Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) enables cancer cells to develop resistance to multiple anticancer drugs. Functional inhibitors of P-gp have shown promising efficacy in early clinical trials, but their long-term safety is yet to be established. A novel approach to overcome drug resistance is to use siRNA-mediated RNA interference to silence the expression of the efflux transporter. Because P-gp plays an important role in the physiological regulation of endogenous and xenobiotic compounds in the body, it is important to deliver P-gp targeted siRNA and anticancer drug specifically to tumor cells. Further, for optimal synergy, both the drug and siRNA may need to be temporally colocalized in the tumor cells. In the current study, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel, along with P-gp targeted siRNA, using poly(D,L-lactide-co-glycolide) nanoparticles to overcome tumor drug resistance. Nanoparticles were surface functionalized with biotin for active tumor targeting. Dual agent nanoparticles encapsulating the combination of paclitaxel and P-gp targeted siRNA showed significantly higher cytotoxicity in vitro than nanoparticles loaded with paclitaxel alone. Enhanced therapeutic efficacy of dual agent nanoparticles could be correlated with effective silencing of the MDR1 gene that encodes for P-gp and with increased accumulation of paclitaxel in drug-resistant tumor cells. In vivo studies in a mouse model of drug-resistant tumor demonstrated significantly greater inhibition of tumor growth following treatment with biotin-functionalized nanoparticles encapsulating both paclitaxel and P-gp targeted siRNA at a paclitaxel dose that was ineffective in the absence of gene silencing. These results suggest that that the combination of P-gp gene silencing and cytotoxic drug delivery using targeted nanoparticles can overcome tumor drug resistance.
A series
of organometallic ruthenium(II) complexes containing iminophosphorane
ligands have been synthesized and characterized. Cationic compounds
with chloride as counterion are soluble in water (70–100 mg/mL).
Most compounds (especially highly water-soluble 2) are
more cytotoxic to a number of human cancer cell lines than cisplatin.
Initial mechanistic studies indicate that the cell death type for
these compounds is mainly through canonical or caspase-dependent apoptosis,
nondependent on p53, and that the compounds do not interact with DNA
or inhibit protease cathepsin B. In vivo experiments of 2 on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an
impressive tumor reduction (shrinkage) of 56% after 28 days of treatment
(14 doses of 5 mg/kg every other day) with low systemic toxicity.
Pharmacokinetic studies showed a quick absorption of 2 in plasma with preferential accumulation in the breast tumor tissues
when compared to kidney and liver, which may explain its high efficacy
in vivo.
Heterometallic compounds as anticancer agents demonstrating in vivo potential for the first time. Titanocene–gold derivatives: promising candidates for renal cancer.
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