Intracellular Peptide Delivery for Targeted Destruction of Cancer

描述(申请人提供)：我们的长期目标是开发一种有针对性的聚合物载体，可用于将促凋亡多肽输送到体内的癌细胞中。我们建议使用“智能”聚合物载体，这种载体能够保护他们的治疗货物，并在生理PH值下以隐形的方式在体内传播。当细胞摄取并进入更酸性的内体隔室时，智能聚合物变得疏水，这使得它们的膜被破坏，并允许它们释放到细胞质中。我们计划使用RAFT聚合方法，这种方法允许受控的聚合物合成，并随后连接到治疗性多肽和靶向分子。通过这种方式，将开发出一种药物，它优先定位于癌细胞，并提供一种可引发细胞死亡的多肽。基于这一概念，这项工作的总体目标是开发一种肿瘤细胞特异性聚合物多肽药物，该药物可在引发癌细胞凋亡的同时避免对健康组织的毒性。我们将通过三个主要目标实现这一目标。目标1将是开发一种“智能”的聚合物-多肽偶联方案，将在培养的癌细胞中诱导死亡。目标2将涉及开发一种策略，将我们的药物专门靶向癌细胞，我们将使用小鼠肿瘤模型验证靶向效率。目标3将以我们在目标1和目标2中的发现为基础，设计一种优化的肿瘤靶向、促凋亡多肽聚合递送系统，然后在小鼠模型中测试其减少肿瘤生长的能力。总而言之，这些目标的结果有可能为设计药理学药物建立一个新的范例，以提供有效调节细胞凋亡或其他生物过程的生物活性多肽，用于癌症和其他病理的治疗。与公共卫生的相关性--常规的癌症治疗，如放射和化疗，并不直接针对癌细胞。因此，它们并不总是有效的，而且在患者的健康组织中也会产生实质性的毒性。我们正在提出一种策略，该策略将专门针对癌细胞，并在其致瘤转化的基础上攻击它们，从而在增加抗肿瘤能力的同时将负面副作用降至最低。

DESCRIPTION (provided by applicant): Our long-term goal is to develop a targeted, polymeric carrier that can be utilized to deliver pro-apoptotic peptides intracellularly to cancerous cells in vivo. We are proposing to use "smart" polymer carriers that are capable of protecting their therapeutic cargo and traveling through the body in a stealth-like fashion at physiologic pH. Upon cellular uptake and entry into more acidic, endosomal compartments, smart polymers become hydrophobic, which makes them membrane disruptive and allows their release into the cytoplasm. We plan to use the RAFT polymerization method, which allows for controlled polymer synthesis and subsequent conjugation to both therapeutic peptides and targeting molecules. In this way, a pharmaceutical will be developed that localizes preferentially to cancerous cells and delivers a peptide that will trigger cell death. Based on this concept, the overall objective of this work is to develop a tumor cell specific polymer- based peptide drug that triggers apoptosis in cancerous cells while avoiding toxicity in healthy tissues. We will build toward this goal through three main aims. Aim 1 will be to develop a "smart" polymer-peptide conjugation scheme that will induce death in cultured cancer cells. Aim 2 will involve developing a strategy to specifically target our drug to cancer cells, and we will validate the targeting efficiency using a mouse tumor model. Aim 3 will be to build on our findings from Aims 1 and 2 to design an optimized tumor- targeted, pro-apoptotic peptide polymeric delivery system and then test its ability to reduce tumor growth in a mouse model. Collectively, the outcomes from these aims have the potential to establish a new paradigm for the design of pharmacologic agents to deliver bioactive peptides that effectively modulate apoptosis or other biological processes for the treatment of cancer and other pathologies. Relevance to Public Health- Conventional cancer treatments, such as radiation and chemotherapy, do not directly target cancerous cells. As a result, they are not always effective and also produce substantial toxicity within the patient's healthy tissues. We are proposing a strategy that will specifically target cancer cells and attack them at the very underpinnings of their tumorigenic transformation, thus increasing the antitumor capacity while minimizing negative side effects