Enhancing biopharmaceutical performance of an anticancer drug by long chain PUFA based self-nanoemulsifying lipidic nanomicellar systems

Abstract

The aim of this study was to develop polyunsaturated fatty acid (PUFA) long chain glyceride (LCG) enriched self-nanoemulsifying lipidic nanomicelles systems (SNELS) for augmenting lymphatic uptake and enhancing oral bioavailability of docetaxel and compare its biopharmaceutical performance with a medium-chain fatty acid glyceride (MCG) SNELS. Equilibrium solubility and pseudo ternary phase studies facilitated the selection of suitable LCG and MCG. The critical material attributes (CMAs) and critical process parameters (CPPs) were earmarked using Placket-Burman Design (PBD) and Fractional Factorial Design (FFD) for LCG- and MCG-SNELS respectively, and nano micelles were subsequently optimized using I- and D-optimal designs. Desirability function unearthed the optimized SNELS with T <5min, D <100nm, Rel >85% and Perm >75%. The SNELS demonstrated efficient biocompatibility and energy dependent cellular uptake, reduced P-gp efflux and increased permeability using bi-directional Caco-2 model. Optimal PUFA enriched LCG-SNELS exhibited distinctly superior permeability and absorption parameters during ex vivo permeation, in situ single pass intestinal perfusion, lymphatic uptake and in vivo pharmacokinetic studies over MCG-SNELS.

<p>Pharmacokinetic studies of nanoparticles as a delivery system for conventional drugs and herb-derived compounds for cancer therapy: a systematic review</p>

“…Data are presented as mean values for nanoformulation vs free drugDrug-loadedNanoparticleAnimals used (n)/cell lineRoute, doseAnalytical techniquePharmacokinetic parameters (mean)OutcomesReferenceDaunorubicinCS–PLGA and PLGAWister rats (n=6)MCF-7 cell lineOral, 10 mg/kg bwUHPLC-MS/MSAUC 0–48 : 15,729, 8674.65 vs 1393 ng.hr/mL; C max : 591, 318.55 vs 44.65 ng/mL: T max : 4.00, 4.00 vs 2.00 hrs; t 1⁄2 : 152.7, 119.39 vs 54.55 hrs.Improved pharmacokinetics with CS-PLGA loaded drug than PLGA loaded drug with increased AUC (11.29-fold), C max (1.86-fold), T max (2-fold), and prolonged t 1/2 (2.8-fold).Potential to avoid first pass metabolism with CYP450 and P-gp mediated efflux.22LecithmerWistar rats (n=6) K562and Hop62celllinesIV, 4 mg/kg bwHPLCAUC: 31.2 vs 39.7 ng hr/mL; t 1⁄2 : 1.96 vs 1.63 hrs; Vd: 81.68 vs 57.46 L; CL: 28.87 vs 23.24 L/hrsThe only significantly improved pharmacokinetic was V d (1.42-fold) with the rapid uptake of the reticuloendothelial system. Slightly Prolonged t 1/2 (1.2-fold) decreased AUC (1.3-fold); Increased CL (1.24-fold)23DocetaxelPHBVCharles Foster Rats (n=6).MCF-7 cell lineIV, 25 mg/kg bwHPLCAUC 0-t : 914.9 vs 565 μg/mL*hr; C max : 15.53 vs 41.06 μg/mL; T max : 72 vs 6 hrs; t 1 ⁄2: 41.8 vs 5.09 hrs; CL: 0.019 vs 0.044 L/hr; V ss : 2.49 vs 0.171 L/hrsImproved pharmacokinetics: Increased AUC (1.6-fold); prolonged t 1/2 (8.2-fold); increased V d (2.3-fold); decreased CL (2.3-fold)3LCG-SNELS vs MCG-SNELSRats (n=3)Caco-2 cell lineOral, 20 mg/kg bwUPLCAUC: 9197.7, 7425.8 vs 847.2 ng·hr/mL; C max : 1597.2, 612.5 vs 346.9 ng/mL; T max : 1.42, 2.74 vs 3.27 hrsImproved pharmacokinetics: Increased AUC and C max of LCG-SNELS loaded drug compared with MCH-SNELS loaded drug and free drug;LCG-SNELS: a preferred drug carrier than MCG-SNELS for better drug delivery to tumor cells.11PS-PDLLAMale Sprague–Dawley (SD) rats (n=3).PC-3 cell lineIV, 1 mg/kg bw(LC-MS/MS)AUC: 23.56 vs 10.18 μg·min/mL; t 1⁄2 : 134.7 vs 57.8 mins; CL: 42.60 vs 99.03 mL/min/kg; V ss : 3260.9 vs 864.3 mL/kgImproved ...…”

“…The anticancer activity of taxanes involves disruption of the mitotic spindle by binding to microtubules and thereby inhibiting the depolymerization of the microtubules, leading to mitotic arrest at the G2/M phase of the cell cycle 1–4,6,7. PTX and DTX display anticancer activity and have been used in the treatment of various cancers especially breast,2–4,6–11 ovarian,1–4,6–8,11 lung,1–4,6,7,9,11 head and neck,1,2,6,11 colon,1,4 bladder,1,2 prostate,2,7,11 and gastric2,3 cancers, esophageal, endometrium carcinoma,2 hepatocarcinoma,12 acute leukemia,1 and Kaposi’s sarcoma 4. The clinical application of currently available taxanes meets some challenges including poor water solubility, high protein binding, first-pass metabolism, high affinity to P-glycoprotein (P-gp), and some serious side effects.…”

“…One of the strategies proposed to address the problem of toxicity and poor pharmacokinetic properties with these drugs is the use of a novel drug delivery system such as nanoparticles. A wide range of biocompatible, biodegradable, and nontoxic polymeric nanoparticles were employed to improve the pharmacokinetic profiles of DTX and PTX to increase the plasma drug concentrations and solubility, and intracellular accumulation to tumors cells via enhanced permeability and retention (EPR) effect 1–4,6–9,11,12…”

“…Lipid-based nanocarriers such as self-nano emulsifying lipidic nanomicellar systems (SNELS) were also used to deliver DTX. Both long-chain and medium-chain glycerides were applied to enhance oral drug bioavailability 11. The nanocarriers of long-chain glycerides enriched with SNELS delivering DTX were shown to markedly increase the AUC and C max of DTX compared with the medium-chain glyceride SNELS.…”

Improving the biopharmaceutical attributes of mangiferin using vitamin E-TPGS co-loaded self-assembled phosholipidic nano-mixed micellar systems

“…On similar heels, MCF-7 and MDA-MB-231 cells (2.5 × 10 5 ) were incubated with DiOC 2 alone, DiOC 2 with SPNMS, and DiOC 2 with vinblastine at 37 °C, along with DiOC 2 at 4 °C. The fluorescence intensity was measured in a TECAN fluorescence microplate reader at an excitation wavelength of 485 nm and an emission wavelength of 530 nm [ 50 ].…”