Targeted drug and gene delivery systems for lung cancer therapy.
OBJECTIVE
To evaluate the efficacy of a novel docetaxel derivative of deslorelin, a luteinizing hormone-releasing hormone (LHRH) agonist, and its combination in vivo with RGD peptide conjugated nanoparticles encapsulating an antiangiogenic, anti-vascular endothelial growth factor (VEGF) intraceptor (Flt23k; RGD-Flt23k-NP) in H1299 lung cancer cells and/or xenografts in athymic nude BALB/c mice.


METHODS
The in vitro and in vivo efficacy of the deslorelin-docetaxel conjugate was evaluated in H1299 cells and xenografts in athymic nude mice. Coadministration of deslorelin-docetaxel conjugate and RGD-Flt23k-NP was tested in vivo in mice. Tumor inhibition, apoptosis, and VEGF inhibition were estimated in each of the treatment groups.


RESULTS
The conjugate enhanced in vitro docetaxel efficacy by 13-fold in H1299 cells compared with docetaxel at 24 hours, and this effect was inhibited following reduction of LHRH receptor expression by an antisense oligonucleotide. Combination of the conjugate with the RGD-Flt23k-NP in vivo resulted in an 82- and 15-fold tumor growth inhibition on day 39 following repeated weekly i.v. injections and a single intratumoral (i.t.) injection, respectively. These effects were significantly greater than individual targeted therapies or docetaxel alone. Similarly, apoptotic indices for the combination therapy were 14% and 10% in the i.v. and i.t. groups, respectively, and higher than the individual therapies. Combination therapy groups exhibited greater VEGF inhibition in both the i.v. and i.t. groups.


CONCLUSIONS
Docetaxel efficacy was enhanced by LHRH receptor-targeted deslorelin conjugate and further improved by combination with targeted antiangiogenic nanoparticle gene therapy. Combination of novel targeted therapeutic approaches described here provides an attractive alternative to the current treatment options for lung cancer therapy.
Sundaram
Sneha
S
Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado 80045, USA.
Trivedi
Ruchit
R
Durairaj
Chandrasekar
C
Ramesh
Rajagopal
R
Ambati
Balamurali K
BK
Kompella
Uday B
UB
D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D018014:Gene Transfer Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008495:Medical Oncology / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D009842:Oligopeptides / Q000494:pharmacology; D017329:Triptorelin Pamoate / Q000031:analogs & derivatives / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D042461:Vascular Endothelial Growth Factor A; D017329:Triptorelin Pamoate; C047981:arginyl-glycyl-aspartic acid; C066438:deslorelin