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.

项目概要/摘要 目前癌症治疗依赖于手术、放疗和全身化疗。虽然这些技术 极大地改善了癌症治疗，但它们也有损害健康组织的风险，并且消除不完全 的癌症。使用纳米粒子（NP）作为药物输送载体可以通过专门的方法减少这些问题 积聚在肿瘤组织中。进一步的纳米颗粒可以提高药物的生物利用度，扩大药物的范围 癌症治疗的潜在疗法。尽管在 NP 领域已经取得了一些成功， 对于临床批准的制剂，大多数依赖于被动积累方式并依赖于表面 与聚乙二醇（PEG）链缀合。不幸的是，被动积累可能不会让某些人受益 癌症类型和最近 PEG 在商业产品中的广泛使用导致抗 PEG 的流行 人群中的抗体可能会降低基于 PEG 的疗法的功效。据此，有一个很大的 需要设计具有改进特性的下一代纳米粒子，用于在不使用 PEG 的情况下治疗癌症。 用于癌症药物输送的一种有前景的纳米颗粒系统是层层（LbL）纳米颗粒，它已显示出巨大的前景 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。磅级 由一种简单的组装方法组成，涉及将聚合物物质从水中交替吸附到 可以通过静电、氢键或其他分子相互作用介导的基底。这 该过程可以轻松地对纳米粒子进行表面修饰，这已被证明能够实现癌细胞靶向和 控制亚细胞定位。然而，人们对如何监控和控制仍缺乏了解。 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-NP 进行交付。在F99阶段，我会探索如何逐层调制层架构—— 层（LbL）NP。本工程中分层及其他关键层时溶液条件的影响 特征将被调查。颗粒将装载白细胞介素 12，这是一种有效的免疫刺激剂 蛋白质，评估优化制剂的体外和体内转移性卵巢的治疗效果 癌症模型。在K00阶段，重点将从系统稳定性转向表征 针对癌症治疗的基因治疗的细胞摄取和细胞内分解。基因疗法有 在过去的几十年里取得了许多令人兴奋的新突破，但由于其在癌症治疗中的应用受到限制 靶向性差，转染效率低。我将设计一个 NP 配方库并表征它们 体外和体内的摄取和细胞内分解，以确定可调节基因的关键 NP 特性 治疗功效。此外，我将设计和优化新免疫治疗的核酸组合 构建通过优化的基因治疗配方进行递送。