Intracellular Peptide Delivery for Targeted Destruction of Cancer

描述（由申请人提供）：我们的长期目标是开发一种靶向的聚合物载体，其可用于在体内将促凋亡肽细胞内递送至癌细胞。我们建议使用“智能”聚合物载体，其能够保护其治疗货物并在生理pH下以类似隐形的方式穿过身体。在细胞摄取并进入更酸性的内体隔室后，智能聚合物变得疏水，这使得它们破坏膜并允许它们释放到细胞质中。我们计划使用RAFT聚合方法，该方法允许受控的聚合物合成和随后与治疗肽和靶向分子的缀合。通过这种方式，将开发出一种药物，该药物优先定位于癌细胞，并提供一种触发细胞死亡的肽。基于这一概念，本工作的总体目标是开发一种肿瘤细胞特异性的基于聚合物的肽药物，其在癌细胞中触发凋亡，同时避免在健康组织中的毒性。我们将通过三个主要目标来实现这一目标。目标1将是开发一种“智能”聚合物-肽缀合方案，该方案将诱导培养的癌细胞死亡。目标2将涉及开发一种将我们的药物特异性靶向癌细胞的策略，我们将使用小鼠肿瘤模型验证靶向效率。目的3将是建立在我们来自目的1和2的发现的基础上，以设计优化的肿瘤靶向的促凋亡肽聚合物递送系统，然后测试其在小鼠模型中减少肿瘤生长的能力。总的来说，这些目标的结果有可能建立一个新的范式，用于设计药物，以提供有效调节细胞凋亡或其他生物过程的生物活性肽，用于治疗癌症和其他病理学。与公共卫生的相关性-传统的癌症治疗，如放疗和化疗，不直接针对癌细胞。因此，它们并不总是有效的，并且还在患者的健康组织内产生大量毒性。我们正在提出一种策略，专门针对癌细胞，并在其致瘤转化的基础上攻击它们，从而增加抗肿瘤能力，同时最大限度地减少负面副作用。

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