Melanocortin-1 Receptor Targeted Ultrasmall Silica nanoparticles for Alpha- and

翻译后摘要：拟议的研究的目标是开发新的放射性标记的超小核壳 用α黑素细胞刺激激素肽类似物（DOTA-αMSH）修饰的纳米颗粒（C'点） 其靶向黑素皮质素-1受体（MC 1-R），该受体在黑色素瘤细胞上过表达，用于靶向放射治疗。 DOTA-αMSH-C'点将用β粒子发射体177 Lu和α发射体225 Ac进行放射性标记。 结合后，放射性标记的DOTA-αMSH-C'点内化到黑素瘤细胞中， 放射性核素在细胞内靠近细胞核的位置用于最佳的放射沉积。这种做法是创新的 因为纳米平台改变了单个组分的性质，例如黑色素瘤亲和素， αMSH肽的MC 1-R亲和力和结合的放射性核素的药代动力学，以产生 具有上级黑色素瘤靶向和体内治疗性质的超小纳米颗粒。中央 假设是用α 225 Ac和β 177 Lu发射放射性核素C ′点纳米颗粒靶向治疗 由于最佳的黑色素瘤肿瘤靶向和辐射耦合， 体内清除动力学快速。初步数据支持这一假设，并表明DOTA- αMSH-C' dots对黑色素瘤靶向肽具有上级亲和力和体内药代动力学特性 一个人此外，C' dots的初步临床试验表明，它们对人类是安全的，预示着 D 0 TA-αMSH-C'点的平移电势。 DOTA-αMSH-C'点的开发和优化将由3个具体目标指导。1)确定 黑皮质素-1受体（MC 1-R）靶向二氧化硅纳米颗粒的优化可调表面化学， 实现有利的细胞结合、摄取、亚细胞定位。2)评价225 Ac-和177 Lu-DOTA-αMSH- B16/F10同基因小鼠中的C“点缀合物”体内靶向特异性、药代动力学和清除特征 和M21人异种移植黑色素瘤荷瘤小鼠，以确定铅放射性标记的DOTA-αMSH- C点平台。3)将使用电极导线225 Ac进行体内表征和安全性评估， 177 Lu标记的DOTA-αMSH缀合物，以支持临床试验的IND申请。治疗研究， 将研究225 Ac和177 Lu标记的DOTA-αMSH-C'点单独或与免疫疗法组合。 恶性黑色素瘤是最致命的皮肤癌。它对化疗有很强的抵抗力， 免疫疗法和外部束辐射导致低持久响应率。最近，几个新 治疗剂被批准用于黑色素瘤治疗;然而，反应通常是短暂的（6-12 几个月），由于耐药性和替代信号通路的激活。的发展 放射性标记的DOTA-αMSH-C'点纳米颗粒是重要的，因为它们的施用将导致高度的细胞毒性。 用于治疗的具有低正常组织暴露的局部肿瘤照射，解决了对 开发用于晚期黑色素瘤的新的有效治疗。

Abstract: The goal of the proposed research is to develop novel radiolabeled ultrasmall core shell nanoparticles (C' dots) decorated with alpha melanocyte stimulating hormone peptide analogs (DOTA-αMSH) that target the melanocortin-1 receptor (MC1-R) overexpressed on melanoma cells for targeted radiotherapy. The DOTA-αMSH-C' dots will be radiolabeled with the beta particle emitter 177Lu and the alpha emitter 225Ac. Upon binding, the radiolabeled DOTA-αMSH-C' dots are internalized into the melanoma cells sequestering the radionuclide within the cell near the nucleus for optimal radiation deposition. This approach is innovative because the nanoplatform transforms the properties of the individual components, such as the melanoma avid αMSH peptide's MC1-R affinity and the pharmacokinetics of the conjugated radionuclides, to yield an ultrasmall nanoparticle with superior melanoma targeting and in vivo therapeutic properties. The central hypothesis is that C' dot nanoparticle targeted therapy with alpha 225Ac and beta 177Lu emitting radionuclides will result in efficacious melanoma treatment due to optimal melanoma tumor targeting and irradiation coupled with rapid in vivo clearance kinetics. Preliminary data supports the hypothesis and shows that the DOTA- αMSH-C' dots have superior affinity and in vivo pharmacokinetic properties to the melanoma targeting peptide alone. Moreover, initial clinical trials with C' dots demonstrated they were safe in humans, foreshadowing the translational potential of the DOTA-αMSH-C' dots. Development and optimization of DOTA-αMSH-C' dots will be guided by 3 specific aims. 1) Determine the optimized tunable surface chemistry for melanocortin-1 receptor (MC1-R) targeted silica nanoparticles to achieve favorable cellular binding, uptake, subcellular localization. 2) Evaluate 225Ac- and 177Lu- DOTA-αMSH- C' dot conjugates' in vivo targeting specificities, pharmacokinetics and clearance profiles in B16/F10 syngeneic and M21 human xenografted melanoma tumor bearing mice to determine the lead radiolabeled DOTA-αMSH- C' dot platform. 3) In vivo characterization and safety assessment will be performed with the lead 225Ac and 177Lu labeled DOTA-αMSH conjugates to support an IND application for clinical trials. Therapy studies with the 225Ac and 177Lu labeled DOTA-αMSH-C' dots alone or combined with immunotherapy will be investigated. Malignant melanoma is the most deadly form of skin cancer. It is extraordinarily resistant to chemotherapy, immunotherapy and external beam radiation resulting in low durable response rates. Recently, several new therapeutics were approved for melanoma treatment; however, the responses are usually short-lived (6-12 months) due to drug resistance and activation of alternative signaling pathways. The development of radiolabeled DOTA-αMSH-C' dot nanoparticles is significant since their administration will result in highly localized tumor irradiation with low normal tissue exposure for therapy addressing a critical unmet need for the development of novel efficacious treatments for advanced staged melanoma.