Co-encapsulation of Tamoxifen and Quercetin in Polymeric Nanoparticles: Implications on Oral Bioavailability, Antitumor Efficacy, and Drug-Induced Toxicity

The present investigation reports the preparation, optimization, and characterization of orally administrable PLGA-NPs co-encapsulated with tamoxifen (Tmx) and quercetin (QT). The developed formulation was found to have particle size 185.3 +/- 1.20 nm, PDI 0.184 +/- 0.004, entrapment efficiency 67.16 +/- 1.24% Tmx, 68.60 +/- 1.58% QT at a Tmx/QT ratio of 1:2 w/w. The stability of the freeze-dried formulation was established in simulated gastrointestinal fluids for 8 h and at, accelerated stability condition for 3 months. DPPH free radical scavenging assay;confirmed, that the functional architecture of QT was retained in freeze-dried NPs. Higher cellular Uptake, cytotoxicity; and nuclear co-localization of Tmx-QT-NPs. in MCF-7 cells revealed higher efficiency of the formulation. At the same time, higher. Caco-2 cell uptake revealed its potential for oral delivery, which was well corroborated, with in vivo pharmacokinetics, which suggested similar to 5-fold and similar to 3-fold increase in oral bloavailability as compared to. the free Tmx citrate and free QT, respectively.. Concomitantly, significantly higher tumor suppression was observed in the case of the developed formulation in contrast to respective free drug(s) and their combination when tested against a DMBA-induced breast cancer model in female SD rats. Multiple oral administrations of Tmx-QT-NPs efficiently controlled the tumor angiogenesis as revealed by normalized levels of respective markers (MMP-2 and MMP-9). The safety profile of Tmx-QT-NPs was also established, and no measurable hepatotoxicity or oxidative stress was observed when measured as a function of respective biochemical markers in contrast to free drug(s) and their combinations. In a nutshell, the co-encapsulation strategy with PLGA-NPs could be a promising approach in improving oral delivery of Tmx and QT for cancer therapy.