Mechanistic Analysis of Polyelectrolyte-Based Colloidal Drug Carriers

1133795 Lapitsky智力优点：提出了一项基础研究，将多价反离子交联的纳米微粒和纳米颗粒的性质与它们的分子相互作用和形成动力学联系起来。目前，它们的制备和在药物递送中的应用在很大程度上依赖于试验和错误，并且关于该主题的文献仍然限于经验数据。虽然带相反电荷的聚电解质的络合作用已经研究了多年，但对颗粒形成过程的详细理解被极强的结合、快速动力学和长时间的链重排所混淆。另一方面，多价反离子交联的纳米粒子的形成机制（由于其较弱的分子间相互作用，其研究更容易处理）实际上仍然未被探索。在对它们的药物释放特性的理解中存在类似的差距，这些特性已经（并继续）被不适合胶体颗粒的实验方法严重错误地表征。这种设计准则的缺乏严重限制了它们的性能，并且在药物昂贵的情况下，导致高的研发成本。为了解决这个问题，本研究旨在获得对控制它们的参数的定量和机理性理解（1）结构，（2）稳定性和（3）药物包封/释放特性，通过探索它们的胶体性质如何随着分子相互作用的变化而演变。这将通过用一系列分子和胶体表征技术（例如，等温滴定量热法、光散射和停流荧光光谱法），并使用现有的单分散胶体形成、吸附和扩散模型分析结果。利用PI？该项目将产生三个变革性成果：（1）它将为聚电解质基胶体药物载体的设计和应用提供机理和定量指导（2）它将桥接现有方法（和机理模型）用于从低分子量组分到基于聚电解质的胶体的单分散胶体的制备，以及（3）它将产生重要的机制洞察到微米和纳米粒子形成的过程中，从对相反电荷的聚电解质，这不能在实验上直接探测非常详细。更广泛的影响：该项目将使开发更安全，更有效和更便宜的药物产品的口服，鼻腔和眼科药物输送。具体来说，它将建立基本的指导方针，以确保新兴的（基于聚电解质的）药物载体将药物输送到其预期的目标，而不会导致过量。此外，从这项研究中获得的基本见解可以推进医疗和环境诊断，个人护理产品和食品的设计。托莱多大学的强大环境工程专业知识将促进这一点，该项目将培训本科生、研究生和高中生使用材料表征技术以及聚合物、胶体和制药科学的基础知识。这种培训将使他们在广泛的行业或学术界取得成功。这项工作的结果将发表在同行评审的期刊上，并在专业会议上发表。重要的是，这项工作也将与大学相结合？的推广活动。PI将向高中生介绍大学为托莱多公立学校提供的一天工程师计划中的刺激响应聚电解质，并将继续参与移民学生教师工程（ETMS; CIVE 4950/5940）远程学习课程。ETMS为农村社区的教师提供研究生培训，这些教师教农民工的孩子，目的是开发一套实验，证明数学，科学和工程对日常生活的重要性。PI最近参与了ETMS，并且已经开发了几个使用家用产品中发现的刺激响应聚合物的演示（例如，藻酸盐、聚（丙烯酸）和甲基纤维素）来加强高中化学中所学的概念。

1133795LapitskyIntellectual Merits: A fundamental study is proposed to relate the properties of multivalent counterioncrosslinked polyelectrolyte micro- and nanoparticles to their molecular interactions and formationkinetics. Currently, both their preparation and application in drug delivery largely rely on trial and error, and the literature on this subject remains limited to empirical data. While the complexation of oppositely charged polyelectrolytes has been studied for many years, detailed understanding of the particle formation process has been confounded by extremely strong binding, fast kinetics and long timescales of chain rearrangements. The formation mechanism of multivalent counterion-crosslinked polyelectrolyte particles on the other hand, (whose investigation is more tractable due to their weaker intermolecular interactions) remains virtually unexplored. Similar gaps exist in the understanding of their drug release properties, which have been (and continue to be) grossly mischaracterized by experimental methods that are unsuitable for colloidal polyelectrolyte particles. This lack of design guidelines severely limits their performance and, in cases where the drug is expensive, leads to high research and development costs.To address this, the research aims to gain a quantitative and mechanistic understanding of the parameters that govern their (1) structure, (2) stability and (3) drug encapsulation/release properties, by exploring how their colloidal properties evolve with changes in their molecular interactions. This will be achieved by probing the process of particle formation and drug encapsulation/release with an array of molecular and colloidal characterization techniques (e.g., isothermal titration calorimetry, light scattering and stopped-flow spectrofluorimetry), and analyzing the results using existing models for the formation of monodisperse colloids, adsorption and diffusion. Leveraging on the PI?s prior work on polyelectrolyte self-assembly and drug delivery, this project will yield three transformative outcomes: (1) it will provide mechanistic and quantitative guidelines for the design and application of polyelectrolyte-based colloidal drug carriers (2) it will bridge existing methods (and mechanistic models) for the preparation of monodisperse colloids from low molecular weight constituents to polyelectrolyte-based colloids and (3) it will yield important mechanistic insight into the process of micro- and nanoparticle formation from pairs of oppositely-charged polyelectrolytes, which cannot be experimentally probed in great detail directly.Broader Impacts: The project will enable development of safer, more effective and less expensive pharmaceutical products for oral, nasal and ophthalmic drug delivery. Specifically, it will establish essential guidelines for ensuring that emerging (polyelectrolyte-based) drug carriers will deliver drugs to their intended targets, and not lead to overdosing. Furthermore, the fundamental insights gained from this research could advance the design of medical and environmental diagnostics, personal care products and foods. This will be facilitated by the strong environmental engineering expertise at the University of Toledo.The project will train undergraduate, graduate and high school students in the use of materials characterization techniques, and the fundamentals of polymer, colloid and pharmaceutical science. This training will poise them for successful careers in a wide range of industries or academia. Findings from this work will be published in peer-reviewed journals and presented at professional meetings. Importantly, this work will also be integrated with the university?s outreach activities. The PI will introduce high school students to stimulus-responsive polyelectrolytes in the Engineer for a Day program that the university offers to Toledo Public Schools, and will continue his involvement in the Engineering for Teachers of Migrant Students (ETMS; CIVE 4950/5940) distance learning course. ETMS provides graduate training for teachers in rural communities who teach children of migrant farm workers, and aims to develop a set of experiments that demonstrate the importance of mathematics, science and engineering to everyday life. The PI has recently become involved with ETMS, and has already developed several demonstrations that use stimulus-responsive polymers found in household products (e.g., alginate, poly(acrylic acid), and methylcellulose) to reinforce concepts that are learned in high school chemistry.