Formulation Optimization and In Vitro Characterization of Granisetronloaded Polylactic-co-glycolic Acid Microspheres Prepared by a Dropping-in-liquid Emulsification Technique.

PURPOSE: Traditional dosage forms of granisetron (GRN) decrease patient compliance associated with repeated drug administration because of the short half-life of the drug. METHODS: In this study, novel GRN-loaded Polylactic-co-glycolic Acid (PLGA) sustained-release microspheres were prepared for the first time via a dropping-in-liquid emulsification technique. The effects of various factors, such as pH of the outer phase, Tween 80, Polyvinyl Alcohol (PVA) concentrations, and hardening process, on the Encapsulation Efficiency (EE), Drug Loading (DL), and particle size of microspheres were extensively studied. The physicochemical properties, including drug release, surface morphology, crystallinity, thermal changes, and molecular interactions, were also studied. RESULTS: GRN has a pH-dependent solubility and it exhibits a remarkably high solubility under acidic condition. The EE of the alkaline medium (pH 8) was higher than that of the acidic medium (pH 4.0). EE and DL decreased in the presence of Tween 80 in the outer phase, whereas EE significantly increased during hardening. The particle size of microspheres was not affected by PVA and Tween 80 concentrations, but it was influenced by PVA volume and hardening. X-ray diffraction and differential scanning calorimetry results showed that the physical state of the drug changed from a crystalline form to an amorphous form, thereby confirming that the drug was encapsulated into the PLGA matrix. Fourier transform-infrared spectroscopy confirmed that some molecular interactions occurred between the drug and the polymer. GRN-loaded PLGA microspheres showed sustained release profiles of over 90% on week 3. CONCLUSION: GRN-loaded PLGA microspheres with sustained-release were successfully prepared, and they exhibited a relatively high EE without Tween 80 as an emulsifier and with the hardening process.

Combretastatin A4-loaded Poly (Lactic-co-glycolic Acid)/Soybean Lecithin Nanoparticles with Enhanced Drug Dissolution Rate and Antiproliferation Activity.

OBJECTIVE: This study aimed to prepare combretastatin A4 (CA4)-loaded nanoparticles (CA4 NPs) using poly(lactic-co-glycolic acid) (PLGA) and soybean lecithin (Lipoid S100) as carriers, and further evaluate the physicochemical properties and cytotoxicities of CA4 NPs against cancer cells. METHODS: CA4 NPs were prepared using a solvent evaporation technique. The effects of formulations on CA4 NPs were investigated in terms of particle size, zeta potential, encapsulation efficacy, and drug loading. The physicochemical properties of CA4 NPs were characterized using transmission electron microscopy, X-ray powder diffraction, differential scanning calorimetry, and Fourier transform infrared spectra. The drug release from CA4NPs was performed using a dialysis method. In addition, the cytotoxicity of CA4NPs against human alveolar basal epithelial (A549) cells was also evaluated. RESULTS: CA4 NPs prepared with a low organic/water phase ratio (1:20) and high drug/PLGA mass ratio (1:2.5) exhibited a uniform hydrodynamic particle size of 142 nm, the zeta potential of -1.66 mV, and encapsulation efficacy and drug loading of 92.1% and 28.3%, respectively. CA4 NPs showed a significantly higher release rate than pure CA4 in pH 7.4 phosphate-buffered solution with 0.5% Tween 80. It was found that the drug molecules could change from the crystal state to an amorphous form when loaded into the PLGA/Lipoid S100 matrix, and some molecular interactions could also occur between the drug and PLGA. Importantly, CA4 NPs showed a remarkably higher antiproliferation activity against A549 cancer cells compared to pure CA4. CONCLUSION: These results suggested the promising potential of PLGA/Lipoid S100 nanoparticles as the drug delivery system of CA4 for effective cancer therapy.

Collagenase IV and clusterin-modified polycaprolactone-polyethylene glycol nanoparticles for penetrating dense tumor tissues.

Purpose: Novel collagenase IV (ColIV) and clusterin (CLU)-modified polycaprolactone-polyethylene glycol (PCL-PEG) nanoparticles that load doxorubicin (DOX) were designed and fully evaluated in vitro and in vivo. Methods: PCL-PEG-ColIV was synthesized by linking PCL-PEG and ColIV through a carbodiimide method. DOX-loaded nanoparticles (DOX-PCL-PEG-ColIV) were self-assembly prepared, followed by noncovalently adsorbing CLU on the DOX-PCL-PEG-ColIV surface to obtain DOX-PCL-PEG-ColIV /CLU nanoparticles, which can penetrate through the tumor extracellular matrix (ECM) and inhibit phagocytosis by macrophage. The physicochemical properties of nanoparticles were characterized. The cellular uptake and antiphagocytosis ability of nanoparticles in MCF-7 tumor cells and RAW264.7 cells were investigated. The penetration ability of nanoparticles was individually evaluated in the two-dimensional (2D) and three-dimensional (3D) ECM models. The tissue distribution and antitumor effect of nanoparticles were evaluated in MCF-7 cell-bearing nude mice. Results: Compared with DOX-PCL-PEG-COOH nanoparticles, DOX-PCL-PEG-ColIV/CLU nanoparticles could effectively overcome the phagocytosis by RAW264.7 and showed excellent cellular uptake in MCF-7 cells. In addition, they showed remarkable penetration ability through the 2D and 3D ECM models. DOX-PCL-PEG-ColIV/CLU nanoparticles significantly reduced the drug distribution in the liver and spleen and enhanced the drug accumulation in tumor tissue compared with DOX-PCL-PEG-COOH or DOX-PCL-PEG-ColIV nanoparticles. DOX-PCL-PEG-ColIV/CLU nanoparticles showed remarkable antitumor effect but did not cause severe pathological damages in the main tissues, including the heart, liver, spleen, lung, and kidney. Conclusion: Novel ColIV and CLU-modified PCL-PEG nanoparticles showed excellent cellular uptake, ECM penetration, antiphagocytosis, and antitumor effects both in vitro and in vivo.