Jin-Seok Choi

Enhancing the in vitro anticancer activity of albendazole incorporated into chitosan-coated PLGA nanoparticles.

To improve the solubility and anticancer activity of albendazole (ABZ), chitosan (CS)-coated poly-dl-lactic-co-glycolic acid (PLGA) nanoparticles were developed. CS was used to coat ABZ-loaded PLGA nanoparticles to enhance both mucoadhesiveness and colloidal stability. CS-coated PLGA nanoparticles were prepared by suspending the nanoparticles in CS solution after solvent diffusion. The CS-coated PLGA nanoparticles were characterized, and ABZ release was studied in vitro from various formulations. The mucoadhesive properties and in vitro anticancer activities of CS-coated PLGA nanoparticles were investigated by measurement of zeta potentials and the MTT assay, respectively. Spherical nanoparticles below 500nm in diameter were successfully prepared; the particle size distribution was narrow. Complete encapsulation of ABZ in CS-coated PLGA nanoparticles was confirmed by SEM, FTIR, DSC, and XRD. The particle sizes of CS-coated PLGA nanoparticles were in the range of 260-480nm; the encapsulation efficiency was 43.4-54.6%; and the yield 58.5-67.8%. The zeta potential of CS-coated nanoparticles was above +27mV and stability was maintained for 4 weeks. At pH 7.4, the in vitro release of ABZ from nanoparticles (P188-5) was 200-fold higher than that from untreated ABZ; this persisted for 12h. Moreover, ABZ release from CS-coated PLGA nanoparticles (P188-CS0.5) was 1.5-fold higher than that from untreated ABZ at pH 1.2. Additionally, the ABZ-loaded CS-coated nanoparticles exhibited superior mucoadhesion and improved cytotoxicity. The results show that CS coating of PLGA nanoparticles may improve the anticancer effect and the mucoadhesive properties of ABZ-loaded nanoparticles.

Design of PVP/VA S-630 based tadalafil solid dispersion to enhance the dissolution rate

&NA; Tadalafil (TDF) is a Biopharmaceutics Classification System (BCS) class II drug; the efficacy thereof is critically limited by inherent poor water solubility. Solid dispersion (SD) techniques are widely used to improve the bioavailability of drugs that are poorly water‐soluble. Herein, we used an SD technique to improve the solubility and in vitro dissolution rate of TDF; a solvent evaporation method was applied involving the use of hydrophilic carriers (PVP/VA S‐630) and assistants (malic acid or meglumine). The TDF‐SD formulations were evaluated in terms of the solubility, in vitro dissolution, and stability. Physical properties were confirmed by field‐emission scanning electron microscopy, differential scanning calorimetry, powder X‐ray diffraction, and Fourier transform infrared spectroscopy (FT‐IR). TDF‐SD formulations containing assistants (malic acid or meglumine) and various solubilizers exhibited significantly enhanced solubility in distilled water (DW) (up to 27.3‐fold; 18.5 ± 0.16 &mgr;g/mL with PVP/VA S‐630) compared with TDF alone (0.73 ± 0.08 &mgr;g/mL). However, the dissolution rate of malic acid based formulation was decreased as the PVP/VA S‐630 content increased compared to meglumine based formulation. Thus, the optimal TDF‐SD formulation (TDF/meglumine/PVP/VA S‐630/Aerosil 200: 1/3/5/3) exhibited a greater dissolution rate (89.1 ± 3.9%) than TDF alone (6.2 ± 2.5%) and Cialis® powder (16.0 ± 1.9%) in DW. The final TDF‐SD formulation was amorphous in nature and exhibited good stability. In conclusion, TDF‐SD was successfully improved in vitro dissolution rate of TDF compared to commercial products (Cialis®) in the dissolution media without sodium lauryl sulfate (SLS). Graphical abstract Figure. No caption available.

