Engineered PLGA Core-Lipid Shell Hybrid Nanocarriers Improve the Efficacy and Safety of Irinotecan to Combat Colon Cancer.

Poly(lactide-co-glycolide) (PLGA) is a biocompatible and biodegradable copolymer that has gained high acceptance in biomedical applications. In the present study, PLGA (Mw = 13,900) was synthesized by ring-opening polymerization in the presence of a biocompatible zinc-proline initiator through a green route. Irinotecan (Ir) loaded with efficient PLGA core-lipid shell hybrid nanocarriers (lipomers, LPs) were formulated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000] (DSPE-PEG-2000), using soya lecithin, by a nanoprecipitation method, and the fabricated LPs were designated as P-DSPE-Ir and P-DSPE-PEG-Ir, respectively. The formulated LPs were further validated for their physicochemical properties and biological potential for colon cancer application. The potential delivery of a poorly water-soluble chemotherapeutic drug (Ir) was studied for the treatment of colon cancer. LPs were successfully prepared, providing controlled size (80-120 nm) and surface charge (∼ -35 mV), and the sustained release properties and cytotoxicity against CT-26 colon cancer cells were studied. The in vivo biodistribution and tumor site retention in CT-26 xenograft tumor-bearing Balb/C mice showed promising results for tumor uptake and retention for a prolonged time period. Unlike P-DSPE-Ir, the P-DSPE-PEG-Ir LP exhibited significant tumor growth delay as compared to untreated and blank formulation-treated groups in CT-26 (subcutaneous tumor model) after 4 treatments of 10 mg irinotecan/kg dose. The biocompatibility and safety of the LPs were confirmed by an acute toxicity study of the optimized formulation. Overall, this proof-of-concept study demonstrates that the PLGA-based LPs improve the efficacy and bioavailability and decrease neutropenia of Ir to combat colon cancer.

Oral In-Situ Nanoplatform with Balanced Hydrophobic-Hydrophilic Property for Transport Across Gastrointestinal Mucosa.

Transport of oral nanocarriers across the GI epithelium necessitates transport across hydrophilic mucus layer and the hydrophobic epithelium. Based on hydrophobic-hydrophilic balance, Curcumin-Lipomer (lipid-polymer hybrid nanoparticles) comprising hydrophobic stearic acid and hydrophilic Gantrez™ AN 119 (Gantrez) were developed, by a radical in-situ approach, to successfully traverse both barriers. A monophasic preconcentrate (Cur-Pre) comprising Cur (Curcumin), stearic acid, Gantrez and stabilizers, prepared by simple solution, was added to an aqueous phase to instantaneously generate Curcumin-Lipomer (Cur-Lipo) of nanosize and high entrapment efficiency (EE). Cur-Lipo size and EE was optimized by Box-Behnken Design. Cur-Lipomers of varying hydrophobic-hydrophilic property obtained by varying the stearic acid: Gantrez ratio exhibited size in the range 200-400 nm, EE > 95% and spherical morphology as seen in the TEM. A decrease in contact angle and in mucus interaction, evident with increase in Gantrez concentration, indicated an inverse corelation with hydrophilicity, while a linear corelation was observed for mucopenetration and hydrophilicity. Cur-SLN (solid lipid nanoparticles) which served as the hydrophobic reference revealed contact angle > 90°, maximum interaction with mucus and minimal mucopenetration. The ex-vivo permeation study through chicken ileum, revealed maximum permeation with Cur-Lipo1 and comparable and significantly lower permeation of Cur-Lipo1-D and Cur-SLN proposing the importance of balancing the hydrophobic-hydrophilic property of the nanoparticles. A 1.78-fold enhancement in flux of hydrophobic Cur-SLN, with no significant change in permeation of the hydrophilic Cur-Lipomers (p > 0.05) following stripping off the mucosal layer was observed. This reiterated the significance of hydrophobic-hydrophilic balance as a promising strategy to design nanoformulations with superior permeation across the GI barrier.

Development of Lipomer Nanoparticles for the Enhancement of Drug Release, Anti-microbial Activity and Bioavailability of Delafloxacin.

Delafloxacin (DFL) is a novel potent and broad-spectrum fluoroquinolone group of antibiotics effective against both Gram-positive and negative aerobic and anaerobic bacteria. In this study, DFL-loaded stearic acid (lipid) chitosan (polymer) hybrid nanoparticles (L-P-NPs) have been developed by single-emulsion-solvent evaporation technique. The mean particle size and polydispersity index (PDI) of optimized DFL-loaded L-P-NPs (F1-F3) were measured in the range of 299-368 nm and 0.215-0.269, respectively. The drug encapsulation efficiency (EE%) and loading capacity (LC%) of DFL-loaded L-P-NPs (F1-F3) were measured in the range of 64.9-80.4% and 1.7-3.8%, respectively. A sustained release of DFL was observed from optimized DFL-loaded L-P-NPs (F3). Minimum inhibitory concentration (MIC) values of the DFL-loaded L-P-NPs (F3) appeared typically to be four-fold lower than those of delafloxacin in the case of Gram-positive strains and was 2-4-fold more potent than those of delafloxacin against Gram-negative strains. The pharmacokinetic study in rats confirmed that the bioavailability (both rate and extent of absorption) of DFL-loaded L-P-NPs was significantly higher (2.3-fold) than the delafloxacin normal suspension. These results concluded that the newly optimized DFL-loaded L-P-NPs were more potent against both Gram-positive and negative strains of bacteria and highly bioavailable in comparison to delafloxacin normal suspension.

Asymmetric lipid-polymer particles (LIPOMER) by modified nanoprecipitation: role of non-solvent composition.

Asymmetric lipid polymer nanostructures (LIPOMER) comprising glyceryl monostearate (GMS) as lipid and Gantrez AN 119 (Gantrez) as polymer, revealed enhanced splenic accumulation. In the present paper, we attempt to explain the formation of asymmetric GMS LIPOMER using real time imaging. Particles were prepared by precipitation under static conditions using different non-solvent phase compositions. The process was video recorded and the videos converted to time elapsed images using the FFmpeg 0.10.2 software at 25 frames/sec. Non-solvent compositions comprising >30% of IPA/Acetone revealed significant stranding of the solvent phase and slower onset of precipitation(2-6s). At lower concentrations of IPA and acetone, and in non-solvent compositions comprising ethanol/water the stranding phenomenon was not evident. Further, rapid precipitation(<1 s) was evident. Nanoprecipitation based on the Marangoni effect is a result of diffusion stranding, interfacial turbulence, and mass transfer of solvent and non-solvent resulting in solute precipitation. Enhanced diffusion stranding favored by high interaction of GMS and Gantrez(low ΔPol), and the low solubility parameter(Δδtotal) and high mixing enthalpy(ΔHM) of GMS in IPA resulted in droplets with random shapes analogous to an amoeba with pseudopodia, which on precipitation formed asymmetric particles. Asymmetric particles could be readily designed through appropriate selection of solutes and non-solvent phase by modified nanoprecipitation.