Synthesis and Characterization of Expansile Polymeric Nanoparticles for Drug Delivery

ID：MPS/dmr/bmat(7623)1006601 PI：Grinstaff，Mark ORG：Boston University标题：用于药物输送的可扩展聚合物纳米颗粒的合成和表征电学优点：使用聚合物进行药物输送的当前挑战之一是在特定位置触发药物释放的能力。防止过早或不受控制的药物释放是一个关键的设计要求。PI和他的团队正在设计、合成和评估一种新型的用于药物输送的聚合物纳米颗粒(NP)，这种纳米颗粒最初是疏水的，但当细胞内化和局部pH降低时，会转变为亲水结构--即水凝胶颗粒。这种从疏水到亲水的转变导致所包裹的药物释放和肿胀，体积变化300倍。在这些NP在体外和体内成功使用的初步发表结果的基础上，PI提出了一项详细的机理研究，以表征和理解聚合物化学和生物材料的工作原理。具体地说，他和他的团队将紫杉醇(Pax)包裹在纳米颗粒中，并确定影响纳米颗粒尺寸、肿胀率、pH响应性、体积变化、紫杉醇释放、肿瘤细胞摄取、细胞内颗粒转运、内体释放和细胞毒性的关键分子和纳米特征。这些研究解决了两个假设：(1)紫杉醇只会在这种疏水到亲水的转变中释放；以及(2)紫杉醇可膨胀纳米粒(Pax ENPs)比非膨胀纳米粒(Pax NeNP)、传统的Pax PLGA NP制剂、紫杉醇白蛋白结合颗粒(Abraxane)或游离紫杉醇/乳油油具有更高的细胞内紫杉醇浓度。这项研究的结果将产生重大影响，提供对这种交付方法的详细机械理解以及开发新的聚合物载体和生物材料的知识。BROADER影响：拟议活动的更广泛影响如下：(1)PI致力于教育，并开发了与此主题相关的新的两个学期的课程，名为生物材料I和II，在波士顿大学工程学院和艺术与科学学院交叉列出。国际科学基金会和他的研究生也参与了推广计划，包括波士顿城市伙伴NSF GK12计划，该计划为波士顿公立学校系统中的高中科学课程提供联合导师，这些学校的学生大多是少数族裔或经济上处于不利地位的学生；(2)国际科学基金会将继续通过波士顿大学科学和工程研究实习计划和SEED计划为高中生提供研究机会；(3)国家科学基金会的资金将用于支持波士顿大学的一名本科生在暑期学习，这表明了国际科学基金会对本科生的持续承诺。PIE还参与了两个暑期研究项目(NSF-REU和NSF-STEM学术保持和成功计划)，这些项目针对的是本科生女性或代表性较低的少数族裔学生；(4)NSF对该项目的资助将用于支持一名工程学和一名化学研究生，他们将受益于包括合成有机化学、应用聚合物研究和生物材料研究在内的跨学科教育经验。学生们将在实验室并肩工作，在那里他们将交流思想，相互学习，并接受各种分析仪器的培训。在Grinstaff实验室接受培训的学生被鼓励独立和创造性地思考，同时认识到与其他专家合作的重要性；以及(5)PI和他的学生将继续在同行评议的期刊上发表结果，并参加全国性的会议，介绍他们的研究。PI还将开发一个聚合物合成协议数据库，描述当前和过去的聚合物合成，公众可以从网络上获取该数据库。

ID: MPS/DMR/BMAT(7623) 1006601 PI: Grinstaff, Mark ORG: Boston UniversityTitle: Synthesis and Characterization of Expansile Polymeric Nanoparticles for Drug DeliveryINTELLECTUAL MERIT: One of the current challenges in using polymers for drug delivery is the ability to trigger the release of the drug at a specific site. Preventing premature or uncontrolled drug release is a key design requirement. The PI and his group are designing, synthesizing, and evaluating a new type of polymeric nanoparticle (NP) for drug delivery that is initially hydrophobic, but upon cellular internalization and a lowering of local pH, transforms into a hydrophilic structure - namely a hydrogel particle. This hydrophobic-to-hydrophilic transformation results in release of the encapsulated drug and swelling with a change in volume of 300 fold. Building upon the initial published results with these NP used successfully in vitro and in vivo, the PI proposes a detailed mechanistic study to characterize and understand the polymer chemistry and biomaterials principles at work. Specifically, he and his group will encapsulate paclitaxel (Pax) within the nanoparticles and identify the key molecular and nanoscale characteristics that affect nanoparticle size, swelling rate, pH responsiveness, volume change, paclitaxel release, uptake by tumor cells, intracellular particle trafficking, endosomal release, and cytotoxicity. These studies address two hypotheses: (1) that paclitaxel will only release upon this hydrophobic to hydrophilic transition; and (2) that the paclitaxel loaded expansile nanoparticles (Pax eNPs) will afford a higher intracellular concentration of paclitaxel than nonexpansile (Pax neNP), conventional Pax PLGA NP formulations, paclitaxel albumin-bound particles (Abraxane), or free paclitaxel/Cremophor. The results of this research will have a significant impact by affording a detailed mechanistic understanding of this delivery method as well as knowledge for the development of new polymer carriers and biomaterials.BROADER IMPACTS: The broader impacts of the proposed activities are as follows: (1) The PI is committed to education and has developed a new two-semester course, related to this topic, entitled Biomaterials I and II that is cross-listed in Boston University's School of Engineering and the College of Arts and Sciences. The PI and his graduate students have also been involved in outreach programs, including the Boston Urban Fellow NSF GK12 Program which provides co-instructors for high school science courses in those Boston Public School systems where a majority of the students are underrepresented minorities or economically disadvantaged; (2) The PI will continue to provide research opportunities to high school students through the BU Research Internship Program for Science and Engineering and Project SEED programs; (3) NSF funding will be used to support one BU undergraduate student in the summer, illustrating the PI's continued commitment to undergraduates. The PI is also participating in two summer research programs (NSF-REU and NSF-PROgram in STem Academic Retention and Success), which target undergraduate women or underrepresented minority students; (4) NSF funding for this project will be used to support one engineering and one chemistry graduate student who will benefit from an interdisciplinary educational experience that encompasses training in synthetic organic chemistry, applied polymer research, and biomaterials research. The students will work side-by-side in the laboratory where they will exchange ideas and learn from each other, as well as receive training on a variety of analytical instruments. Students trained in the Grinstaff Laboratory are encouraged to think independently and creatively while recognizing the importance of working collaboratively with other experts; and (5) The PI and his students will continue to publish results in peer-reviewed journals and attend national meetings to present their research. The PI will also develop a polymer synthesis protocol database describing the current and past polymer syntheses that will be accessible to the public from the Web.