Lipid-functionalized Dextran Nanosystems to Overcome Multidrug Resistance in Cancer: A Pilot Study

Abstract

Background The toxicity of anticancer agents and the difficulty in delivering drugs selectively to tumor cells pose a challenge in overcoming multidrug resistance (MDR). Recently, nanotechnology has emerged as a powerful tool in addressing some of the barriers to drug delivery, including MDR in cancer, by utilizing alternate routes of cellular entry and targeted delivery of drugs and genes. However, it is unclear whether doxorubicin (Dox) can be delivered by nanotechnologic approaches. Questions/Purposes We asked whether (1) Dox-loaded lipidfunctionalized dextran-based biocompatible nanoparticles (Dox/NP) can reverse MDR, (2) Dox/NP has more potent cytotoxic effect on MDR tumors than poly(ethylene glycol)-modified liposomal Dox (PLD), and (3) multidrug resistance protein 1 (MDR1) small interfering RNA loaded in these nanoparticles (siMDR1/NP) can modulate MDR. Methods To create stable Dox/NP and siMDR1/NP, we used two different lipid-modified dextran derivatives. The effect of Dox or Dox/NP was tested on drug-sensitive osteosarcoma (KHOS) and ovarian cancer (SKOV-3) cell cultures in triplicate and their respective MDR counterparts KHOS R2 and SKOV-3 TR in triplicate. We determined the effects on drug retention, transfection efficacy of siMDR1/ NP, and P-glycoprotein expression and the antiproliferative effect between Dox/NP and PLD in MDR tumor cells. Results Fluorescence microscopy revealed efficient uptake of the Dox/NP and fluorescently tagged siMDR1/ NP. Dox/NP showed five-to 10-fold higher antiproliferative activity at the 50% inhibitory concentration than free Dox in tumor cells. Dox/NP showed twofold higher activity than PLD in MDR tumor cells. siMDR1/NP (100 nM) suppressed P-glycoprotein expression in KHOS R2 . Conclusions Dextran-lipid nanoparticles are a promising platform for delivering Dox and siRNAs. Clinical Relevance Biocompatible dextran-based nanoparticles that are directly translatable to clinical medicine

Polymeric nanoparticle-based delivery of microRNA-199a-3p inhibits proliferation and growth of osteosarcoma cells

“…Our group and others have previously shown that dextran-based nanoparticles are able to efficiently deliver both the chemotherapy drug doxorubicin as well as siRNA to osteosarcoma cells with no apparent toxicity. [31][32][33]37 We also previously found that dextran-based nanoparticles can efficiently transport siRNA into tumor cells. 32,33 More recently, cationized dextran nanoparticles encapsulated with C-X-C chemokine receptor type 4 (CXCR4) siRNA have been shown to significantly downregulate CXCR4 expression in colorectal cancer, both in vitro and in vivo.…”

“…32,33 Briefly, a stock solution of 5 mg/mL (~2.5 mM) dextran thiol, 5 mg/mL (~2.5 mM) dextran hexylamine, 5 mg/mL (125 µM) PEG-thiol, and 2 µM miR solution was prepared. For obtaining a 100 nM miR concentration, a 120 µL stock solution of miR was mixed with 40 µL of dextran-thiol stock solution using a vortex shaker.…”

“…31 In different cancer model systems, dextran-based nanoparticles have been able to transport drugs and multidrug resistance (MDR1) siRNA efficiently into tumor cells to overcome drug resistance. 32,33 We hypothesize that dextranbased nanoparticles could also be an ideal carrier for the delivery of therapeutic miRs into cancer cells. In the study reported here, we employed miR-199a-3p and let-7a as candidate miRs to determine the efficiency of miR delivery in osteosarcoma cells using a dextran-based self-assembling nanoparticle platform.…”

Translational Nano-Medicines: Targeted Therapeutic Delivery for Cancer and Inflammatory Diseases

“…ATP mediated efflux pumps is one of the most well studied mechanism of MDR and several therapeutic strategies using small molecules and biologics have been used to overcome this resistance (43,44). However drug resistance attributed to activation of antiapoptotic cellular defense is also known to lead to drug resistance.…”

“…Kobayashi et al extended the application of dextran nanoparticles for the delivery of siRNA by loading MDR1 siRNA in octylamine-modified dextran, dextran-PEG, and dextran thiol (44). The nanoparticles were in the size range of 101±3 nm with a zeta potential of −0.22 mV.…”