Understanding drug delivery through an integrated barcoding approach

通过集成条形码方法了解药物输送

• 批准号: 10301623
• 负责人: Natalie Boehnke
• 金额: $ 15.4万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301623
• 关键词: Advisory Committees; Affinity; Agar; Bar Codes; Binding; Biodistribution; Biological; Biology; Cancer Biology; Cancer cell line; Cell Communication; Cell Line; Cells; Characteristics; Chemical Engineering; Chemicals; Chemistry; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Complex; Cytolysis; DNA; Detection; Development; Disease; Disease Resistance; Dose; Drug Delivery Systems; Drug Targeting; Environment; Evaluation; Flow Cytometry; Fluorescence; Formulation; Genes; Genetic; Genomics; Goals; Heterogeneity; Immune; Immunocompetent; Immunocompromised Host; In Vitro; Individual; Institutes; Institution; Knock-out; Label; Magic; Malignant Neoplasms; Malignant neoplasm of ovary; Mass Fragmentography; Mass Spectrum Analysis; Mediating; Mentorship; Mesenchymal; Modality; Modeling; Mus; Organ; Patients; Play; Polymers; Population; Property; Recurrence; Research Personnel; Research Proposals; Sampling; Site; Structure-Activity Relationship; Surface; Survival Rate; System; Techniques; Technology; Therapeutic Uses; Time; Tissues; Training; Translating; Translations; Tumor Biology; Validation; Work; anticancer research; aryl halide; base; cancer cell; carboxylate; career; chemotherapy; detection limit; genetic signature; high throughput analysis; in vivo; in vivo evaluation; materials science; multiple omics; nanocarrier; nanomedicine; nanoparticle; nanoparticle delivery; neoplastic cell; novel therapeutics; particle; pre-clinical; protein expression; screening; self assembly; success; targeted treatment; therapy resistant; tool; trafficking; transcriptome sequencing; tumor; tumor heterogeneity; uptake

Project Summary Despite being hailed as the “magic bullet” that would selectively target and cure cancer, only a handful of nanoparticles have been successfully translated to the clinic, and their full potential remains yet to be realized. In fact, nanoparticle accumulation in tumors continues to be dismally low, with less than 1% of the injected dose reaching its target. This is largely attributed to the complexity and heterogeneity of both the biological environment and nanoparticle constructs, making it impossible to deconvolute individual factors contributing to nanoparticle targeting and accumulation in tumors. Therefore, there is a critical need to better understand and define the attributes that define successful nanocarriers. This is particularly urgent in lethal cancers that stand to benefit tremendously from new and targeted therapies, like ovarian cancer, which has a 25% 5-year survival rate and 70% recurrence rate following chemotherapy, often leading to treatment resistant disease. To develop effective drug delivery strategies, it is critically important to understand the characteristics of tumors, nanoparticles, and their interactions, such as by identifying the genetic features associated with high nanoparticle uptake and accumulation. To accomplish this, the work proposed herein features a chemical barcoding approach to enable pooled high throughput analysis of nanoparticles in a pre-clinical context, enabling the identification and correlation of genetic features responsible for successful nanoparticle targeting through a multi-omics approach. Successful development of this barcoding platform will entail 1) rapid integrated in vitro screening of pooled NP formulations, 2) in vivo single system evaluation of nanoparticle accumulation at the tissue and cellular level, and 3) use of pooled barcoded nanoparticles to correlate particle trafficking in patient derived models of ovarian cancer. This strategy will provide a holistic evaluation of nanoparticle structure-function relationships with tumor accumulation and enable the identification of genetic components implicated with meaningful nanoparticle interactions, allowing us to leverage these signatures to develop more effective targeted nanoparticles to specific tumor cell populations. The proposed work will take place at MIT’s Koch Institute for Integrative Cancer Research, a premier institution for cancer research with state-of-the-art facilities, under the mentorship of Prof. Paula Hammond, a renowned chemical engineer and polymer chemist with expertise in the self-assembly of materials and drug delivery. An advisory team has carefully been assembled, consisting of Profs. Stuart Schreiber and Angela Koehler for chemical biology and multi-omics analysis guidance, Prof. Joan Brugge for her cancer biology expertise, and Prof. Nathalie Agar for input on mass spectrometry-based analysis. Combined, this research proposal and mentorship team will lay the scientific groundwork and provide the necessary training for the applicant to reach her ultimate goal of successfully starting her independent academic career at the interface of chemistry, biology, and materials science.

项目总结