Improved pharmacological profile of the lipophilic antitumor dichloro-(N-dodecyl)-propanediamine-platinum(II) complex after incorporation into pegylated liposomes

Abstract

Liposome encapsulation of platinum (Pt) drugs has emerged as a promising strategy to overcome their toxicity and cellular Pt resistance. The aim of the present work was to examine the impact of liposome encapsulation of a novel antitumor lipophilic Pt complex, dichloro-(N-dodecyl)-propanediamine-platinum(II) complex (DDPP), on its pharmacological profile as an antitumor agent. Biological assays included acute toxicity and histopathological evaluations, pharmacokinetics, and growth inhibition of B16-F1 tumor cells in C57Bl/6 mice. Comparison was made with cisplatin and free DDPP dissolved in castor oil. DDPP encapsulated in pegylated liposomes showed reduced acute toxicity in mice following intraperitoneal administration, compared with the free complex. Free DDPP at 5 mg Pt/kg induced histopathological alterations in the liver, in contrast to liposomal DDPP and cisplatin. Interestingly, the marked loss of body weight following the treatment of mice with cisplatin was not observed after liposomal DDPP at the same Pt dose. Liposomal DDPP was found to inhibit tumor growth significantly, when administered at 5 mg Pt/kg/day for 3 days, similar to cisplatin, but in contrast to the free complex. Pharmacokinetic studies after intraperitoneal and intravenous administrations at 5 mg Pt/kg indicated greater and more prolonged Pt levels in the plasma, liver, spleen, and kidneys from liposomal DDPP, compared with free DDPP or cisplatin. The tumor concentration of Pt increased after liposomal DDPP over the 24-h period, whereas it decreased after cisplatin. In conclusion, the encapsulation of DDPP in pegylated liposomes reduced the drug toxicity and enhanced its antitumoral activity in mice, as a result of improved drug pharmacokinetics.

Noble metals in medicine: Latest advances

“…The targeting and delivery strategies are based on two types of mechanism: passive and active transport inside tumor cells. A wide range of nanocarriers (nanoparticles, nanotubes, nanomicelles, liposomes, and polymers) have been evaluated to address the first issue [10,[33][34][35][36][37] by exploiting their physicochemical properties (such as the unique shape of nanotubes, which promotes cellular uptake and allows the functionalization of bioactive molecules on their surfaces) and the biological differences between normal and neoplastic cells to increase selectivity. This approach is based on permeability and retention effects, where macromolecules exhibit increased permeability in tumor tissues so they can accumulate due to low lymphatic clearance and slow venous return [38,39].…”

Pharmacokinetics of lipid-drug conjugates loaded into liposomes

“…AUC ratios of various L-LDCs. [34 ], [39] , [10] , [25] , [40] , [32], [41] , [42] , [38] , [43] , [44], [45] , [46] , [4] , [47] , [48] , [49 ] , [50 ] , [ 51 ], [52 ] , [24 ] , [37 ] , [42 ] 3. PKs and biodistribution…”

Platinum(II) and palladium(II) aryl-thiosemicarbazone complexes: synthesis, characterization, molecular modeling, cytotoxicity, and antimicrobial activity

“…As part of our continuing investigations on metal complexes as anticancer [18,19] and antimicrobial [20,21] agents, we report herein the synthesis, characterization, and cytotoxic/ antimicrobial activity of palladium(II) and platinum(II) complexes containing thiosemicarbazone ligands. The compounds were characterized by Raman, IR, and NMR ( 1 H, 13 C, 195 Pt) spectroscopy and elemental analysis, in addition to quantum mechanical calculations.…”