Lipodendrisomes: Co-assembly of New Comb-Rod Dendritic Block Copolymers with Lipids for Tailored Functional Vesicles

设计并合成了一系列由刚性烷基取代的螺旋多肽嵌段和中性亲水性聚酯树枝状嵌段组成的线状-树枝状梳状共聚物，以合成具有受限结构的新型两亲性聚合物。当这些烷基多肽树枝状嵌段共聚物与磷脂共组装时，将产生新的功能囊泡或脂树状体，它们在脂膜表面呈现局部功能密度区域，或呈现规则的形状，其局部功能可能分布在囊泡的缺陷或边缘。此外，烷基链和线状肽的相对长度以及树枝状大分子的生成将被用来调整功能树枝状结构在脂膜内或脂膜外的呈现和排列。这项工作的目标和智力价值在于首次系统和全面地研究了梳状-棒状树枝状嵌段共聚物在溶液状态下与脂质的自组装，并研究了由这种组装产生的稳定的纳米颗粒。通过官能化和操纵嵌段共聚物的分子参数来创建跨越嵌段共聚物膜的受控纳米结构的可能性可能导致具有模仿跨膜蛋白质的功能的聚合物的设计，从而允许调节或门控亲水材料，如离子、小分子或蛋白质穿过树枝状功能化的孤立孔。能够产生有序的、相分离的或簇状的表面基团，在表面呈现大量特定的官能团，可以产生高效的靶向多价药物输送系统。此外，烷基多肽骨架和树枝状头部基团独特的不对称性质似乎会在脂质体中造成缺陷，可能导致多面或不规则的形状或囊泡形态；嵌段共聚物在此类体系中的取向和定位将得到广泛研究。将研究在囊泡特定区域展示功能的嵌段共聚脂树状体的潜在设计，以实现独特多边结构的三维自组装，以及创建独特纳米结构的功能化，以用于从定向流体和表面组装到传感纳米颗粒和具有特定细胞相互作用的生物和生物医学系统的一系列应用。最后，可逆或不可逆地诱导具有光或热响应基团的膜表面自发形成功能化的门、配体或蛋白质的能力将被检验。非技术摘要：由线性和高度支化的树枝状链段组成的自组装聚合物将被设计成在溶液中与自然产生的脂分子进行自组装。所得到的结构有望通过将特定的所需基团呈现到脂质体表面以生成纳米尺度的蛋白质、配体或无机纳米颗粒簇，或者通过在脂质体中创建模仿细胞膜中的离子通道和蛋白质的独特通道来为传统脂质体引入独特的功能。更好地了解这些设计的元件在脂质体系统中的行为可能会导致指导人工跨膜蛋白或膜活性表面元件开发的设计原则。这些系统可能会产生新的材料系统，用于跨膜输送药物或蛋白质、离子或小分子，或操纵表面的细胞受体。本文介绍的研究是研究者研究和教学计划的组成部分，包括在实验室环境下对本科生和研究生进行教育和培训，将自组装概念整合到本科生和研究生课程的聚合物科学教学中。对学生的辅导涉及各个层面，包括学术和职业问题、工作和家庭问题，其中包括一些妇女和少数族裔学生。她参与了麻省理工学院的暑期研究计划，鼓励未被充分代表的少数族裔本科生进入研究生院学习，并参与了一项高中教师交流计划，让教师接触到聚合物科学和胶体科学领域的研究和新概念。

TECHNICAL SUMMARY:A newly designed series of linear-dendritic comb-rod copolymers consisting of a rigid alkyl substituted helical polypeptide block and a neutral hydrophilic polyester dendritic block will be designed and synthesized to create novel amphiphiles with constrained architectures. When these alkyl-peptide dendritic block copolymers co-assemble with phospholipids, new functional vesicles, or lipodendrisomes, will be generated which present regions of localized functional density on the surfaces of lipid membranes or exhibit regular shapes for which localized function may be distributed at defects or edges of the vesicle. Furthermore, the relative length of the alkyl chains and linear peptide block, as well as the dendrimer generation, will be used to tune the presentation and arrangement of functional dendritic structures within or without the lipid membrane. It is the objective and intellectual merit of this work to undertake the first systematic and inclusive examination of comb-rod dendritic block copolymer self-assembly with lipids in the solution state, and the investigation of the stabilized nanoparticles resulting from this assembly. The potential to create controlled nanostructures that span the membrane of the block copolymer via functionalization and manipulation of molecular parameters of the block copolymer could lead to the design of polymers with function that mimic transmembrane proteins, allowing the regulation or gating of hydrophilic materials such as ions, small molecules or proteins across dendritic-functionalized isolated pores. The capability of generating ordered, phase segregated or clustered surface groups that present high numbers of specific functional groups on the surface could yield highly effectual targeted polyvalent drug delivery systems. Furthermore, the unique asymmetric nature of the alkyl-peptide backbone and dendritic head group appear to create defects in liposomes that may result in faceted or irregular shapes or vesicle morphologies; the orientation and localization of the block copolymer in such systems will be studied extensively. The potential design of block copolymer lipodendrisomes that exhibit functionality in specific regions of the vesicle will be examined for three dimensional self-assembly of the unique polygonal structures, as well as functionalization to create unique nanostructures for a range of applications from orientational fluidic and surface assembly to sensing nanoparticles and biological and biomedical systems with specific cellular interactions. Finally, the ability to reversibly or irreversibly induce the spontaneous formation of functionalized gates, ligands or proteins on membrane surfaces with photo- or thermo-responsive groups will be examined.NON-TECHNICAL SUMMARY:Self-assembling polymers consisting linear and highly branched dendritic segments will be designed to undergo self-assembly in solution with naturally occurring lipid molecules. The resulting structures are anticipated to introduce unique functionality to traditional liposomes by presenting specific desired groups to the surface of the liposome to generate nanoscale clusters of protein, ligand or inorganic nanoparticles, or by creating unique channels in the liposomes that mimic the ion channels and proteins in cell membranes. A greater understanding of how these designed elements behave in liposomal systems could lead to design principles guiding the development of artificial transmembrane proteins or membrane-active surface elements. These systems may yield new materials systems for the delivery of drugs or proteins, ions, or small molecules across the membrane or the manipulation of cell receptors at surfaces. The research described here is an integral part of the investigator's research and teaching plan, and includes the education and training of undergraduate and graduate students in the laboratory environment, the integration of concepts of self-assembly in the teaching of polymer science in undergraduate and graduate courses. The mentorship of students takes place on every level, including academic and career issues, work and family concerns, and includes a number of women and minority students. Outreach of the PI includes her involvement in the MIT Summer Research Program to encourage underrepresented minority undergraduates to attend graduate school, and the participation in a high school teacher exchange program to expose teachers to research and new concepts to teach in the polymer science and colloid science areas.