Renally Excreted Multimodal Core-Shell Silica Nanoparticles as Tumor-Selective Ra

描述（由申请人提供）：转移性黑色素瘤的预后非常差，中位生存期不到 1 年。大多数患者没有令人满意的治疗方法；治疗主要是姑息性的，并能产生短期效益。快速发展的纳米医学领域的重大进展有可能深刻影响癌症的诊断和治疗。多功能颗粒平台结合并向肿瘤提供多种功能，与单个分子相比具有明显的优势，并准备进入临床实践。通过将肿瘤选择性肽和治疗部分附着到颗粒表面以创建这样的平台，可以选择性地靶向和治疗癌症。荧光核壳二氧化硅纳米粒子是临床上有前景的无毒“粒子实验室平台”，它表现出卓越的每粒子亮度和稳定性，并成功集成了癌症诊断和放射治疗的多种功能。经过调整以适应肾脏清除的尺寸，在将小肽配体和放射性标记附着到其表面以创建组合的 PET-光学探针后，该颗粒显示出增强的受体结合效力和有利的靶向动力学。因此，它代表了唯一可通过肾脏排泄的无机 PET 光学探针，可同时靶向体内肿瘤，且不会产生毒性问题。除了尺寸考虑之外，最佳体内性能还要求颗粒表面化学得到良好控制且可重复。这需要共同调整肽配体的数量和聚乙二醇（PEG）链长以及颗粒表面的接枝密度，以实现有利的靶向和清除特征。对于无机纳米颗粒，尚不清楚表面化学变化如何调节生物特性。该提案的长期目标是为 FDA IND 批准的约 7 纳米直径核壳二氧化硅纳米颗粒结构开发和实施良好的表面设计，用于人类转移性黑色素瘤的检测、分期和治疗规划。 该提案的目的是：（1）确定靶向二氧化硅纳米颗粒的最佳可调节表面化学，以使用不同数量的环状精氨酸-甘氨酸-天冬氨酸-酪氨酸（cRGDY）肽、PEG链长度和接枝密度来实现有利的黑色素瘤受体结合； (2) 研究为 cRGDY 结合探针建立的最佳配方化学是否可以扩展到带有黑色素瘤特异性肽 (1-MSH) 的替代探针； (3) 评估 124I-cRGDY-PEG-和 124I-1MSH-PEG-点的体内肿瘤选择性积累以及靶向放射性核素治疗的可行性； (4)通过附加治疗放射性标记对肿瘤和正常组织进行靶向放疗和18FDG PET反应监测。 这项研究的成功将为未来在转移性黑色素瘤患者中进行 I/II 期临床试验提供研究性新药应用，并为更广泛地应用于其他携带受体的恶性肿瘤提供潜力。基于小配体靶向平台的通用模板的建立，探针翻译到临床的效率还可以得到提高。 公共健康相关性：转移性黑色素瘤是美国发病率最快的癌症之一，其预后非常差，并且提供的治疗选择很少。我们建议优化 FDA IND 批准的黑色素瘤靶向纳米颗粒探针的化学表面设计，该探针可用于组合 PET 和光学成像。这些多功能颗粒代表了一种用于疾病检测、分期、靶向放射治疗和改善人类转移性黑色素瘤临床结果的新工具。

DESCRIPTION (provided by applicant): Metastatic melanoma has a very poor prognosis, with a median survival of less than 1 year. There are no satisfactory treatments for most patients; therapies are largely palliative and yield short-term benefit. Significant advances in the rapidly growing field of nanomedicine have the potential to profoundly impact cancer diagnosis and treatment. Multifunctional particle platforms that combine and deliver several functionalities to tumors offer distinct advantages over individual molecules, and are poised to move into clinical practice. By attaching tumor-selective peptides and therapeutic moieties to particle surfaces to create such platforms, cancers may be selectively targeted and treated. Fluorescent core-shell silica nanoparticles are clinically-promising non- toxic "lab-on-a-particle platforms" that demonstrate exceptional per particle brightness and stability, and have successfully integrated multiple functionalities for cancer diagnostics and radiotherapeutics. Tuned to sizes for renal clearance, the particle shows increased receptor binding potency and favorable targeting kinetics after small peptide ligands and radiolabels are attached to its surface to create a combined PET-optical probe. As such, it represents the only renally excretable, inorganic, PET-optical probe that simultaneously targets tumors in vivo without attendant toxicity issues. In addition to size considerations, optimal in vivo performance dictates that particle surface chemistry be well-controlled and reproducible. This requires collectively tailoring the number of peptide ligands and polyethylene glycol (PEG) chain lengths and grafting densities on particle surfaces to achieve favorable targeting and clearance profiles. For inorganic nanoparticles, it is not known how surface chemistry variations modulate biological properties. The long-term objective of this proposal is to develop and implement good surface designs for our FDA IND approved ~7-nm diameter core-shell silica nanoparticle architectures for detection, staging, and therapy planning of human metastatic melanoma. This proposal aims to: (1) determine the optimal tunable surface chemistry for targeted silica nanoparticles to achieve favorable melanoma receptor binding using variable numbers of cyclic arginine-glycine-aspartic acid-tyrosine (cRGDY) peptides, PEG chain lengths, and grafting densities; (2) investigate whether optimally formulated chemistries established for cRGDY-bound probes can be extended to alternative probes bearing melanoma-specific peptides (1-MSH); (3) assess in vivo tumor-selective accumulations of 124I-cRGDY-PEG- and 124I-1MSH-PEG-dots and feasibility of targeted radionuclide therapy; and (4) perform targeted radiotherapy and 18FDG PET response monitoring of tumors and normal tissues by attaching therapeutic radiolabels. The success of this study will enable the generation of investigational new drug applications for conducting future Phase I/II clinical trials in metastatic melanoma patients, offering the potential for wider application to other receptor-bearing malignancies. The efficiency of probe translation to the clinic may additionally be improved based upon the establishment of generalized templates for small ligand targeting platforms. PUBLIC HEALTH RELEVANCE: Metastatic melanoma, one of the fastest rising cancers in the United States, has a very poor prognosis, and offers very few treatment options. We propose the optimization of chemical surface designs for an FDA IND approved, melanoma-targeting nanoparticle probe which can be used for combined PET and optical imaging. These multifunctional particles represent a novel tool for the disease detection, staging, targeted radiotherapy, and improved clinical outcome of human metastatic melanoma.