Solubilization and formulation of chrysosplenol C in solid dispersion with hydrophilic carriers

We investigated how to overcome problems associated with the solubility, dissolution, and oral bioavailability of the poorly water-soluble drug compound, chrysosplenol C (CRSP), as well as the effects of single and binary hydrophilic polymers (PVP K-25 and/or PEG 6000) on the solubility and dissolution parameters of CRSP. Then an optimized formulation was further developed with a surfactant. To select a surfactant suitable for a CRSP-loaded solid dispersion (SD), the solubility of CRSP in distilled water containing 1% surfactant was compared with the solubilities in other surfactants. Sodium lauryl sulfate (SLS) showed the highest drug solubility. Overall, a formulation containing CRSP, binary hydrophilic polymers (PVP and PEG 6000), and SLS at a ratio of 2.0/0.2/1.1/0.7 showed the optimum in vitro release profile. This optimized formulation had better safety properties than pure CRSP in cell viability examinations. SD formulations were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and Fourier-transform infrared (FT-IR) spectroscopy. Our optimized SD formulation is expected to improve the bioavailability of CRPS because it improves the solubility and dissolution rate of CRSP.

Effects of paclitaxel nanocrystals surface charge on cell internalization

In this study, we investigated the influence of paclitaxel nanocrystals (PTX-NC) surface charge on cell internalization and cell cytotoxicity. PTX-NCs were prepared using the nano-precipitation method. The surface-modified PTX-NCs were prepared using an absorption method with positively charged poly(allylamine hydrochloride) (PAH) and negatively charged poly(sodium 4-styrenesulfonate) (PSS). The morphologies of the surface-modified and unmodified PTX-NCs were characterized by field emission scanning electron microscopy. An in vitro drug release study was performed in phosphate-buffered saline (pH 7.4) containing 0.5% (w/v) Tween 80 for 48h. Cell internalization was evaluated at time intervals of 0.5, 1, and 2h, and cell cytotoxicity was analyzed for 24h using A549 cells. Three different types of PTX-NCs with a mean size of around 300-400nm were successfully prepared. The zeta-potential revealed PSS-PTX-NCs (-22.7±5.1 mV), PTX-NCs (- 2.4±2.9 mV), and PAH-PTX-NCs (+ 19.3±3.4 mV). The three types of PTX-NC exhibited higher drug release than pure PTX. The positive charge on PTX-NC resulted in higher cell uptake and cell cytotoxicity than the negative charge on PTX-NC. Moreover, the positive charge on PTX-NC showed stronger interactions with bovine serum albumin. In conclusion, the positive charge on PTX-NCs improved cell internalization, cell cytotoxicity, and interactions with bovine serum albumin.

Development of surface curcumin nanoparticles modified with biological macromolecules for anti-tumor effects

The rationale of this study was to improve the stability, cellular uptake, and evaluate the cytotoxicity of surface modified curcumin nanoparticles (CUR NP). CUR NP were surface modified with proteins (transferrin [Tf] and gelatin [GT]) by adsorption to improve their stability and targeting property. CUR NP were evaluated for stability, in vitro drug release, cellular uptake and cell cytotoxicity. The particle sizes of CUR NP were 153.2±56.4nm (CUR NP), 145.0±26.8nm (Tf-CUR NP), and 167.7±42.7nm (GT-CUR NP). The stabilities of Tf-CUR NP and GT-CUR NP were higher than that of CUR NP. Tf-CUR NP and GT-CUR NP showed faster drug release than those shown by CUR NP and CUR (pure) in pH 7.4 PBS and cell media (RPMI) for 36h. The cellular uptake and cytotoxicity of Tf- and GT-modified CUR NP were higher than those of CUR NP in MCF-7 and A549 cells. In conclusion, Tf-CUR NP and GT-CUR NP exhibited improved stability, enhanced cellular uptake, and stronger cytotoxicity.

Development and evaluation of targeting ligands surface modified paclitaxel nanocrystals.

