ABSTRACT
This study aimed at carrying out a preformulation investigation of nanocochleates (NCs) and develop andrographolide-loaded nanocochleates. Preformulation study comprised of exploring the effect of trivalent and divalent ions on transition temperature (TT) of lipid (DMPG-Na), on particle size (PS), entrapment efficacy (EE), zeta potential (ZP) of NCs, and effect of NCs on change in lipid solubility post-NC formation. Further, the andrographolide-loaded nanocochleates made with CaCl2 (ANDNCs) were characterized for ZP, PS, EE, X-ray powder diffraction (PXRD), differential scanning calorimetry (DSC), transition electron microscopy (TEM), in vitro release studies, in vitro anticancer potential on the cell line of human breast cancer (MCF-7), in vivo oral pharmacokinetic studies, and tissue distribution in female Wistar rats. Nanocochleates developed with CaCl2 had a significant reduction in PS (1.78-fold) and ZP (1.38-fold), and elevation of EE (1.17-fold) as compared to AlCl3 developed NCs. Trivalent ions demonstrated elevation of TT as compared to divalent ions. Spiral-shaped ANDNCs demonstrated ZP, PS, and EE of - 121.46 ± 15.12 mV, 360 ± 47 nm, and 68.12 ± 3.81% respectively. In vitro release study of ANDNCs showed a strong pH-dependent release profile due to hydrogen bonding between NCs and andrographolide (AND). Formulated ANDNCs demonstrated 26.99-fold decrease in IC50 value as compared to free AND. Additionally, the oral bioavailability of AND from ANDNCs improved by 1.81-fold as compared to free AND. Furthermore, ANDNCs showed minimum accumulation within the vital organs such as liver, kidney, and spleen. Briefly, the preformulation study laid a platform for better understanding the NCs and its components. Further, developed ANDNCs revealed superior physiochemical properties to be used as an alternative for a clinical setting.
Subject(s)
Antineoplastic Agents/administration & dosage , Diterpenes/administration & dosage , Nanoparticles/chemistry , Neoplasms/drug therapy , Phosphatidylglycerols/chemistry , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Biological Availability , Calorimetry, Differential Scanning , Cations , Diterpenes/pharmacokinetics , Diterpenes/therapeutic use , Doxorubicin/administration & dosage , Doxorubicin/pharmacokinetics , Doxorubicin/therapeutic use , Drug Carriers/chemistry , Female , Humans , Particle Size , Rats , Rats, Wistar , Sodium , Solubility , Tissue DistributionABSTRACT
The motive of study was to develop biotinylated chitosan (BI-CHI) decorated docetaxel (DTX) loaded nanocochleates (BI-CHI-DTX-NC) to achieve controlled drug release, improve bioavailability, targeted delivery and enhanced anticancer potency with the reduced systemic toxicity of DTX. The development involved the loading of DTX to nanocochleates (DTX-NC) through conversion of dimyristoylphosphatidylglycerol-sodium (DMPG-Na) and cholesterol bearing liposome on addition of calcium ions, followed by encapsulated DTX-NC with BI-CHI (BI-CHI-DTX- NC) and compared with DTX and DTX-NC. The release of DTX indicated strong pH dependence and implies strong hydrogen-bonding between nanocochleates and DTX. Formulated BI-CHI-DTX-NC demonstrated higher in-vitro anticancer activity in biotin over expressed human breast cancer MCF-7 cells. The targeting effect for the BI-CHI-DTX-NC was also demonstrated. The concentration of the drug needed for growth inhibition of 50% of cells in a designed time period (GI50) was 1.8 µg/ml for free DTX while it was decreased by 33.34% for the DTX-NC (1.2 µg/ml). Furthermore, the GI50 value of BI-CHI-DTX-NC was 0.2 µg/ml, i.e. an 88.89% decrease was observed as compared to DTX solution. Moreover, bioavailability of DTX from BI-CHI-DTX-NC was increased by 10-folds with longer circulation time and slower plasma elimination with low tissue distribution as compared to DTX solution. The results indicate that the BI-CHI-DTX- NC has the potential to be applied for targeting anticancer drug delivery.