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Principal Investigator: Rebecca Sara Cook
Organization: VANDERBILT UNIVERSITY
Fiscal Year: 2023
Award: $555,637
Funding agency: National Cancer Institute
Cancer nano-formulations for delivery of small molecule drugs are limited by the ability to target only ~10%
of the genome. RNAi molecules can, in theory, be designed against any gene of interest, but siRNA use in clinical
oncology faces delivery barriers such as nuclease degradation, rapid renal clearance, poor distribution into tumor
tissues, and poor cell membrane penetration. To overcome these challenges, most RNAi therapies focus on
synthetic lipo- and poly-plex nano-formulations. Unfortunately, while these technologies typically achieve very
high delivery into the liver, high-penetrance siRNA tumor delivery remains elusive.
The overarching goal of this project is to develop siRNA chemical modifications that provide potent, safe,
tumor-penetrating, and molecularly targeted nano-therapeutics against currently undruggable tumor drivers. The
approach builds upon our recently published proof of principle siRNA molecules end-modified through a PEG45
linker with a diacyl lipid (siRNA-EG45<L2), which forms a nano-complex with albumin (alb-NC) in situ following
intravenous injection. This albumin “hitchhiking” siRNA-EG45<L2 enhances siRNA pharmacokinetic properties, is
very safe, provides natural tumor tropism, and increases tumor delivery level, homogeneity of tumor delivery,
and tumor:liver delivery ratio compared to conventional nano-polyplexes formed with in vivo-jetPEI (PEI-NPs).
The alb-NCs especially outperformed PEI-NPs for accumulating within challenging patient derived xenograft
(PDX) tumors that have reduced access to delivery by the enhanced permeability and retention (EPR) effect.
The specific goal of this proposal is to further explore and optimize siRNA chemical modifications for in
situ formation of effective alb-NCs. We will benchmark new candidates against conventional nano-formulations
in simple (xenograft), immune-competent (allograft) and rigorous (PDX and spontaneous) tumor models. This
platform will be validated for silencing of the oncogene myeloid cell leukemia 1 (Mcl-1) to treat triple negative
breast cancer (TNBC). Mcl-1 is a vetted target with relevance in a broad range of cancers, supporting its use for
proof-of-concept. Furthermore, TNBC is a highly aggressive clinical breast cancer subtype with few treatment
options. TNBC patients are currently relegated to chemotherapies, and do not typically benefit from molecularly-
targeted therapies.
This project is uniquely accessible by our multi-PI interdisciplinary team with bioengineering expertise in
intracellular biologic drug delivery nanotechnologies (Duvall), chemical synthesis (Uddin), analysis of noncoding
RNA transport on serum components (Vickers), Mcl-1 pathway modulation and analysis (Cook), and cutting
edge preclinical models, including PDX, for testing experimental therapies (Brantley-Sieders). Our basic
science expertise will be supplemented by consultation with Dr. Ingrid Mayer, a medical oncologist involved in
breast cancer clinical trials at Vanderbilt. This group will enable previously inaccessible investigations toward
development of more effective, tumor-penetrating, and molecularly-targeted TNBC therapeutics.
