Overcoming Drug Resistance in Colon Cancer by Aptamer-Mediated Targeted Co-Delivery of Drug and siRNA Using Grapefruit-Derived Nanovectors

Abstract

Background/Aims: Multidrug resistance (MDR) is the most common cause of chemotherapy failure. Upregulation of P-glycoprotein (P-gp) is one of the main mechanisms underlying MDR. Methods: In this study, we developed a targeted drug and small interfering (si)RNA co-delivery system based on specific aptamer-conjugated grapefruit-derived nanovectors (GNVs) that we tested in MDR LoVo colon cancer cells. The internalization of nanovectors in cancer cells was tested by fluorescence microscopy and flow cytometry. The anti-cancer activity in vitro was determined by colony formation and cell apoptosis assays. The biodistribution of nanovectors was analyzed by live imaging and the anti-cancer activity in vivo was observed. Results: GNVs loaded with aptamer increased doxorubicin (Dox) accumulation in MDR LoVo cells, an effect that was abolished by pretreatment with DNase. The LA1 aptamer effectively promoted nanovector internalization into cells at 4°C and increased the targeted delivery of Dox to tumors. Constructs harboring Dox, LA1, and P-gp siRNA more effectively inhibited proliferation and enhanced apoptosis in cultured MDR LoVo cells while exhibiting more potent anti-tumor activity in vivo than free Dox or GNVs loaded with Dox alone or in conjunction with LA1, an effect that was associated with downregulation of P-gp expression. Conclusion: This GNV-based system may be an effective strategy for overcoming MDR in clinical settings.

Aptamers, the Nucleic Acid Antibodies, in Cancer Therapy

“…Other nanoparticle-aptamer conjugates that have been reported thus far include: conjugating the anti-CD44 aptamer to liposomes loaded with siRNA for gene silencing in CD44-expressing tumor cells in vivo [142], mucin1 aptamer-conjugated chitosan nanoparticles loaded with docetaxel and cMET siRNA that was delivered into mucin1 positive SKBR3 breast cancer cells [143], LA1 aptamer-conjugated grapefruit-derived nanovectors harboring Dox and P-glycoprotein siRNA that could be internalized into multidrug resistance LoVo colon cancer cells [144], self-assembled DNA nanostructures (DNA nanoprisms) decorated with therapeutic siRNAs targeting the GTPase Rab26 and MUC-1 aptamers that target non-small cell lung cancer [145], and paclitaxel-encapsulated PEGylated PLGA nanoparticles that were surface-functionalized with the heparanase aptamers targeting triple-negative breast cancers [146].…”

Dendrimer nanoparticles for colorectal cancer applications

“…The chemotherapeutic approach alone has not been found to be very efficient in CRC as the drug molecules may not reach the target site with an effective concentration and suffer a non-specific distribution, with only a small fraction of the drug reaching the tumor [91,92].…”

Aptamers as Delivery Agents of siRNA and Chimeric Formulations for the Treatment of Cancer

“…The knockdown of P-gp was increased significantly, decreasing a resistance to chemotherapeutics in the cells [18]. To overcome multi-drug resistance (MDR), an MD-specific aptamer-conjugated grapefruit-derived nanovectors (GNVs) was used for co-delivery of siRNA and doxorubicin (DOX), resulting in a potent anti-tumor activity [19].…”