Human serum albumin-based polymeric nanoparticles for ratiometric co-encapsulation and co-delivery of palbociclib and tamoxifen citrate for synergistic effect in breast cancer management.

In conventional co-delivered chemotherapeutic strategies, the disparity in physicochemical properties and non-coordinated pharmacokinetic profile is largely overlooked. To overcome these long-standing challenges, we prepared a Palbociclib (PAL) and Tamoxifen citrate (TC) co-loaded in a synergetic fashion into a Human serum albumin nanoparticle (PAL/TC-HSA-NPs). It was optimised through Box-Behnken design of experiment and had a Particle size, Polydispersity index, and zeta potential of 155.7 ± 8.12 nm, 0.15 ± 0.01, and - 19.52 ± 2.04 mV. At both pH conditions of 5.5 and 7.4, it displayed a prolonged release profile over 48 h. The molecular dynamics and simulation study confirmed an energetically stable protein-ligand interaction and well-submerged active moieties in the binding pockets of HSA. The maximal in vitro cytotoxicity caused by PAL/TC-HSA-NPs is attributed to a synergistic effect, along with active targeting achieved via the gp60 and SPARC proteins. In a flow cytometry study, PAL/TC-HSA-NPs showed maximal apoptosis and G0/G1 phase arrest in MDA-MB-231 cells. The AUC0-t for PAL and TC in PAL/TC-HSA-NPs were found to be 26.16 ± 4.2 ppm*h and 18.25 ± 2.5 ppm*h, respectively, which were 1.17-fold and 1.44-fold higher than PAL and TC in PAL-TC (1:1) solution. The final tumour weight was found to be 2.62-fold reduced in comparison to the free PAL-TC group. In in vivo bioimaging, after a 24 h study, FITC-HSA-NP showed a pronounced fluorescence signal at the tumour site that remained detectable over an extended period. Overall, PAL/TC-HSA-NPs showed excellent tumour targeting, efficacy and biosafety.