiochemical properties of the stable; taxane loaded micelle as well as the binding affinity of the MC1R targeted micelles on live cells. Specific aim 2 will focus on the in vivo behavior of the MC1R targeted micelle in comparison to the untargeted; drug loaded micelle as well as free drug. Key experiments will include maximum tolerated dose, pharmacokinetics, biodistribution and efficacy. Completion of these aims will provide essential preclinical data for the further advancement of a taxane loaded, MC1R targeted micelle formulation into IND-enabling Phase 2 studies.

描述（由申请人提供）：根据美国癌症协会，美国一半的男性和三分之一的女性在一生中会患上癌症。虽然化疗大大提高了癌症患者的生存率，但它是以严重的毒性和在某些情况下的低反应率为代价的。为了解决这些缺点，有必要对药物输送创新进行平等投资，以提高这些治疗的成功率并改善这些患者的生活质量。为了实现这些目标，需要药物递送载体，其对施用后稀释稳定，可以避免生物屏障（例如网状内皮系统（RES）摄取），并且响应于实体瘤环境中遇到的生理刺激（即pH水平的变化）递送药物。此外，采用主动靶向策略的药物递送系统将在体内靶向肿瘤细胞的能力方面获得额外的优势，并进而增加化疗剂在肿瘤部位的局部暴露。由两亲性嵌段共聚物组装形成的聚合物胶束是一种特殊类型的纳米载体，由于其通过将疏水性药物包封在胶束的核心内而赋予疏水性药物水溶性的能力，其是有吸引力的。虽然使用的聚合物胶束配备了癌症特异性靶向基团是特别有前途的化疗，其目前的临床实用性是有限的，由于其在生物学相关的environments.In努力解决这种不稳定性问题，聚合物胶束为基础的药物输送系统，利用新的稳定技术开发。这种稳定化技术利用可逆的pH依赖性交联化学，其在生理pH下稳定胶束，但响应于较低pH环境（例如肿瘤周围或内体内的区域）释放药物。紫杉烷类是一种广泛使用的化疗药物，但其疗效受到全身毒性的限制。在此，我们提出了在稳定的胶束递送系统中包封紫杉烷类，其目标是通过增加递送至肿瘤的药物的量并减少对健康细胞的暴露来扩大紫杉烷类的治疗指数。黑色素瘤是对紫杉烷类显示临床前反应的特定适应症的一个例子。由于转移性黑色素瘤没有有效的治疗方法，诊断患有这种致命疾病的患者将受益于配备有黑色素瘤特异性靶向基团的紫杉烷负载的药物递送系统。因此，我们将MC1R特异性靶向肽连接到胶束表面以增强肿瘤摄取和保留。MC1R是真正的黑色素瘤标志物，在转移瘤中具有高和广泛的表达。具体目标1将研究稳定的紫杉烷负载胶束的理化性质以及MC1R靶向胶束对活细胞的结合亲和力。具体目标2将重点关注MC1R靶向胶束与非靶向、载药胶束以及游离药物相比的体内行为。关键实验将包括最大耐受剂量、药代动力学、生物分布和疗效。这些目标的完成将为进一步推进紫杉烷负载的MC1R靶向胶束制剂进入IND 2期研究提供必要的临床前数据。