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: 10682653
• 负责人: Natalie Boehnke
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682653
• 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; delivery vehicle; 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.

项目摘要 尽管被誉为选择性靶向和治愈癌症的“灵丹妙药”， 纳米颗粒已经成功地应用于临床，其全部潜力仍有待实现。 事实上，纳米颗粒在肿瘤中的积聚仍然非常低，不到注射剂量的1% 达到其目标。这在很大程度上归因于生物学的复杂性和异质性。 环境和纳米颗粒结构，使得不可能去卷积有助于 纳米颗粒靶向和肿瘤中的积累。因此，迫切需要更好地了解和 定义定义成功的纳米载体的属性。这对于那些致命的癌症来说尤其紧迫， 从新的靶向治疗中受益匪浅，如卵巢癌，5年生存率为25%。 化疗后70%的复发率，通常导致治疗抵抗性疾病。发展 有效的药物递送策略，了解肿瘤的特征至关重要， 纳米颗粒及其相互作用，例如通过识别与高纳米颗粒相关的遗传特征， 吸收和积累。为了实现这一点，本文提出的工作的特点是化学条形码的方法 为了在临床前环境中实现纳米颗粒的合并高通量分析， 以及通过多组学成功靶向纳米颗粒的遗传特征的相关性 approach.这种条形码平台的成功开发将需要1）快速整合的体外筛选， 合并的NP制剂，2）纳米颗粒在组织和细胞中累积的体内单一系统评价， 水平，和3）使用合并的条形码化纳米颗粒来关联患者来源的模型中的颗粒运输。 卵巢癌该策略将提供纳米颗粒结构-功能关系的整体评估 与肿瘤积累，并使识别的遗传成分牵连有意义的 纳米颗粒相互作用，使我们能够利用这些签名来开发更有效的靶向 针对特定肿瘤细胞群体的纳米颗粒。这项拟议中的工作将在麻省理工学院的科赫研究所进行， 综合癌症研究，一个首屈一指的癌症研究机构，拥有最先进的设施，根据 Paula哈蒙德教授是著名的化学工程师和聚合物化学家，在 材料的自组装和药物输送。一个咨询小组已经精心组建， 教授Stuart Schreiber和Angela Koehler化学生物学和多组学分析指导，Joan教授 Brugge教授的癌症生物学专业知识，以及Nathalie Agar教授对基于质谱的分析的投入。 结合起来，这项研究提案和导师团队将奠定科学基础，并提供 为申请人提供必要的培训，以实现成功开始独立学术的最终目标 从事化学、生物学和材料科学的工作。