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Principal Investigator: Jacob Daggett Ramsey
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2023
Award: $39,214
Funding agency: National Cancer Institute
Abstract/Project Summary
Polymeric micelles are powerful drug delivery vehicles with a promising future. There are currently no US Food
and Drug Administration approved polymeric micelle formulations, but some have been approved by the
European Medicines Agency and other international regulatory bodies. Traditional pharmacokinetic analysis
focuses on two drug fractions-unbound free drug and drug which is bound to serum proteins. However, the
inclusion of nanoparticles complicates pharmacokinetic analysis by introducing a third drug fraction which is
nanomedicine encapsulated. Encapsulation into polymeric micelles alters drug partitioning to serum proteins.
Polymeric micelles can preferentially accumulate into tumor tissues, improving tumor drug exposure. Little is
known about how polymer-drug interactions influence drug partitioning between polymeric micelles and serum
proteins. My preliminary data shows that we have developed an in vitro assay to measure micelle-protein
partitioning which recapitulates known in vivo behavior, like the high protein binding of the drug warfarin. For the
F99 phase of my proposal, I hypothesize that the in vitro partitioning of drug is related to polymer-drug
interactions which we observe by NMR, micro-DSC, and molecular dynamics. In particular, we have shown that
drug interaction with parts of the polymeric micelle hydrophilic corona leads to improved drug loading, and may
lead to stronger retention in the polymeric micelles. In Aim 1.1, I propose to study how these measured polymer-
drug interactions affect drug partitioning in a validated in vitro assay. This in vitro drug partitioning could correlate
to tumor-drug exposure in vivo in a mouse model of triple negative breast cancer. In Aim 1.2, I hypothesize that
improved micelle drug retention, as measured in vitro, will improve the distribution of drug to the tumor in vivo as
measured by AUC and Cmax. Understanding how polymer-drug interactions influence partitioning and tumor
exposure will lead to reduced preclinical studies and improved therapeutic outcomes. We will be able to select
optimal formulations by applying in vitro partitioning results to pharmacokinetic modeling to predict tumor drug
exposure. In Aim 1.3, we will analyze drug fractions in non-human primates to determine if drug partitioning is
recapitulated in more human-like species. Altogether, the proposed F99 phase work will improve our
understanding of polymeric micelle formulations and how drug retention affects tumor exposure and therapeutic
efficacy. In the K00 phase, I propose to focus on polymer-nucleic acid and polymer-protein complexes for cancer
therapeutics and vaccines. Utilizing the same principles from the F99 phase, polymer-cargo interactions can be
used to inform targeted drug delivery of these different cargoes. My dissertation project and future postdoctoral
work will provide the necessary training experience to prepare me for an independent research career focused
on cancer therapeutics.
Terms: <Accounting><Affect><Animal Cancer Model><Animal Model><Animal Models and Related Studies><Antineoplastic Vaccine><Assay><Autoregulation><Behavior><Binding><Binding Proteins><Bioassay><Biologic Assays><Biological Assay><Blood Plasma><Blood Serum><Breast Cancer Model><Breast tumor model><Cancer Treatment><Cancer Vaccines><Cancers><Circulation><Clinic><Clinical><Clinical Trials><Combined Modality Therapy><Data><Dialysis><Dialysis procedure><Dose><Drug Combinations><Drug Delivery><Drug Delivery Systems><Drug Exposure><Drug Formulations><Drug Interactions><Drug Kinetics><Drug Targeting><Drugs><Encapsulated><Ensure><Equilibrium><European><Exposure to><Food and Drug Administration><Formulation><Future><Goals><Homeostasis><Human><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><In Vitro><Individual><International><Ligand Binding Protein><Ligand Binding Protein Gene><Liver><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Measurable><Measurement><Measures><Medication><Medicine><Micelles><Modeling><Modern Man><Molecular Dynamics Simulation><Molecular Interaction><Multimodal Therapy><Multimodal Treatment><Neoplasm Vaccines><Nucleic Acids><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Phase><Physiological Homeostasis><Plasma><Plasma Serum><Play><Polymers><Postdoc><Postdoctoral Fellow><Protein Binding><Proteins><Proxy><Research><Research Associate><Reticuloendothelial System, Serum, Plasma><Role><Serum><Serum Proteins><System><TNBC><Technology><Therapeutic><Thermodynamic><Thermodynamics><Toxic effect><Toxicities><Training><Translating><Translations><Treatment Efficacy><Tumor Tissue><Tumor Vaccines><USFDA><United States Food and Drug Administration><Vaccines><Warfarin><Weight><Work><anti-cancer therapy><anti-tumor vaccine><anticancer therapy><antitumor vaccine><balance><balance function><bound protein><cancer microenvironment><cancer therapy><cancer-directed therapy><career><chemotherapy><combination therapy><combined modality treatment><combined treatment><copolymer><delivery vector><delivery vehicle><dialysis therapy><drug disposition><drug distribution><drug metabolism><drug/agent><experience><hepatic body system><hepatic organ system><hydrophilicity><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><in vitro Assay><in vivo><intervention efficacy><lipid based nanoparticle><lipid nanoparticle><malignancy><mammary cancer model><mammary tumor model><model of animal><molecular dynamics><mouse model><multi-modal therapy><multi-modal treatment><murine model><nano medicinal><nano medicine><nano particle><nano-sized particle><nanomedicinal><nanomedicine><nanoparticle><nanosized particle><neoplasm/cancer><next generation><non-human primate><nonhuman primate><novel><nucleic acid delivery><pharmacokinetic model><polymer><polymeric><post-doc><post-doctoral><post-doctoral trainee><pre-clinical><pre-clinical study><preclinical><preclinical study><protein complex><rational design><research associates><small molecule><social role><success><therapeutic efficacy><therapeutic outcome><therapy efficacy><therapy outcome><translation><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor microenvironment><vaccine for cancer><weights>