Picoplatin

The structures of the anticancer drug compounds satraplatin and picoplatin are optimized, and theoretical studies done by Density Functional Theory (DFT) to investigate the optical properties, global chemical descriptors, and band gap were calculated using the obtained Frontier molecular orbital values. The theoretically obtained data of the platinum drugs found to possess low energy gap values and low chemical hardness with high chemical softness describe that the compounds are chemically stable and most reactive. Using the molecular docking process, the binding mechanisms of the satraplatin and picoplatin drugs with cancer DNA structures were studied, and the results were analyzed. For the two drug compounds examined, satraplatin has shown the least binding energies at -5.06kcal/mol compared to picoplatin at -2.69 kcal/mol, and conformations with root mean square deviation (RMSD) values by DNA structures are less than or equal to 2.00 Å in targeting the specific DNA target residues of the reference bound ligand. The grid box was generated using the selective grid parameters using the Autodock 4.2 program. The drug molecules found to have the least binding energy value with the lowest inhibition constant implicate the good docking score towards the DNA structure by the docking studies. DFT studies also show good structural properties and chemical reactivity. From the obtained results, satraplatin and picoplatin were found to have good chemical descriptors and good binding affinity and are best suited for biological molecular targets.

The goal of the current study is to improve the characteristics and bioavailability of the drug picoplatin (PPt) by encapsulating it in chitosan nanoparticles (CS NPs) which allows for the targeted delivery of cytotoxic cargo to cancerous tissue, reducing toxic side effects and raising the therapeutic index. When picoplatin was delivered into the CS, it was able to produce a complex with CS (PPt@CS NPs) that had an appropriate particle size of 275 ± 10 nm, a reasonably low PDI of 0.15 ± 0.05, and high stability (ζ = -22.1 ± 0.3 mV). Since almost all pharmaceuticals work by binding to specific proteins or DNA, the in vitro binding mechanism and affinity of bovine serum albumin (BSA), low molecular building units of nucleic acids (5-GMP), and Glutathione (GSH) (considering that cisplatin resistance could be due to a reaction between cisplatin and GSH) to PPt and PPt@CS NPs were examined using stopped-flow and other spectroscopic approaches. Through two reversible processes, a rapid second-order binding followed by a slower first-order isomerization reaction, and a static quenching mechanism, PPt and PPt@CS NPs bind to BSA with relative reactivity of around (PPt)/(PPt@CS NPs) = 1/2.5. The 5-GMP interaction studies demonstrated that, in addition to changing the binding mechanism, PPt's encapsulation in CS increases its rate of reaction through coordination affinity. PPt interacted with 5-GMP via two reversible processes, a rapid second-order binding to phosphate followed by a slower first-order migration to the N7 of pyrimidine moiety. PPt@CS NPs showed weaker binding to GSH compared to PPt and hence PPt@CS NPs exhibits a lower resistance factor. It was also found that the in vitro drug release of PPt@CS NPs in PBS at pH 7.4 was steady, releasing 30 % of the PPt in just 5 h. Nonetheless, 75 % of the release in a pH 5.4 solution containing 10 mM GSH-a solution that mimics the tumor microenvironment-shows that the PPt@CS NPs system is sensitive to GSH and specifically targets malignant tissue. The encapsulation of PPt in CS complex maintained its anticancer activity, as shown by an in vitro cell-survival assay on HepG2 cancer cell lines and also cleavage efficiency toward the minor groove of pBR322 DNA via the hydrolytic way. These findings collectively suggested that inclusion PPt in CS would be an effective strategy to formulate a novel picoplatin formulation intended for use as targeted anticancer treatment.