Biodegradable hollow CuS nanoparticles for photothermal cancer therapy

描述(申请人提供)：光热消融(PTA)疗法为不能手术的肿瘤提供了一种微创治疗。金纳米结构等纳米粒子与强大的光热耦合效应相结合，极大地提高了PTA的药效。另一方面，目前使用的PTA有几个局限性，如治疗转移性癌症的效果较差；纳米颗粒的非生物降解性，以及纳米颗粒在血流灌注较差的肿瘤部位向肿瘤间质的运输受限。这个 限制性运输可能导致亚致死剂量的热转移，并可能导致肿瘤复发和产生耐药性。中空CuS纳米粒子(HCuSNPs)是一类新型的光热纳米粒子。我们的初步研究表明，与黄金类似物相比，HCuSNPs是可生物降解的，并通过肾脏消除。我们推测，HCuSNPs为控制肿瘤复发和转移提供了先进的多模式光热治疗方法。本项目的具体目标是：(1)评价HCuSNPs的代谢和毒性；(2)开发HCuSNPs介导的癌症光热治疗的多阶段递送；(3)探索HCuSNPs佐剂介导的原位光免疫疗法(ISPI)。在目标1中，我们将检测聚乙二醇单核苷酸的细胞命运和代谢，并分析聚乙二醇单剂量和重复剂量的毒性。在目的2中，我们将利用光声成像来分析HCuSNPs在小鼠移植瘤模型中的肿瘤递送阶段，并通过多阶段递送来验证PTA的效果。在目标3中，我们将评估HCuSNPs-佐剂介导的ISPI诱导的免疫应答，并评估其局部和远端的抗肿瘤效果。这些研究将在异种移植、同种异体移植和自发乳腺癌模型中进行。在世界范围内，乳腺癌是女性第二常见的恶性肿瘤。多模式PTA的成功验证不仅为原发乳腺癌，也为转移性乳腺癌提供了一种重要的治疗策略。显然，这项技术与光纤的使用相结合，可以 可用于治疗多种癌症，甚至是深层组织的癌症。

DESCRIPTION (provided by applicant): Photothermal ablation (PTA) therapy provides a minimally invasive treatment for inoperable tumors. Nanoparticles such as gold nanostructures, along with strong photothermal coupling effect, have been shown to greatly enhance the efficacy of PTA. On the other hand, currently used PTA has several limitations such as less effectiveness in treating metastatic cancer; non-biodegradability of the nanoparticles, and restrictive transport of nanoparticles into tumor interstitium in a poorly perfused tumor site. The restrictive transport likely results in sublethal dose of heat transfer and may cause tumor recurrence and develop resistance. Hollow CuS nanoparticles (HCuSNPs) belong to a new class of photothermal nanoparticles. As shown in our Preliminary Study, HCuSNPs, in contrast to gold analogs, were biodegradable and eliminated through the kidney. We hypothesize that the HCuSNPs provide advanced multimodality photothermal therapeutic approaches for control of tumor recurrence and metastases. The Specific Aims of this project are: (1) to evaluate metabolism and toxicity of HCuSNPs; (2) to develop HCuSNPs-mediated multistage delivery for cancer photothermal therapy; and (3) to explore HCuSNPs-adjuvant-mediated in situ photoimmunotherapy (ISPI). In Aim 1, we will examine the cellular fate and metabolism of the PEG-HCuSNPs; and analyze single and repeated dose toxicity of the PEG-HCuSNPs. In Aim 2, we will use photoacoustic imaging to analyze the stages of tumor delivery of HCuSNPs in mouse tumor xenograft model; and validate the effect of PTA through the multistage delivery. In Aim 3, we will assess the immune response induced by HCuSNPs-adjuvant-mediated ISPI; and evaluate the local and distal anti-tumor effect. These studies will be performed in xenograft, allograft and spontaneous models of breast cancer. Worldwide, breast cancer is the second most frequently diagnosed malignancy in women. A success in validating the proposed multimodality PTA will provide an important therapeutic strategy not only for primary but also for metastatic breast cancer. Clearly, this technology, in combination with the use of fiberoptics, can be used to treat a broad range of cancers even in deep tissues.