Abstract
To overcome the toxicity, pharmacokinetics and drug resistance associated with doxorubicin (DOX), a strategy was developed by encapsulating DOX- loaded-PLGA-PVA- nanoparticles within chitosan-dextran sulfate nanoparticles (CS-DS) [CS-DS-coated-DOX-loaded -PLGA-PVA-NP] and study the sensitivity against DOX- resistance- breast cancer cells (MCF-7-DOX-R). These CS-DS and PLGA-PVA double coated DOX are spherical, stable, polydispersed and have zeta potential +2.89 mV. MCF-7- DOX-R cells were derived by exposing increasing doses of DOX in MCF-7 cells. These cells were resistance to 500 nM of DOX while parental cells were susceptible at 150 nM. The double coated NP caused more cytotoxicity in cancer and MCF-7-DOX-R cells without affecting the normal cells in comparison to DOX-loaded-PLGA-PVA-NP. These NP enhances the uptake of DOX in MCF-7-DOX-R cells and caused apoptosis by increasing apoptotic nuclei, Bax/Bcl-xL ratio, cleaved product PARP-1, tumor suppressor gene p21, p53, topoisomerase inhibition activity, DNA damage and decreasing the migratory potential of cells. An increased S phase arrest was noted in DOX and DOX- loaded- PLGA-PVA-NP treated cells but reduction of S phase and simultaneous increase of Sub-G1 was observed in double coated-NP. Thus, data revealed that CS-DS- DOX- loaded PLGA-PVA- NP caused DOX-resistance cell death by inducing inhibition of topoisomerase activity followed by DNA damage.
Highlights
Cancer cells exhibits resistance mechanism to chemotherapeutic drugs due to one of the following mechanism i.e. enhanced detoxification of the drugs through increased metabolism and decrease in drug uptake
chitosandextran sulfate nanoparticles (CS-DS) coated DOX loaded-PLGA-PVA-NP showed high degree of stability indicated by UV-Vis spectrophotometric analysis (Fig. 1a)
Transmission Electron Microscopy (TEM) data revealed that DOX loaded PLGA-PVA as well as CS-DS coated DOX loaded PLGAPVA-NPs are spherical and polydispersed with the size of 1 μm and 50 nm, respectively (Fig. 1b I & II)
Summary
Cancer cells exhibits resistance mechanism to chemotherapeutic drugs due to one of the following mechanism i.e. enhanced detoxification of the drugs through increased metabolism and decrease in drug uptake. Past 2–3 decades have seen rigorous research on nanomedicine for cancer treatment Nanocarriers, such as hydrogels, polymeric nanoparticles, liposomes, and self-assembling nanofibers enhances the therapeutic efficiency of anticancer drugs by facilitating local drug uptake and developing drug bioavailability due to the passive targeting ability by the enhanced permeability and retention (EPR) effect[3]. It exhibit low toxicity and enhances the penetrating potential of molecules across mucosal surfaces[5]. On these premises, our idea here was to develop an experimental strategy for encapsulation of DOX loaded PLGA-PVA nanoparticles within chitosan-dextran sulfate nanoparticles. We hypothesized to perform a dual coating on DOX with PLGA-PVA and CS-DS nanoparticles to enhance the effectiveness of DOX, to overcome DOX resistance and to reduce the toxicity associated with the same
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