Qbd based and Box-Behnken design assisted Oral delivery of stable lactone (active) form of Topotecan as PLGA nanoformulation: Cytotoxicity, pharmacokinetic, in vitro, and ex vivo gut permeation studies

Abstract

Topotecan being highly water-soluble drug with a property of getting converted from biologically active lactone form to biologically inactive carboxylate form, thus making it a candidate with very less bioavailability; so, our approach was to develop a stable Topotecan lactone (active) form nanoparticles (TNPs). TNPs were developed and optimized successfully with size of 130.0 ± 3.9 nm, 0.102 ± 0.009 PDI and zeta potential of −18.0 ± 2.1 mV. The percent entrapment efficiency of active lactone form of Topotecan (TOP) in optimized formulation of TNPs was 65.72 ± 1.9%, that was enhanced by approximately 15% from 65.72 ± 1.9% to 73.27 ± 2.1% by using Zn2+ ions as a complexing agent between PLGA polymer and Topotecan drug. Lyophilized TNPs under DSC study showed the entrapment of TOP in amorphous or solution form, which was further confirmed by XRD studies. In vitro release study depicts that the drug TOP in TNPs showed initial burst release followed by sustained release for up to 72 h in PBS (pH 7.4). Ex-vivo gut permeation study revealed that TNPs enhanced the permeation of TOP through the gut. Further, in vivo pharmacokinetic data showed that the oral bioavailability of TOP was increased by four folds from TNPs. TNPs in comparison to TOP drug also showed a significant reduction in IC50 in cell line studies on MCF-7/Adr resistant cells.