Polypropyleneimine and polyamidoamine dendrimer mediated enhanced solubilization of bortezomib: Comparison and evaluation of mechanistic aspects by thermodynamics and molecular simulations

- The present study reports the application of PAMAM and PPI dendrimers in solubilizing bortezomib with possible mechanism.
- Improved solubility of bortezomib through dendrimers could significantly contribute its successful anticancer potential.
- Molecular simulation and thermodynamic studies proved the electrostatic interaction as underlying mechanism.

Bortezomib (BTZ) is the first proteasome inhibitor approved by the US-FDA is majorly used for the treatment of newly diagnosed and relapsed multiple myeloma including mantle cell lymphoma. BTZ is hydrophobic in nature and is a major cause for its minimal presence as marketed formulations. The present study reports the design, development and characterization of dendrimer based formulation for the improved solubility and effectivity of bortezomib. The study also equally focuses on the mechanistic elucidation of solubilization by two types of dendrimers i.e. fourth generation of poly (amidoamine) dendrimers (G4-PAMAM-NH2) and fifth generation of poly (propylene) imine dendrimers (G5-PPI-NH2). It was observed that aqueous solubility of BTZ was concentration and pH dependent. At 2 mM G5-PPI-NH2 concentration, the fold increase in bortezomib solubility was 1152.63 times in water, while approximately 3426.69 folds increase in solubility was observed at pH 10.0, respectively (p < 0.05). The solubility of the drug was increased to a greater extent with G5-PPI-NH2 dendrimers because it has more hydrophobic interior than G4-PAMAM-NH2 dendrimers. The release of BTZ from G5-PPI-NH2 complex was comparatively slower than G4-PAMAM-NH2. The thermodynamic treatment of data proved that dendrimer drug complexes were stable at all pH with values of ΔG always negative. The experimental findings were also proven by molecular simulation studies and by calculating RMSD and intermolecular hydrogen bonding through Schrodinger software. It was concluded that PPI dendrimers were able to solubilize the drug more effectively than PAMAM dendrimers through electrostatic interactions.

172