Polymeric nanoparticles with imaging capability for therapeutic peptide delivery

描述（由申请方提供）：前列腺癌（PCa）导致的死亡通常发生在患者发生转移性去势抵抗性前列腺癌（mCRPC）时。虽然目前的mCRPC治疗提高了生存率，但这种疾病仍然无法治愈，并且治疗会导致严重的副作用，如阳痿和尿失禁。此外，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和痛苦的，这表明需要新的成像剂，可以利用敏感的分子成像技术，如PET（正电子发射断层扫描）。具有癌细胞特异性活性的治疗性肽是mCRPC特别有前途的治疗选择。最近，我们发现了CT 20 p，一种新的细胞毒性肽，靶向线粒体生理学中的癌症特异性差异。CT 20 p是一种有前途的抗转移药物;然而，为了开发CT 20 p用于mCRPC的临床用途，需要满足一些挑战，包括血清中的低稳定性和蛋白酶降解。迫切需要允许向疾病区域递送和监测治疗肽的新平台技术。为此，我们的目标是开发一种靶向分子纳米治疗诊断（双重治疗和诊断）平台，该平台将高浓度的CT 20 p递送至PCa，并具有在PCa小鼠模型中成像肽功效的能力。为了将CT 20 p递送至PCa，肽将被封装在用聚谷氨酸化叶酸官能化的超支化聚酯纳米颗粒（HBPE-NP）内，这是一种靶向PSMA的创新递送方法，PSMA是一种在PCa肿瘤和转移性病变中高度表达但在正常前列腺中不表达的PCa特异性细胞表面蛋白。为了赋予我们的NPs成像能力，聚合物将被修饰以接枝去铁胺（DFO），一种用于稳定包封89 Zr-PET成像探针的螯合配体。我们假设，与89 Zr共包封的靶向HBPE[CT 20 p] NP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CT 20 p的生物分布。计划了三个目标，其中HBPE-DFO[CT 20 p]-NP的合成将被优化以获得89 Zr和CT 20 p负载的有效螯合（目标1），并且一系列聚谷氨酸化叶酸-HBPE-DFO [CT 20 p]-NP将被合成并测试以通过PSMA靶向PCa细胞（目标2）。使用PCa的鼠模型的PET成像将用于评估CT 20 p的递送和功效。我们的HBPE-DFO [CT 20 p]-NP的潜在临床价值将在PCa的鼠模型中使用完整或去势的小鼠以及在淋巴结和骨转移模型中进行研究（目的3）。我们的研究结果将是HBPE-DFO[CT 20 p]-NP（不含89 Zr），可直接用于治疗mCRPC，而不会产生与当前治疗相关的严重副作用，而治疗诊断版本（含89 Zr）将提供临床前数据，从而促进PET成像用于监测快速生长的前列腺肿瘤和治疗结果。

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. Furthermore, current methods to detect PCa and monitor treatment outcomes are typically invasive and painful, indicating a need for new imaging agents that can take advantage of 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 cytotoxic peptide that targets cancer-specific differences in mitochondrial physiology. CT20p is a promising anti-metastatic agent; however, to develop the clinical use of CT20p for mCRPC, there are challenges that need to be met, including low stability in serum and degradation by proteases. New platform technologies that allow for the delivery and monitoring of therapeutic peptides to areas of disease are urgently needed. To this end, 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, an innovative delivery approach to target PSMA, a PCa-specific cell surface protein 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 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 CT20p 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 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. 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 HBPE-DFO[CT20p]- NPs (without 89Zr) that can be directly used for the treatment of mCRPC without the serious side effects associated with current therapies, while the theranostic version (with 89Zr) will provide the pre-clinical data that will advance the use of PET imaging for monitoring fast growing prostate tumors and treatment outcomes.