Abstract
Multidrug resistance is a major therapeutic challenge faced in the conventional chemotherapy. Nanocarriers are beneficial in the transport of chemotherapeutics by their ability to bypass the P-gp efflux in cancers. Most of the P-gp inhibitors under phase II clinical trial are facing failures and hence there is a need to develop a suitable carrier to address P-gp efflux in cancer therapy. Herein, we prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin against highly drug resistant HeLa cells. The experimental results revealed that improved cellular uptake, enhanced drug intensity profile with greater percentage of apoptotic cells was attained when doxorubicin loaded magnetic nanocapsules were used in the presence of external magnetic field. Hence, we conclude that this magnetic field assisted nanocapsule system can be used for delivery of chemotherapeutics for potential therapeutic efficacy at minimal dose in multidrug resistant cancers.
Many cancer drugs fail when cancer cells become drug resistant. Indeed, multidrug resistance (MDR) is a major therapeutic challenge. One way that tumor cells attain MDR is by over expression of molecular pumps comprising of P-glycoprotein (P-gp) and multidrug resistant proteins (MRP), which can expel chemotherapeutic drugs out of the cells. In this study, the authors prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin. The results show that there was better drug delivery and efficacy even against MDR tumor cells.
Schematic diagram SD1. Layer-by-layer deposition of alternatively charged polyelectrolytes protamine (PRO) and carboxymethyl cellulose (CMC) on silica nanoparticles. The template was leached to produce hollow nanocapsules (NCp) and utilized for drug loading (Dox-NCp). Ferrite nanoparticles (Fe3O4) were attached on the NCp surface (Dox-MNC) and used for magnetic field (MF) assisted cellular uptake in drug resistant (DR) cancer cells. DR cells treated with free Dox remained intact while those treated with Dox-NCp underwent apoptosis. [Display omitted]
Schematic diagram SD2. Cellular uptake of Dox-MNC in drug resistant cells. (1) Transferrin protein (Tfp) attaches with Fe3O4 particles (Tf-Fe) on the MNC surface and binds with transferrin receptor protein (TfRe) in the cell membrane. (2) Tf-Fe-TfRe complex getting internalized by clathrin mediated endocytosis (CME). (3) Tf-Fe-TfRe getting dissociated in late endosome. (4) Dox releasing from NCp at cytoplasm and (5) Dox entering into nucleus. In the right side of the figure, cells treated with free Dox efflux out the drug by MDR efflux pumps.