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

描述(申请人提供)：转移性黑色素瘤预后非常差，中位生存期不到1年。对于大多数患者来说，没有令人满意的治疗方法；治疗主要是姑息治疗，并产生短期好处。在快速增长的纳米医学领域取得的重大进展有可能深刻影响癌症的诊断和治疗。多功能粒子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，并有望进入临床实践。通过将肿瘤选择性多肽和治疗部分附着到颗粒表面来创建这样的平台，可以选择性地靶向和治疗癌症。荧光核壳二氧化硅纳米颗粒是临床上很有前途的无毒“单颗粒实验室平台”，具有出色的每颗粒亮度和稳定性，并成功地集成了癌症诊断和放射治疗的多种功能。调整到肾脏清除的大小后，该颗粒显示出更高的受体结合能力和良好的靶向动力学，之后小肽配体和放射性标记被连接到其表面以创建组合的PET-光学探针。因此，它是唯一一种肾脏可排泄的无机PET光学探针，可以同时靶向体内的肿瘤，而没有伴随的毒性问题。除了大小因素外，最佳的体内性能还要求颗粒表面的化学成分得到良好的控制和重复性。这需要集体调整多肽配体的数量和聚乙二醇链的长度，以及颗粒表面的接枝密度，以实现良好的靶向性和清除性。对于无机纳米颗粒，还不知道表面化学变化是如何调节生物特性的。这项建议的长期目标是为FDA Ind批准的直径~7 nm的核-壳二氧化硅纳米颗粒体系结构开发和实施良好的表面设计，用于检测、分期和治疗人类转移性黑色素瘤。这项建议旨在：(1)确定靶向二氧化硅纳米颗粒的最佳可调表面化学，以使用可变数量的环状精氨酸-甘氨酸-天冬氨酸-酪氨酸(CRGDY)肽、聚乙二醇链长度和嫁接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含有黑色素瘤特异性多肽(1-MSH)的替代探针；(3)评估124I-cRGDY-PEGY-和124I-1MSH-PEG点的体内肿瘤选择性积聚和靶向放射性核素治疗的可行性；以及(4)通过粘贴治疗性放射性标记对肿瘤和正常组织进行靶向放射治疗和18FDG PET反应监测。这项研究的成功将使研究中的新药应用能够在转移性黑色素瘤患者中进行未来的I/II期临床试验，为更广泛地应用于其他带有受体的恶性肿瘤提供了潜力。在建立小配体靶向平台的通用模板的基础上，可以进一步提高将探针翻译到临床的效率。

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.