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: 10668497
• 负责人: Ivan Susin Pires
• 金额: $ 4.77万
• 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/10668497
• 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; Endosomes; 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; Postdoctoral Fellow; Pre-Clinical Model; Prevalence; Process; Property; Proteins; Radiation; Research; Research Project Grants; Risk; Risk Reduction; Salts; Serum; Serum Proteins; Structure; Surface; System; Techniques; Therapeutic; Time; Tissues; Toxic effect; Transfection; Treatment Efficacy; Tumor Tissue; Water; Work; 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; nanoengineering; 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.

项目总结/文摘

项目成果

Electrostatic adsorption of polyanions onto lipid nanoparticles controls uptake, trafficking, and transfection of RNA and DNA therapies.

聚阴离子在脂质纳米粒子上的静电吸附控制 RNA 和 DNA 疗法的摄取、运输和转染。

• DOI: 10.1073/pnas.2307809121
• 发表时间: 2024
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Nabar,Namita;Dacoba,TamaraG;Covarrubias,Gil;Romero-Cruz,Denisse;Hammond,PaulaT
• 通讯作者: Hammond,PaulaT