Journal
DRUG DELIVERY AND TRANSLATIONAL RESEARCH
Volume 12, Issue 5, Pages 1136-1160Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s13346-021-00990-x
Keywords
Breast cancer; Design of experiments (DoE); Cell culture studies; Optimization; Bioavailability; Solid lipid nanoparticles (SLNs); Raloxifene
Funding
- National UGC Centre of Excellence in NanoBioMedical Applications, Panjab University, liberal grants
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The research focused on the development and evaluation of solid lipid nanoparticles (SLNs) of Raloxifene for enhanced biopharmaceutical performance against breast cancer, showing promising anticancer potential of the developed SLNs.
Raloxifene hydrochloride, a second-generation selective estrogen receptor modulator, has been approved for the management of breast cancer. However, it is known to exhibit poor (similar to 2%) and inconsistent oral bioavailability in humans, primarily ascribable to its low aqueous solubility, extensive first-pass metabolism, P-gp efflux, and presystemic glucuronide conjugation. The present research work entails the systematic development and evaluation of SLNs of RLX for its enhanced biopharmaceutical performance against breast cancer. Factor screening studies were conducted using Taguchi design, followed by optimization studies employing Box-Behnken design. Preparation of SLNs was carried out using glyceryl monostearate and Compritol (R) 888 ATO (i.e., lipid), Phospholipid S-100 (i.e., co-surfactant), and TPGS-1000 (i.e., surfactant) employing solvent diffusion method. The optimized formulation was evaluated for zeta potential, average particle size, field emission scanning electron microscope, transmission electron microscopy, and in vitro release study. Further, MCF-7 cells (cell cytotoxicity assay, apoptosis assay, and reactive oxygen species assay) and Caco-2 cells (cell uptake studies and P-gp efflux assay) were employed to evaluate the in vitro anticancer potential of the developed optimized formulation. In vivo pharmacokinetic studies were conducted in Sprague-Dawley rats to evaluate the therapeutic profile of the developed formulation. The optimized SLN formulations exhibited a mean particle size of 109.7 nm, PDI 0.289 with a zeta potential of - 13.7 mV. In vitro drug dissolution studies showed Fickian release, with release exponent of 0.137. Cell cytotoxicity assay, apoptosis assay, and cellular uptake indicated 6.40-, 5.40-, and 3.18-fold improvement in the efficacy of RLX-SLNs vis-a-vis pure RLX. Besides, the pharmacokinetic studies indicated quite significantly improved biopharmaceutical performance of RLX-SLNs vis-a-vis pure drug, with 4.06-fold improvement in C-max, 4.40-fold in AUC((0-72 h)), 4.56-fold in AUC((0-infinity)), 1.53-fold in K-a,K- 2.12-fold in t(1/2), and 1.22-fold in T-max. Further, for RLX-SLNs and pure drug, high degree of level A linear correlation was established between fractions of drug dissolved (in vitro) and of drug absorbed (in vivo) at the corresponding time-points. Stability studies indicated the robustness of RLX-SLNs when stored at for 3 months. Results obtained from the different studies construe promising the anticancer potential of the developed RLX-SLNs, thereby ratifying the lipidic nanocarriers as an efficient drug delivery strategy for improving the biopharmaceutical attributes of RLX.
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