Document text
Principal Investigator: ANUP KUMER KUNDU
Organization: XAVIER UNIVERSITY OF LOUISIANA
Fiscal Year: 2024
Award: $112,500
Funding agency: National Institute of General Medical Sciences
ABSTRACT
The development of multidrug resistance (MDR) in cancer cells is of grave concern, limiting the
efficacy of anticancer agents and, hence, the failure of breast cancer therapy. Clinical research and
application revealed that in spite of its potential anticancer effects, doxorubicin is highly toxic, and its
long-term application may cause dose-dependent irreversible cardiomyopathy, severe cardiac
toxicity, or liver damage, thereby limiting its application in breast cancer treatment. Even if the drug
is super-efficient, if it still causes off-target toxicity and damages non-cancerous cells and tissues,
the drug wouldn’t be a great remedy to treat that particular disease. As such, the greater potential
of using doxorubicin as anticancer therapeutic depends on the availability of a targeted delivery
vehicle, which will not only enhance the killing of cancer cells but also minimize the off-target
toxicity to non-cancerous cells. The goal of this study is to enhance the delivery of doxorubicin
by formulating an aptamer-labeled liposomal nanoparticle delivery system that will carry and
deliver doxorubicin specifically into chemoresistant Her-2+ breast cancer cells. We have
recently reported that down regulating nuclear expression of MDR1 P-gp (ABCB1 gene) by P-gp
specific siRNA could increase the delivery of doxorubicin to doxorubicin resistant breast cancer cells.
However, since the Dox was delivered as a free drug solution without encapsulating it into a particle
for targeted delivery, it still caused toxicity to other non-cancerous cells. The targeted delivery of
siRNA to knockdown multi-drug resistant genes such as MDR1 P-gp, MRP or BCRP might be helpful
to circumvent MDR using the apt-labeled formulations that we have developed in our lab, however,
there are some questions that still need to be addressed (1) how can we deliver doxorubicin in a
more targeted fashion to the chemoresistant breast cancer cells so that the drug-enhanced
cytotoxicity to cancer cells increases with a minimal toxicity to the non-cancerous cells? We assume
that a targeted delivery system is an utmost requirement whether it is delivering siRNA to silence
chemoresistant genes or an actual chemodrug which will kill cancer cells without killing non-
cancerous cells. To address the chemoresistance as well as off-target toxicity, a targeted delivery
system for doxorubicin needs to be developed which should be innovative, comparable and can
minimize the toxicity to other non-cancerous cells. And (2) a strategy needs to be in place to
determine whether the targeted nanoparticles will carry both doxorubicin and siRNA within the same
particles or in different particles to get the best results preventing chemoresistance and limiting off-
target toxicity. Our hypothesis is that delivering doxorubicin and MDR-silencing siRNAs separately
by targeted nanoparticle system will enhance the cellular toxicity and antitumor effects as compared
to a targeted nanoparticle system that delivers the drug and siRNA simultaneously. This hypothesis
will be tested through two specific aims:
Aim 1: Targeted delivery of doxorubicin liposomes for Her-2 positive breast cancer treatment.
Aim 2: Assess whether the targeted nanoparticles will carry both doxorubicin and siRNA within the
same particles or in different particles to get the best results preventing chemoresistance and limiting
off-target toxicity.
