Nonviral nanoscale-based delivery of antisense oligonucleotides targeted to hypoxia-inducible factor 1 alpha enhances the efficacy of chemotherapy in drug-resistant tumor.
OBJECTIVE
To enhance the efficacy of cancer treatment, we propose a complex approach: simultaneous delivery to the tumor of a chemotherapeutic agent and a suppressor of hypoxia-inducible factor 1 alpha (HIF1A).


METHODS
The novel complex liposomal drug delivery system was developed and evaluated in vitro and in vivo on nude mice bearing xenografts of multidrug-resistant human ovarian carcinoma. The proposed novel complex drug delivery system consists of liposomes as a nanocarrier, a traditional anticancer drug (doxorubicin) as a cell death inducer, and antisense oligonucleotides targeted to HIF1A mRNA as a suppressor of cellular resistance and angiogenesis.


RESULTS
The system effectively delivers active ingredients into tumor cells, multiplies the cell death signal initiated by doxorubicin, and inhibits cellular defensive mechanisms and angiogenesis by down-regulating BCL2, HSP90, and vascular endothelial growth factor proteins. This, in turn, activates caspases, promotes apoptosis, necrosis, and tumor shrinkage. The proposed novel complex multipronged approach enhances the efficiency of chemotherapy.


CONCLUSIONS
The proposed combination therapy prevents the development of resistance in cancer cells, and thus, increases the efficacy of chemotherapy to an extent that cannot be achieved by individual components applied separately. It could form the foundation for a novel type of cancer therapy based on simultaneous delivery of an anticancer drug and a suppressor of HIF1A.
Wang
Yang
Y
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
Saad
Maha
M
Pakunlu
Refika I
RI
Khandare
Jayant J
JJ
Garbuzenko
Olga B
OB
Vetcher
Alexandre A
AA
Soldatenkov
Viatcheslav A
VA
Pozharov
Vitaly P
VP
Minko
Tamara
T
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects*; D051379:Mice; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016376:Oligonucleotides, Antisense; D004317:Doxorubicin