Stem Cell-Directed Nanotheranostics for Cancer Intervention

描述（由申请人提供）：用于癌症干预的干细胞导向纳米治疗癌症生物学和药物递送方法的进展尚未充分转化为癌症诊断或治疗的临床进展。这种脱节的根源在于成像和治疗药物在全身输送时对肿瘤部位的低效输送。众所周知，存在大量的生物屏障，这些屏障构成了不可逾越的障碍，阻碍了生物的正常分布，并限制了药剂有效定位目标的能力。最近，新型的能够提供非侵入性成像和靶向药物递送的药物，即治疗药物，已经出现。纳米颗粒（NPs）已经成为潜在的治疗载体，能够将这两种类型的药物特异性地递送到病理部位。然而，为了发展成为有效的全身给药治疗药物，NPs必须依次避开这些生物屏障。此外，即使在靶向修饰后，NPs也无法在肿瘤部位以保证治疗的剂量积累，从而导致对健康器官的毒性和以治疗为代价的广泛副作用。在此，我建议通过创建一个能够提供上述问题解决方案的平台来解耦NPs的归巢和治疗责任。在这种方法中，脂肪干细胞（ASC）的天然肿瘤倾向将与多级硅纳米梭（MSN）相结合，后者能够携带多种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NP最佳负载到msn中，将为成像和治疗癌症提供理想的治疗方法。ASCs反过来内化装载的msn并介导其选择性递送到肿瘤部位。一旦达到目标，ASC将在肿瘤微环境中释放msn。此后，msn将部署有效载荷，可用于癌症成像和治疗。[这个提案是为了挑战我，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的先决条件。]在Ferrari博士和Li博士的实验室工作，将有机会获得和改进几种技术，如纳米颗粒表征，体外药物毒性分析和成像。此外，该计划还允许我通过研讨会、务虚会、课程和接触其他研究人员的实验室来获得培训，以提高我的演讲、拨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尚未解决的药物传递和分子成像限制提供一种极其新颖和优雅的解决方案。该平台的预期好处包括：1)通过ASC介导的交付避免了障碍；2)防止治疗性NPs的无意释放；3)通过ASC在肿瘤中的定位传递NPs；4)治疗性NPs从msn释放后的控制释放和积累。

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.