Engineering Next-Generation Nanoparticles One Layer at a Time

一次一层地设计下一代纳米粒子

• 批准号: 10528938
• 负责人: Ivan Susin Pires
• 金额: $ 4.83万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528938
• 关键词: Adsorption; Affect; Antibodies; Antineoplastic Agents; Architecture; Binding; Biological; Biological Availability; COVID-19 vaccine; Cancer Control; Cancer Model; Cells; Characteristics; Charge; Chemistry; Clinical; Cytoplasm; Deposition; Drug Controls; Drug Delivery Systems; Drug Kinetics; Effectiveness; Electrostatics; Engineering; FDA approved; Film; Fluorescence Resonance Energy Transfer; Formulation; Goals; Half-Life; Hydrogen Bonding; Immunotherapeutic agent; In Vitro; Interleukin-12; Ionic Strengths; Kinetics; Knowledge; Libraries; Liposomes; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mentors; Methods; Modeling; Modernization; Modification; Molecular Conformation; Monitor; Nucleic Acids; Oncogenes; Operative Surgical Procedures; Pharmaceutical Preparations; Phase; Polyethylene Glycols; Polymers; Population; Pre-Clinical Model; Prevalence; Process; Property; Proteins; Radiation; Research; Research Project Grants; Risk; Salts; Serum; Serum Proteins; Structure; Surface; System; Techniques; Therapeutic; Time; Tissues; Toxic effect; Transfection; Treatment Efficacy; Tumor Tissue; Water; Work; base; biomaterial compatibility; cancer cell; cancer immunotherapy; cancer therapy; cancer type; chemotherapy; crosslink; cytokine; delivery vehicle; density; design; ethylene glycol; experience; extracellular; gene therapy; immunogenic; immunoreactivity; improved; in vivo; macromolecule; nanomaterials; nanoparticle; next generation; nucleic acid delivery; particle; pre-clinical; rational design; receptor; small molecule; spatiotemporal; success; symposium; tool; trend; tumor; tumor microenvironment; uptake

Project Summary/Abstract Cancer treatment currently relies on surgery, radiation, and systemic chemotherapy. While these techniques have greatly improved cancer therapy, they also risk damaging healthy tissue and have incomplete elimination of the cancer. The use of nanoparticles (NPs) as drug delivery vehicles may reduce these issues by specifically accumulating in tumor tissue. Further NPs can improve the bioavailability of drugs, widening the range of potential therapeutics for cancer treatment. Although there have been some successes in the NP field that led to clinically approved formulations, most have relied on passive means of accumulation and depend on surface conjugation with polyethylene glycol (PEG) chains. Unfortunately, passive accumulation may not benefit some cancer types and recent wide-spread use of PEG in commercial products has led to prevalence of anti-PEG antibodies in the population which risk reducing efficacy of PEG-based therapeutics. Accordingly, there is a great need to engineer next-generation NPs with improved properties for cancer treatment without the use of PEG. One promising NP system for cancer drug delivery is layer-by-layer (LbL) NPs which have shown great promise in preclinical models of cancer as a delivery vehicle for small molecules, nucleic acids or macromolecules. LbL consists of a simple assembly method involving the alternating adsorption of polymeric species from water onto a substrate which can be mediated by electrostatics, hydrogen-bonding or other molecular interactions. This process allows for facile surface modification of NPs which has been shown to enable cancer cell targeting and to control subcellular localization. However, there is a dearth of knowledge on how to monitor and control the disassembly of the LbL structure to improve the NP stability and enable precise spatiotemporal control of drug delivery via LbL-NPs. During the F99 phase, I will explore how to modulate the layer architecture in layer-by- layer (LbL) NPs. In this project, the effects of solution conditions during layering and other key layer characteristics will be investigated. Particles will be loaded with interleukin-12, a potent immunostimulatory protein, to evaluate treatment efficacy of optimized formulations in vitro and in an in vivo metastatic ovarian cancer model. During the K00 phase, the focus will transition from systemic stability towards characterization of cellular uptake and intracellular disassembly targeted at gene therapy for cancer treatment. Gene therapy has had many new exciting breakthroughs in the last decades, but its use in cancer treatment has been limited due to poor targeting and low transfection efficacy. I will design a library of NP formulations and characterize their uptake and intracellular disassembly in vitro and in vivo to determine key NP properties that can modulate gene therapy efficacy. Further, I will design and optimize nucleic acid combinations of new immunotherapeutic constructs to deliver via the optimized gene therapy formulations.

项目摘要/摘要 癌症治疗目前依赖于手术，放射和全身化疗。而这些技术 癌症治疗大大改善了，它们也有损害健康组织的风险，并且不完全消除 癌症。使用纳米颗粒（NP）作为药物输送车可能会特别减少这些问题 积聚在肿瘤组织中。进一步的NP可以改善药物的生物利用度，扩大了 癌症治疗的潜在治疗剂。尽管在NP领域取得了一些成功 为了获得临床认可的配方，大多数依赖于被动的积累手段，并依赖于表面 与聚乙烯乙二醇（PEG）链结合。不幸的是，被动积累可能不会受益 癌症类型和最近在商业产品中广泛使用PEG已导致抗PEG患病率 人群中有可能降低基于PEG的治疗疗法的抗体。因此，有一个很棒的 需要在不使用PEG的情况下设计具有改善癌症治疗特性的下一代NP。 癌症药物输送的一种有希望的NP系统是逐层（LBL）NP，它表现出巨大的希望 在癌症的临床前模型中，作为小分子，核酸或大分子的递送载体。 lbl 由一种简单的组装方法组成，涉及从水到水到 可以通过静电，氢键或其他分子相互作用介导的底物。这 过程允许对NP的易于表面修饰，这已证明可以实现癌细胞靶向和 控制亚细胞定位。但是，关于如何监视和控制的知识很少 拆卸LBL结构以提高NP稳定性并实现药物的精确时空控制 通过lbl-nps交付。在F99阶段，我将探索如何在逐个图中调节图层体系结构 层（LBL）NP。在该项目中，分层和其他键层期间解决方案条件的影响 将研究特征。颗粒将装有白介素12，这是一种有效的免疫刺激性 蛋白质，以评估优化配方在体外和体内转移性卵巢中的治疗功效 癌症模型。在K00阶段，重点将从系统稳定性转变为表征 细胞摄取和针对癌症治疗基因治疗的细胞内拆卸。基因疗法具有 在过去的几十年中，有许多新的激动人心的突破，但是由于其在癌症治疗中的使用受到限制 靶向差和转染功效低。我将设计一个NP配方库，并将其描述 在体外和体内摄取和细胞内拆卸，以确定可以调节基因的关键NP特性 治疗功效。此外，我将设计和优化新的免疫治疗的核酸组合 通过优化的基因治疗制剂传递的结构。