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定向纳米治疗诊断学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。这种断开的根源在于全身递送时成像剂和治疗剂向肿瘤部位的低效递送。现在众所周知的是，存在许多生物屏障，这些生物屏障构成了阻碍适当生物分布的不可逾越的障碍，并限制了药剂有效定位于靶标的能力。最近，已经出现了能够提供非侵入性成像和靶向药物递送的新型药剂，称为治疗诊断剂。纳米颗粒（NP）作为潜在的治疗诊断载体已经浮出水面，能够将两种类型的药物特异性地递送到病理部位。然而，为了发展为用于全身给药的有效治疗诊断剂，NP必须依次避开这些生物载体。此外，即使在用靶向部分修饰后，NP也不能以保证治疗的剂量在肿瘤部位积累，导致对健康器官的毒性和以治疗为代价的广泛的副作用。在这里，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，将NP的归巢和治疗责任分离开来。在这种方法中，脂肪干细胞（ASC）的天然肿瘤向性将与多级硅纳米梭（MSN）携带各种NP阵列并以受控方式释放它们的能力相结合。我相信，超顺磁性氧化铁和阿霉素包封的NP到MSN的最佳加载将提供成像和治疗癌症所需的理想治疗诊断方法。ASC又将内化负载的MSN并介导其选择性递送至肿瘤部位。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。[This该提案旨在通过要求我精通多个领域来挑战我，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，将有机会获得和完善多种技术，如纳米颗粒表征，体外药物毒性测定和成像。此外，该计划允许我通过研讨会，务虚会，课程和接触其他研究人员实验室的组合来获得培训，以提高我的演讲，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局限性提供一个非常新颖和优雅的解决方案。该平台的预期益处包括：1）通过ASC介导的递送避免障碍; 2）防止治疗诊断NP意外释放; 3）通过ASC归巢到肿瘤来局部递送NP;和4）治疗诊断NP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.