Creating Safe Biodegradable Photoluminescent Implant Polymers

描述（由申请人提供）：可生物降解聚合物已被制造成各种生物医学植入物，如药物输送纳米颗粒、组织工程支架和矫形装置。1-9使用生物可降解聚合物作为植入材料是有益的，因为一旦植入物的任务完成，植入物可以被降解并被身体清除，不会在体内留下异物。另一方面，由于对分析生物分子、跟踪生物过程、可视化疾病和治疗效果的需求不断增加，荧光标记和成像推动了生命科学和医学研究的显著增长。最常见的荧光显像剂包括有机染料、荧光蛋白和量子点（QDs）。荧光量子点的发现彻底改变了分子成像领域，特别是在肿瘤学应用方面。然而，过去取得的进展并没有减轻它们的高成本和内在毒性问题，这些问题严重阻碍了它们在患者中的临床应用。作为替代品，荧光染料易发生光漂白，荧光蛋白在体内较暗且难以操作。值得注意的是，以上所有显像剂都只是“显像剂”。它们不能单独作为医疗植入物作为药物输送载体或组织工程支架。将生物医学植入物和显像剂结合起来用于药物输送和组织工程是过去几年研究的重要焦点。对于纳米颗粒药物递送，一个重大的挑战是开发多功能纳米颗粒，可以用来跟踪药物递送过程并实时确定治疗效率。尽管将有机染料偶联到可生物降解聚合物上或将量子点封装在可生物降解聚合物中被认为是解决上述挑战的重要一步，但它并没有解决其毒性和体内应用中染料与纳米颗粒标记率低的问题。对于组织工程来说，在没有创伤性外植样本或牺牲动物的情况下，获得体内支架降解和组织浸润/再生的原位和实时信息是一个尚未解决的挑战。使用安全可生物降解的植入聚合物，在体内发射可检测的荧光，将解决药物输送和组织工程中的上述挑战，并为基于荧光标记和成像的其他生物和生物医学应用打开新的窗口。然而，这种生物材料还没有得到。因此，本提案的目标是发现新的体内安全，完全可生物降解的光致发光聚合物（BPLP），不需要偶联有机染料或半导体量子点（QDs），这将有希望用于生物成像和医学植入应用，例如使用BPLP纳米颗粒（可生物降解聚合物“QDs”）在体内跟踪癌症转移。这项工作的预期结果是，我们将了解BPLP独特的光致发光特性背后的机制，并且我们将建立一种方法，将BPLP扩展到不同类型的可生物降解聚合物。我们将通过开发可生物降解的BPLP纳米颗粒（可生物降解聚合物“量子点”）来展示它们的新颖性和实用性，用于生物标记和成像应用，例如跟踪癌细胞在体内的迁移。该提案的影响在于：1)揭示了有趣的荧光机制和定制设计生物可降解光致发光聚合物的方法，将对生物材料科学做出重大贡献；2) BPLPs的发展将带来可生物降解植入生物材料在生物传感、细胞成像、药物输送、组织工程和治疗性纳米医学等广泛生物和生物医学领域应用的范式转变。

DESCRIPTION (provided by applicant): Biodegradable polymers have been fabricated into various biomedical implants such as drug delivery nanoparticles, tissue engineering scaffolds, and orthopedic devices.1-9 Using biodegradable polymers as implant materials is beneficial as the implants may be degraded and cleared by the body once their missions are complete, leaving no foreign materials in the body. One the other hand, florescent labeling and imaging have fueled the significant growth of life science and medical research due to the increasing demands on analyzing biomolecules, tracking biological process, and visualizing diseases and therapeutic efficacy. The most common fluorescent imaging agents include organic dyes, fluorescent proteins and quantum dots (QDs). The discovery of fluorescent QDs has revolutionized the field of molecular imaging, especially in oncology applications. However, progress made in the past has not alleviated much on their high cost and intrinsic toxicity concerns which substantially hinder their clinical use in patients. As alternatives, fluorescent dyes suffer from photobleaching and fluorescent proteins are dim in vivo and hard to manipulate. It is noteworthy that all the above imaging agents are just "imaging agents". They cannot act alone as medical implants to serve as drug delivery vehicles or tissue engineering scaffolds. Combining biomedical implants and imaging agents for drug delivery and tissue engineering has been a significant focus of research in the past few years. For nanoparticle drug delivery, a significant challenge is to develop multifunctional nanoparticles that can be used to track drug delivery processes and determine therapeutic efficiency in real-time. Although conjugating organic dyes to, or encapsulating QDs in, biodegradable polymers was considered as a significant step in addressing above challenges, it does not address the concerns on their toxicity and low dye-to-nanoparticle labeling ratio for in vivo applications. For tissue engineering, obtaining in-situ and real- time information on scaffold degradation and tissue infiltration/regeneration in vivo, without traumatically explanting samples or sacrificing animals, is an unaddressed challenge. Using safe biodegradable implant polymers that intrinsically emit detectable fluorescence in vivo would address the above challenges in drug delivery and tissue engineering, as well as open new windows for other biological and biomedical applications based on fluorescence labeling and imaging. However, such biomaterials have not been available. Therefore, the objective of this proposal is to discover novel in-vivo safe, wholly-biodegradable, photoluminescent polymers (BPLP), without conjugating organic dyes or semiconducting quantum dots (QDs), and which will be promising for bioimaging and medical implant applications, exemplified by tracking cancer metastasis using BPLP nanoparticles (biodegradable polymeric "QDs") in vivo. The expected outcomes of the proposed work are that we will understand the mechanisms behind the unique photoluminescent properties of BPLPs, and that we will establish a methodology to expand the BPLP into different types of biodegradable polymers. We will demonstrate their novelty and utility by developing biodegradable BPLP nanoparticles (biodegradable polymeric "QDs") for biological labeling and imaging applications, exemplified by tracking cancer cell migration in vivo. The Impacts of this proposal lie in that: 1) Unveiling the intriguing fluorescence mechanism and the methods for custom-designing biodegradable photoluminescent polymers will significantly contribute to biomaterials science; and 2) the development of BPLPs should bring paradigm shifts on the use of biodegradable implant biomaterials in a broad range of biological and biomedical fields including biosensing, cellular imaging, drug delivery, tissue engineering, and theranostic nanomedicine.