IN VITRO ANTICANCER ACTIVITY OF 6–THIOGUANINE AND 6-THIOGUANINE LOADED CHITOSAN NANOPARTICLES WITH OR WITHOUT CURCUMIN AND PHARMACOKINETIC STUDIES IN RATS
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Date
2019-08
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SRI VENKATESWARA VETERINARY UNIVERSITY TIRUPATI - 517502. (A.P.) INDIA
Abstract
Cancer is the second leading cause of mortality in the world. Cancer
nanotherapeutics are rapidly progressing and being implemented to overcome several
limitations of conventional drug delivery systems. 6 thioguanine encapsulated chitosan
nanoparticles ( 6 – TG – CNPs ) were formulated by ionic - gelation method. Morphologically ,
the 6 – TG - CNPs were spherical in shape and showed mean size, PDI, z eta potential and
e ntrapment eff iciency of 261.63±6.01nm, 0.3 4 ±0.10, + 15.97±0.46mV and 44.27 per cent , respectively. IR spectra confirmed 6 - TG complex with chitosan. In vitro drug release profile of
6 - TG - CNPs revealed slow but increased ( 91.40 ± 1.08 per cent at 48h) release at pH 4.8
compared to less and sustained ( 73.96 ± 1.12 per cent at 48h) release at pH 7.4. MTT assay was conducted on MCF - 7 and PA - 1 cell lines at 48h incubation to determine per cent cell viability
. IC 50 values of 6- TG, 6 - TG - CNPs and curcumin for MCF - 7 were 23.09, 17.82 and 15.73μM
, respectively. Likewise, IC 50 values of 6 - TG, 6 - TG - CNPs and c urcumin for PA - 1 were 5.81, 3.92
and 12.89μM , respectively. Combination of 6-TG-CNPs (IC25) with curcumin (IC25) on PA-1 and MCF-7 showed percent cell viability of 43.67±0.02 and 49.77±0.05, respectively. The in vitro cytotoxicity potential in terms of per cent cell viability, early apoptosis, G2/M phase arrest and global DNA demethylating activity of 6-TG-CNPs alone and in combination with curcumin proved to be more effective than that of 6-TG on PA-1 cells. The Cmax of 6-TG in 6-TG-CNPs alone and 6-TG-CNPs in curcumin pre-treated groups was found to increased by 1.6-fold and 2-fold, respectively when compared to those observed with 6-TG treated group. The rate and extent of 6-TG absorption was increased by 2.5-fold following 6-TG-CNPs alone and 3.2-fold in curcumin followed by 6-TG-CNPs treated group compared to those observed with 6-TG treated group. The enhanced Cmax and AUC for 6-TG were in the order of curcumin pre-treatment + 6-TG-CNPs>6-TG-CNPs>6-TG groups. The apparent volume of distribution was substantially lower for 6-TG in 6-TG-CNPs alone and 6-TG-CNPs in curcumin pre-treated groups when compared to those observed with 6-TG treated group. Apart from this, volume of distribution at steady-state was also found lower for 6-TG in both the 6-TG-CNPs treated groups. These PK parameters suggests the better tumour targeting efficiency of 6-TG nanoformulations with less toxicity in off-target tissues. Thus, the 6-TG encapsulated chitosan nanoparticles prepared in the present study used either alone or in combination with curcumin present a wide scope for efficient delivery of 6-TG at the target sites.
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