Terms: <14-Hydroxydaunomycin><ABC Transport Protein><ABC Transporter Protein><ABC Transporters><ABC15><ABC20><ABC29><ABCB1><ABCB1 gene><ABCC><ABCC1><ABCC1 gene><ABCG2><ABCG2 gene><ABCP><ATP-Binding Cassette Transporters><ATP-Binding Cassette, Sub-Family G (WHITE), Member 2 Gene><ATP-Binding Cassette, Sub-Family G, Member 2><ATP-Binding Cassette, Subfamily G, Member 2><Acids><Address><Adriamycine><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Aptamer Technology><BCRP><BCRP1><Binding><Body Tissues><Breast Cancer><Breast Cancer Cell><Breast Cancer Resistance Protein><Breast Cancer Treatment><Breast Cancer therapy><Bypass><Cancer Drug><Cancer Treatment><Cardiac Toxicity><Cardiomyopathies><Cardiotoxic><Cardiotoxicity><Cell Body><Cells><Chemoresistance><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy-Oncologic Procedure><Clinical Research><Clinical Study><Combination Chemotherapy Regimen><DNA><Deoxyribonucleic Acid><Deposit><Deposition><Development><Disease><Disorder><Disseminated Malignant Neoplasm><Dose><Doxorubicin><Doxorubicin Liposome><Doxorubicina><Drug resistance><Drugs><EST157481><Encapsulated><Failure><Formulation><GP170><GS-X><Genes><Goals><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><Injury to Liver><Label><Liposomal><Liposomal Doxorubicin><Liposomal-Encapsulated Doxorubicin><Liposomes><Lytotoxicity><MDR Genes><MDR-1><MDR1><MDR1 Protein><MRP1><MRX><MXR1><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Medication><Metastatic Cancer><Metastatic Malignant Neoplasm><Mitoxantrone Resistance Protein><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Multi-Drug Resistance><Multi-drug Resistance Gene><Multi-drug Resistant Gene><Multidrug Resistance><Multidrug Resistance 1><Multidrug Resistance Gene><Multidrug Resistance Gene-1><Multidrug Resistance Gene-1s><Multidrug Resistance Proteins><Multidrug Resistant Gene><Multidrug Resistant Proteins><Multiple Drug Resistance><Multiple Drug Resistant><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Nanotechnology><Neoplastic Disease Chemotherapeutic Agents><Non-Polyadenylated RNA><Normal Cell><Normal Tissue><Normal tissue morphology><Nuclear><Oligo><Oligonucleotides><Outcome><P-GP><P-Glycoprotein><P-Glycoprotein 1 Gene><PGY-1 Protein><PGY1><Pharmaceutical Preparations><Placenta-Specific ATP-Binding Cassette Transporter><Polymers><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Proteins><Quimioterapia><RNA><RNA Gene Products><RNA Interference><RNA Silencing><RNAi><Receptor Protein><Reporting><Resistance><Resistance development><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant development><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Ribonucleic Acid><Sequence-Specific Posttranscriptional Gene Silencing><Short interfering RNA><Small Interfering RNA><Specificity><System><Testing><Therapeutic><Tissues><Toxic effect><Toxicities><Treatment Failure><Tumor Cell><Tumor-Specific Treatment Agents><anti-cancer><anti-cancer drug><anti-cancer therapeutic><anti-cancer therapy><anti-tumor effect><antitumor effect><aptamer><breast tumor cell><cancer cell><cancer chemotherapy><cancer drug resistance><cancer therapy><cancer-directed therapy><chemoresistant><chemotherapy resistance><chemotherapy resistant><clinical applicability><clinical application><conformation><conformational><conformational state><conformationally><conformations><cytotoxicity><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vector><delivery vectors for siRNA><delivery vehicle><developing resistance><developmental><drug resistant><drug/agent><hepatic damage><hepatic injury><innovate><innovation><innovative><knock-down><knockdown><lipid based nanoparticle><lipid nanoparticle><liver damage><liver injury><malignant breast tumor><multi-drug resistant><multidrug resistant><myocardium disease><myocardium disorder><nano particle><nano particle delivery><nano tech><nano technology><nano-sized particle><nano-technological><nanocarrier><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><nanotech><nanotechnological><nanovessel><neoplastic cell><oligos><overexpress><overexpression><particle><polymer><polymeric><prevent><preventing><receptor><resistance gene><resistance locus><resistance to Drug><resistance to cancer drugs><resistant><resistant gene><resistant to Drug><resistant to cancer drugs><short interfering RNA delivery><siRNA><siRNA delivery><side effect><site targeted delivery><small interfering RNA delivery><targeted delivery><therapy failure><uptake>