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

摘要：本研究的目标是开发新型的放射性标记超小型核壳。 修饰有α-黑素细胞刺激素多肽类似物的纳米颗粒(C‘点)(DOTA-αMSH) 针对黑色素瘤细胞上过表达的黑素皮质素-1受体(MC1-R)进行靶向放射治疗。 DOTA-αMSH-C‘点将用β粒子发射体177Lu和阿尔法发射体225Ac进行放射性标记。 在结合时，放射性标记的DOTA-αmsh-C‘点被内化到黑色素瘤细胞中，隔离 在细胞核附近的细胞内的放射性核素，以获得最佳的辐射沉积。这种方法是创新的。 因为纳米平台改变了单个成分的属性，例如黑色素瘤狂热 αMSH多肽的MC1-R亲和力及其结合的放射性核素的药代动力学 具有出色的黑色素瘤靶向性和体内治疗特性的超小纳米颗粒。中环 假设C‘点纳米粒子靶向治疗α225Ac和β177Lu发射放射性核素 由于最佳的黑色素瘤靶向和放射耦合，将导致有效的黑色素瘤治疗 具有快速的体内清除动力学。初步数据支持这一假设，并表明DOTA- αMSH-C‘Dot对黑色素瘤靶向多肽具有更好的亲和力和体内药代动力学特性 独自一人。此外，C‘点的初步临床试验表明，它们在人类身上是安全的，这预示着 DOTA-αMSH-C‘点的平移势。 DOTA-αMSH-C‘DOTS的开发和优化将以三个具体目标为指导。1)确定 黑素皮质素-1受体(MC1-R)靶向二氧化硅纳米颗粒的优化可调表面化学 实现良好的细胞结合、摄取、亚细胞定位。2)评估225Ac-和177Lu-DOTA-αmsh- C‘点结合物’在B16/F10同基因中的体内靶向性、药代动力学和清除性 和M21人黑色素瘤移植瘤荷瘤小鼠测定放射性铅标记的DOTA-α C‘Dot平台。3)将用225Ac和225Ac进行体内表征和安全性评估 177Lu标记的DOTA-αMSH结合物支持用于临床试验的IND应用。治疗研究，与 225Ac和177Lu标记的DOTA-αmsh-C‘斑点或联合免疫治疗将被研究。 恶性黑色素瘤是最致命的皮肤癌。它对化疗有极强的抵抗力， 免疫治疗和外照射导致持久应答率低。最近，几个新的 治疗被批准用于黑色素瘤的治疗；然而，反应通常是短暂的(6-12 几个月)，这是由于耐药和激活替代信号通路所致。的发展。 放射性标记的DOTA-α微球具有重要的意义，因为它们的给药将导致高度的 局部肿瘤照射，低正常组织暴露用于治疗，解决严重的未满足的需求 晚期黑色素瘤新的有效治疗方法的开发。

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.