Inhibition of MDR1 gene expression and enhancing cellular uptake for effective colon cancer treatment using dual-surface-functionalized nanoparticles

Abstract

Nanomedicine options for colon cancer therapy have been limited by the lack of suitable carriers capable of delivering sufficient drug into tumors to cause lethal toxicity. To circumvent this limitation, we fabricated a camptothecin (CPT)-loaded poly(lactic-co-glycolic acid) nanoparticle (NP) with dual-surface functionalization—Pluronic F127 and chitosan—for inhibiting multi-drug resistant gene 1 (MDR1) expression and enhancing tumor uptake. The resultant spherical NPs-P/C had a desirable particle size (~268 nm), slightly positive zeta-potential, and the ability to efficiently down-regulate the expression of MDR1. In vitro cytotoxicity tests revealed that the 24 and 48 h IC50 values of NPs-P/C1 were 2.03 and 0.67 µM, respectively, which were much lower than those for free CPT and other NPs. Interestingly, NPs-P/C1 showed the highest cellular uptake efficiency (approximately 85.5%) among the different drug formulations. Most importantly, treatment of colon tumor-bearing mice with various drug formulations confirmed that the introduction of Pluronic F127 and chitosan to the NP surface significantly enhanced the therapeutic efficacy of CPT, induced tumor cell apoptosis, and reduced systemic toxicity. Collectively, these findings suggest that our one-step–fabricated, dual-surface–functionalized NPs may hold promise as a readily scalable and effective drug carrier with clinical potential in colon cancer therapy.

Combination Therapy for Ulcerative Colitis: Orally Targeted Nanoparticles Prevent Mucosal Damage and Relieve Inflammation

“…As shown in representative TEM images, CS-siCD98/CUR-NPs (Figure 1a) and HA-siCD8/CUR-NPs (Figure 1b) were spherical in shape and had mean diameters of approximately 128.2 and 199.7 nm, respectively. The modest discrepancies in the diameters measured by TEM and DLS were ascribed to differences in the surface states of the NPs under the different test conditions, as also described in our previous studies 44. The NPs are in a fully hydrated (swollen) state when examined by DLS, whereas they have to be completely dehydrated for TEM characterization.…”

Polymeric nanoparticles for colon cancer therapy: overview and perspectives

“…The results indicated that this NP was able to significantly improve the therapeutic efficacy of CPT as well as induce tumor cell apoptosis, hence reducing systemic toxicity. 70 Another study revealed that PLGA-based polymeric oil-core nanocapsules (NCs) for curcumin loading in colon cancer therapy achieved a high drug loading efficiency and markedly smaller tumor volumes. 71 Moreover, a biodegradable MPEG-PLA micelle was employed to deliver curcumin by Xiang Gao and coworkers.…”

A Hyaluronidase-Responsive Nanoparticle-Based Drug Delivery System for Targeting Colon Cancer Cells

“…Efficient cellular uptake is a major requirement for the therapeutic efficacy of nanoparticles (3). To test the targeting specificity of MSN-HA, we evaluated the cellular uptake of MSN-HA/rhodamine B by Colon-26 cells and HT-29 cells.…”

“…These efforts have shown great promise for improving cancer treatment. The reported DDS have involved polymeric nanoparticles (3), liposomes (4), dendrimers (5), inorganic nanoparticles (6), and protein nanoparticles (7). Some of these delivery vehicles take advantage of the enhanced permeability and retention (EPR) effect, through which drugs passively accumulate in tumors due to the leakiness of the vasculature surrounding the mass (8).…”