Novel hydrophilic drug polymer nano-conjugates of Cisplatin showing long blood retention profile: its release kinetics, cellular uptake and bio-distribution.

ABSTRACT

The present study evaluates the efficacy of drug polymer self folding nano-conjugates of pectin-cisplatin to enhance blood circulating levels of cisplatin. The binding of nano-conjugate was confirmed by a peak-shift in UV-spectra. Physical characterization was done by DLS and TEM. Pharmacokinetics and bio-distribution of the nano-conjugates were performed at various time points in normal, Balb-c mice. Zeta Potential showed the shielding effect on the negative potential of pectin that was approximately 7 times more than the pectin chains when conjugated with cisplatin. TEM confirmed the formation of a hydrophilic, easily re-dispersible nano-conjugate in the size range of 100 nm. Release kinetics in plasma showed that the pectin-cisplatin conjugate is a stable, slow and sustained system with no burst effect. Immuno-fluorescence analysis of J-774, a mouse macrophage cell line, was assessed after incubating the cells with pectin chains tagged with FITC as well as Pectin-Cisplatin-FITC conjugates. With the cellular uptake of these particles in J-774, 40% of the cells showed an uptake post 30 min of incubation. However, Pectin chains were clearly eliminated. The plasma proteins facilitate the release of cisplatin with 85-89% of the drug being released in 17 days, and only 57% of drug was released in approximately 30 days without plasma. The reduced negative charge on the conjugate helps in adhesion to the cell surface and subsequent uptake by cells as evidenced by cell uptake studies on J-774 cell line. Nano-conjugates showed long blood retention profile in mice and the cisplatin was found in circulation even after 24 hrs. Pharmacokinetic study clearly indicates that it can form a novel anticancer drug that possesses good efficacy and has a safer profile than cisplatin.