Polymeric nanoparticles with imaging capability for therapeutic peptide delivery

描述(由申请人提供)：前列腺癌(PCA)死亡通常是患者发生转移性去势抵抗型前列腺癌(MCRPC)的结果。虽然目前对mCRPC的治疗可以提高存活率，但这种疾病仍然无法治愈，治疗会导致严重的副作用，如阳萎和大小便失禁。目前检测前列腺癌和监测治疗结果的方法通常是侵入性的，这表明需要使用敏感的分子成像技术的新显像剂，如正电子发射断层扫描(PET)。具有癌细胞特异性活性的治疗性多肽是治疗mCRPC的一种特别有前途的选择。最近，我们发现了CT20p，一种新的针对肿瘤特异性线粒体生理学差异的有丝分裂毒肽。CT20p是一种很有前途的抗转移药物，因为它能引起细胞脱离诱导的细胞死亡；然而，要将CT20p用于mCRPC的临床应用，还需要克服一些挑战，如血清稳定性较低。迫切需要用于将治疗性多肽输送和监测到疾病领域的新平台技术。我们的目标是开发一种靶向分子纳米治疗(双重治疗和诊断)平台，将高浓度的CT20p输送到PCa，并具有在PCa小鼠模型中成像多肽功效的能力。为了将CT20p运送到PCA，多肽将被包裹在超支化聚酯纳米颗粒(HBPE-NPs)中，这些纳米颗粒由聚谷氨酸叶酸功能化，聚谷氨酸叶酸是PCA特异性细胞表面蛋白PSMA的天然配体。PSMA在前列腺癌和前列腺癌转移灶中高表达，而在正常前列腺组织中不表达。为了赋予我们的纳米粒子成像能力，该聚合物将被修饰以接枝去铁胺(DFO)，这是一种稳定包裹89Zr-PET成像探针的螯合配体。我们假设PSMA靶向HBPE[CT20p]纳米粒，与89Zr共包裹，将产生一个强大的治疗平台，以减少PCa生长和转移扩散，同时能够在拟议的临床前研究中评估颗粒的生物分布。计划了三个目标，其中HBPE-DFO[CT20P]-NPs的合成将进行优化，以获得89Zr的有效螯合、聚乙二醇化和CT20p负载(目标1)，以及一系列聚谷氨酸叶酸-HBPE-DFO[CT20P]-NPs的合成并通过PSMA靶向PCa细胞(目标2)。使用小鼠PCA模型的PET成像将用于评估CT20P的传递和疗效，并将进行药代动力学研究。我们的HBPE-DFO[CT20P]-NPs的潜在临床价值将在PCa小鼠模型、使用完整或去势的小鼠以及在淋巴转移和骨转移模型中进行研究(目标3)。我们的研究成果将是以PSMA为靶向的HBPE-DFO[CT20P]-NPs(不含89Zr)，可直接用于mCRPC的治疗，而治疗版本(含89Zr)将提供临床前数据，以推进PET成像用于监测快速增长的前列腺癌和治疗结果。

DESCRIPTION (provided by applicant): Death due to prostate cancer (PCa) generally results when patients develop metastatic castration-resistant prostate cancer (mCRPC). While current treatments for mCRPC improve survival, the disease still remains incurable, and treatments result in severe side effects, such as impotence and incontinence. Current methods to detect PCa and monitor treatment outcomes are typically invasive, indicating a need for new imaging agents that use sensitive molecular imaging technologies such as PET (positron emission tomography). Therapeutic peptides, with cancer cell specific activity, are an especially promising treatment option for mCRPC. Recently, we discovered CT20p, a novel mitotoxic peptide that targets cancer-specific differences in mitochondrial physiology. CT20p is a promising anti-metastatic agent because it causes detachment-induced cell death; however, to develop the clinical use of CT20p for mCRPC, there are challenges that need to be met, such as low stability in serum. New platform technologies for the delivery and monitoring of therapeutic peptides to areas of disease are urgently needed. Our objective is to develop a targeted molecular nanotheranostic (dual therapy and diagnostic) platform that delivers CT20p in high concentrations to PCa and has the capacity for imaging peptide efficacy in murine models of PCa. To deliver CT20p to PCa, the peptide will be encapsulated within hyperbranched polyester nanoparticles (HBPE-NPs) that are functionalized with polyglutamated folates, that natural ligand for a PCa-specific cell surface protein, PSMA. PSMA is highly expressed in PCa tumors and metastatic lesions but not normal prostate. To endow our NPs with imaging capabilities, the polymer will be modified to graft desferrioxamine (DFO), a chelating ligand for stable encapsulation of a89Zr-PET imaging probe. We hypothesize that PSMA-targeted HBPE[CT20p]NPs, co-encapsulated with 89Zr, will yield a powerful therapeutic platform to reduce PCa growth and metastatic spread, while enabling assessment of particle bio- distribution in the proposed pre-clinical studies. Three aims are planned in which the synthesis of HBPE- DFO[CT20p]-NPs will be optimized to obtain effective chelation of 89Zr, pegylation and CT20p loading (Aim 1), and a series of polyglutamated folate-HBPE-DFO[CT20p]-NPs will be synthesized and tested to target PCa cells via PSMA (Aim 2). PET imaging, using murine models of PCa, will be used to assess delivery and efficacy of CT20p and pharmacokinetics studies will be performed. The potential clinical value of our HBPE- DFO[CT20p]-NPs will be investigated in murine models of PCa, using mice that are intact or castrated, and in models of lymph node and bone metastasis (Aim 3). The outcome of our research will be PSMA-targeted, HBPE-DFO[CT20p]-NPs (without 89Zr) that can be directly used for the treatment of mCRPC without the side effects associated with current therapies, while the theranostic version (with 89Zr) will provide the pre-clinical data to advance the use of PET imaging for monitoring fast growing prostate tumors and treatment outcomes.