Synthesis and Characterization of Expansile Polymeric Nanoparticles for Drug Delivery

用于药物输送的可膨胀聚合物纳米颗粒的合成和表征

• 批准号: 1006601
• 负责人: Mark Grinstaff
• 金额: $ 42万
• 依托单位: Trustees of Boston University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1006601&HistoricalAwards=false
• 关键词: Synthesis; Characterization; Expansile; Polymeric; Nanoparticles

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.

ID：MPS/DMR/BMAT（7623）1006601 主要研究者：Grinstaff，Mark ORG：Boston University波士顿大学用于药物递送的可膨胀聚合物纳米颗粒的合成和表征智力优势：当前使用聚合物用于药物递送的挑战之一是在特定位点触发药物释放的能力。 防止过早或不受控制的药物释放是关键的设计要求。 PI和他的团队正在设计，合成和评估一种新型的聚合物纳米颗粒（NP），用于药物递送，最初是疏水性的，但在细胞内化和局部pH值降低后，转化为亲水性结构-即水凝胶颗粒。 这种疏水性到亲水性的转变导致包封药物的释放和体积变化为300倍的溶胀。 基于这些NP在体外和体内成功使用的初步发表结果，PI提出了一项详细的机制研究，以表征和理解聚合物化学和生物材料的工作原理。 具体来说，他和他的团队将紫杉醇（Pax）封装在纳米颗粒内，并确定影响纳米颗粒大小，溶胀速率，pH响应性，体积变化，紫杉醇释放，肿瘤细胞摄取，细胞内颗粒运输，内体释放和细胞毒性的关键分子和纳米级特征。 这些研究解决了两个假设：（1）紫杉醇将仅在这种疏水性到亲水性转变时释放;和（2）装载紫杉醇的可膨胀纳米颗粒（Pax eNP）将提供比非膨胀性（Pax neNP）、常规Pax PLGA NP制剂、紫杉醇白蛋白结合颗粒（Abraxane）或游离紫杉醇/Cremophor更高的紫杉醇细胞内浓度。 这项研究的结果将通过提供对这种递送方法的详细机械理解以及新聚合物载体和生物材料开发的知识产生重大影响。更广泛的影响：拟议活动的更广泛影响如下：（1）PI致力于教育，并开发了一个新的两个学期的课程，与此主题有关，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上市。 PI和他的研究生也参与了外展计划，包括波士顿城市研究员NSF GK 12计划，该计划为波士顿公立学校系统的高中科学课程提供共同讲师，其中大多数学生是代表性不足的少数民族或经济弱势群体;（2）PI将继续通过BU科学与工程研究实习计划和项目SEED计划为高中生提供研究机会;（3）NSF的资助将用于支持一个BU本科生在夏天，说明PI的继续承诺，本科生。PI还参加了两个夏季研究项目（NSF-REU和NSF-PROgram在STEM学术保留和成功），其目标是本科女生或代表性不足的少数民族学生;（4）NSF对该项目的资助将用于支持一名工程和一名化学研究生，他们将受益于跨学科的教育经验，包括合成有机化学，应用聚合物研究，和生物材料研究。 学生们将在实验室里并肩工作，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。 鼓励在Grinstaff实验室接受培训的学生独立思考和创造性思考，同时认识到与其他专家合作的重要性;和（5）PI和他的学生将继续在同行评审的期刊上发表结果，并参加国家会议以展示他们的研究。 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，公众可以通过网络访问。