Stem Cell-Directed Nanotheranostics for Cancer Intervention

描述(由申请人提供)：干细胞导向的纳米抗癌药物用于癌症干预癌症生物学和药物输送方法的进展尚未充分转化为诊断或治疗癌症的临床进展。这种脱节的根源是全身给药时成像和治疗剂对肿瘤部位的低效给药。现在众所周知，存在着许多生物障碍，这些障碍阻碍了适当的生物分布，并限制了药物有效定位于目标的能力。最近，出现了能够提供非侵入性成像和靶向药物输送的新型药物，称为治疗药物。纳米颗粒(NPs)作为潜在的治疗载体已经浮出水面，能够将这两种类型的药物特异性地输送到病变部位。然而，为了进化为有效的全身给药的治疗药物，NPs必须顺序地避开这些生物屏障。此外，即使在装饰了靶向部分后，NPs也未能在保证治疗的剂量下在肿瘤部位积聚，导致对健康器官的毒性和以牺牲治疗为代价的一系列副作用。在此，我建议通过创建一个能够为上述问题提供解决方案的平台，使非政府组织的归宿和治疗责任脱钩。在这种方法中，脂肪干细胞(ASC)的天然肿瘤趋向性将与多级硅纳米梭(MSN)相结合，以携带不同阵列的NPs并以受控的方式释放它们。我相信，将超顺磁性氧化铁和阿霉素包裹的纳米粒最佳地负载到MSN中，将为成像和治疗癌症提供理想的治疗方法。ASCs将反过来内化装载的MSN，并介导它们选择性地输送到肿瘤部位。一旦达到目标，ASC将在肿瘤微环境中释放MSN。此后，MSN将部署可用于癌症成像和治疗的有效载荷。[这项提议旨在挑战我，要求我精通多个领域，这是在生物医学研究和纳米医学领域取得成功所必需的先决条件。在法拉利博士和李博士的实验室工作，将有机会获得和改进几项技术，如纳米颗粒表征、体外药物毒性分析和成像。此外，该计划允许我接受培训，通过研讨会、务虚会、课程和接触其他调查人员实验室，提高我的陈述、赠款写作和批判性分析技能。]我相信，干细胞生物学与纳米技术的有益结合将为目前药物输送和分子成像方面尚未解决的限制提供一种极其新颖和优雅的解决方案。这一平台的预期好处包括：1)通过ASC介导的传递避免障碍；2)防止非故意释放治疗用纳米粒；3)通过将ASC定位于肿瘤来局部传递治疗用纳米粒；以及4)从MSN释放治疗用纳米粒时的受控释放和累积。

DESCRIPTION (provided by applicant): Stem Cell-Directed Nanotheranostics for Cancer Intervention Progress in cancer biology and drug delivery approaches have not adequately translated into clinical advances in the diagnosis or treatment of cancer. This disconnect is rooted in the inefficient delivery of imaging and therapeutic agents to the tumor site upon systemic delivery. It is now well-known that a multitude of biological barriers exist that pose insurmountable obstacles impeding the proper bio-distribution, and limiting the ability of the agent to effectively localize at the target. Recently, novel classes of agents capable of providing non- invasive imaging and targeted drug delivery, known as theranostic agents, have emerged. Nanoparticles (NPs) have surfaced as potential theranostic vectors capable of delivering both types of agents specifically to pathological sites. However to evolve as effective theranostic agents for systemic administration, NPs must sequentially evade these biobarriers. Moreover, even after decoration with targeting moieties, NPs have failed to accumulate at the tumor site at dosages that guarantee therapy, resulting in toxicity to healthy organs and a wide array of side effects at the expense of treatment. Herein I propose to decouple the homing and therapeutic responsibilities of NPs by creating a platform capable of providing solutions to the aforementioned problems. In this approach, the natural tumor tropism of adipose stem cells (ASC) will be combined with multistage silicon nanoshuttles (MSN) ability to carry a diverse array of NPs and release them in a controlled fashion. I believe that the optimal loading of superparamagnetic iron oxide and doxorubicin-encapsulated NP into MSNs will provide for the ideal theranostic approach needed to image and treat cancer. The ASCs will in turn internalize the loaded-MSNs and mediate their selective delivery to the tumor site. Once the target has been reached, the ASC will release MSNs within the tumor microenvironment. Thereafter, the MSNs will then deploy the payload, which can be used for cancer imaging and therapy. [This proposal is designed to challenge me by requiring me to become proficient in multiple areas, a prerequisite necessary for a successful career in biomedical research and nanomedicine. Working in the labs of Dr. Ferrari and Li, will allow for the opportunity to acquire and refine several techniques such as nanoparticle characterization, in vitro drug toxicity assays and imaging. In addition, the plan allows for me to attain training to enhance my presentation, grant writing and critical analysis skills through a combination of seminars, retreats, courses and exposure to other investigators labs.] I believe the beneficial combination of stem cell biology with nanotechnology will provide for an extremely novel and elegant solution to the current unsolved limitations in drug delivery and molecular imaging. The anticipated benefits from this platform include: 1) Avoidance of barriers by ASC mediated delivery; 2) Protection against inadvertent release of theranostic NPs; 3) Localized delivery of NPs by homing of ASC to tumor; and 4) Controlled release and accumulation of theranostic NPs upon release from MSNs.