Terms: <1,2-Ethanediol><2-Hydroxyethanol><Abraxane><Address><Albumins><Allografting><Apoptosis><Apoptosis Pathway><Apoptotic><Automobile Driving><BRCA1><BRCA1 gene><Basic Research><Basic Science><Benchmarking><Best Practice Analysis><Binding><Biodistribution><Biological><Biomedical Engineering><Blood Serum><Breast Cancer><Breast Cancer 1 Gene><Breast Cancer Model><Breast Cancer Patient><Breast Cancer Type 1 Susceptibility Gene><Breast Cancer therapy><Breast Tumor Patient><Breast tumor model><Caelyx><Cancer Genes><Cancer-Promoting Gene><Cancers><Cell Body><Cell membrane><Cells><Chemicals><Chemistry><Cholesterol><Clinical><Clinical Oncology><Consultations><Cytoplasmic Membrane><DOX SL><DOXSL><Development><Dihydroxyethanes><Dose><Doxilen><Doxorubicin HCl Liposome><Doxorubicin Hydrochloride Liposome><Drug Delivery><Drug Delivery Systems><Drug Formulations><Drug Kinetics><Drugs><Early Onset Gene Breast Cancer 1><Endosomes><Ethanediols><Ethylene Glycols><Evacet><Experimental Therapies><Extrahepatic><FDA approved><Face><Formulation><Functional RNA><Gene Inactivation><Gene Silencing><Genes><Genome><Goals><Hepatic><Hepatic Cells><Hepatic Neoplasms><Hepatic Parenchymal Cell><Hepatocyte><Hereditary Breast Cancer 1><Heterograft><Heterologous Transplantation><Human><Immunocompetent><In Situ><In Vitro><Injections><Investigation><Investigational Therapies><Investigational Treatments><Lipid Binding><Lipids><LipoDox><Liposomal Doxorubicin Hydrochloride><Liver><Liver Cells><Liver neoplasms><Luciferase Immunologic><Luciferases><MCL-1><MCL1><MCL1 gene><Malignant Neoplasms><Malignant Tumor><Measures><Medical Oncologist><Medication><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular Interaction><Molecular Target><Monoethylene Glycol><Murine><Mus><Myocet><Nanotechnology><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Oligo><Oligonucleotides><Oncogenes><Organ><PARP Inhibitor><PARP-1 inhibitor><PARPi><PDX model><Pathway interactions><Patient derived xenograft><Penetrance><Penetration><Permeability><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Plasma Membrane><Poly(ADP-ribose) Polymerase Inhibitor><Poly(ADP-ribose) polymerase 1 inhibitor><Position><Positioning Attribute><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Pre-Clinical Model><Preclinical Models><Programmed Cell Death><Property><Publishing><Quelling><RNA Interference><RNA Interference Therapy><RNA Silencing><RNA Transport><RNA interference therapeutics><RNA interference-based therapy><RNAi><RNAi therapeutics><RNAi therapy><RNAi-based therapeutics><RNAi-based therapy><RNF53><Receptosomes><Renal clearance function><Ribonucleic Acid Transport><Safety><Sequence-Specific Posttranscriptional Gene Silencing><Serum><Serum Albumin><Serum Proteins><Short interfering RNA><Site><Small Interfering RNA><TNBC><Technology><Testing><Therapeutic><Toxic effect><Toxicities><Toxicology><Transforming Genes><Transgenic Organisms><Treatment Efficacy><Tropism><Tumor Tissue><Untranslated RNA><Work><Xenograft><Xenograft procedure><Xenotransplantation><benchmark><bio-engineered><bio-engineers><bioengineering><biologic><biological engineering><brca 1 gene><c myc><c-myc Genes><cancer clinical trial><cancer sub-types><cancer subtypes><chemical synthesis><chemotherapy><clinical translation><clinically translatable><cmyc><consultation><cooking><design><designing><developmental><doxil><driving><drug/agent><endosome membrane><ethylene glycol><experimental therapeutic agents><experimental therapeutics><faces><facial><hepatic body system><hepatic neoplasia><hepatic neoplasm><hepatic organ system><hepatic tumor><immune competent><improved><in vitro activity><in vivo><inhibitor><interest><intervention efficacy><intravenous injection><knock-down><knockdown><lead candidate><lipid based nanoparticle><lipid bound><lipid nanoparticle><liver tumor><malignancy><malignant breast neoplasm><malignant breast tumor><mammary cancer model><mammary tumor model><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mutant><myeloid cell leukemia 1><myeloid cell leukemia sequence 1><myeloid leukemia cell differentiation protein><nano><nano formulation><nano medicinal><nano medicine><nano polymer><nano tech><nano technology><nano-technological><nanocomplexes><nanoformulation><nanomedicinal><nanomedicine><nanopolymer><nanotech><nanotechnological><nanotherapeutic><neoplasm/cancer><noncoding><nuclease><oligos><oncology clinical trial><orthotopic breast adenocarcinoma><orthotopic breast cancer><orthotopic breast carcinoma><orthotopic breast tumor><pathway><patient derived xenograft model><pharmaceutical><plasmalemma><pre-clinical><preclinical><renal clearance><response><screening><screenings><siRNA><siRNA delivery><siRNA therapy><siRNA-based therapeutic><small molecule><small molecule inhibitor><success><taxane><theories><therapeutic efficacy><therapeutic siRNA><therapy efficacy><transcriptional silencing><transgenic><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor xenograft><v-myc Avian Myelocytomatosis Viral Oncogene Cellular Homolog><xeno-transplant><xeno-transplantation>