To overcome the toxicity of excipient or blank nanoparticles for drug delivery nano-system, the surface modified paclitaxel nanocrystals (PTX-NC) have been developed. PTX-NCs were prepared by nano-precipitation method. The surface of PTX-NCs were modified by grafting with apo-transferrin (Tf) or hyaluronic acid (HA). The physical properties of PTX-NCs were evaluated by field emission scanning electron microscope (FE-SEM), zeta-sizer, zeta-potential, differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectrometry. In vitro drug release study was performed in phosphate buffered saline (PBS) with or without 0.5% (w/v) Tween 80 for 24h. Cellular uptake was studied at time intervals of 0.5, 1, and 2h in MCF-7 cells, and cell growth inhibition study was performed for 24h using MCF-7 cells (cancer cells), and HaCaT cells (normal cells). Three different types of PTX-NCs with a mean size of 236.0±100.6nm (PTX-NC), 302.0±152.0nm (Tf-PTX-NC) and 339±180.6nm (HA-PTX-NC) were successfully prepared. The drug release profiles showed 29.1%/6.9% (PTX (pure)), 40.7%/23.9% (PTX-NC), 50.5%/25.1% (Tf-PTX-NC) and 46.8/24.8% (HA-PTX-NC) in PBS with/without 0.5% (w/v) Tween 80 for 24h, respectively. As per the results, the drug release of PTX-NCs showed the faster release as compared to that of PTX (pure). Surface modified PTX-NCs exhibited higher values for cell permeability than unmodified PTX-NC in the cellular uptake study. Surface modified PTX-NCs inhibited the cell growth approximately to 60% in MCF-7 cells, however effect of surface modified PTX-NCs on normal cell line was lower than the PTX-NC and PTX (pure). In conclusion, biological macromolecules (Tf or HA) surface modified PTX-NC enhanced the cellular uptake and the cell growth inhibition.

Development of docetaxel nanocrystals surface modified with transferrin for tumor targeting

The purpose of this study was to develop the surface modification of docetaxel nanocrystals (DTX-NCs) with apo-Transferrin human (Tf) for improving the cellular uptake and cytotoxicity of DTX. DTX-NCs were prepared by a nanoprecipitation method, and the surface modified with Tf by an adsorption method (Tf-DTX-NCs). The morphology and particle size of DTX-NCs and Tf-DTX-NCs were characterized using a field emission scanning electron microscope and zetasizer. An in vitro drug release study was performed in phosphate-buffered saline containing 0.5% (w/v) Tween 80 for 24 hours. Cellular uptake was studied at 0.5, 1, and 2 hours. A cytotoxicity study was performed using the A549 (human lung cancer) cell line after 24-, 48-, and 72-hour treatments. The mean sizes were 295±97 and 398±102 nm for DTX-NCs and Tf-DTX-NCs, respectively. Tf-DTX-NCs and DTX-NCs exhibited rapid drug release, whereas DTX (pure) was slowly released. Tf-DTX-NCs showed higher cellular uptake than DTX-NCs in confocal microscopic and quantitative studies. Moreover, at DTX concentration of 100 µg/mL, Tf-DTX-NCs (82.6%±0.8%) showed higher cytotoxicity than DTX-NCs (77.4%±4.1%) and DTX (pure; 20.1%±4.6%) for 72-hour treatment. In conclusion, Tf-DTX-NCs significantly improved the cellular uptake and cytotoxicity of DTX in the A549 cell line.

Surface modification of docetaxel nanocrystals with HER2 antibody to enhance cell growth inhibition in breast cancer cells

Here, we describe docetaxel nanocrystals (DTX-NCs) surface-modified with Herceptin® (HCT) for combination cancer therapy. Using nano-precipitation and adsorption method, DTX-NCs and HCT-DTX-NCs were successfully prepared. The morphologies of DTX-NCs and HCT-DTX-NCs were characterized by field emission scanning electron microscopy (FE-SEM). The particle size and surface charge were evaluated by zeta-sizer and zeta-potential, respectively. Moreover, DTX-NCs and HCT-DTX-NCs were evaluated in terms of an in vitro drug release, cellular uptake and cytotoxicity. We hypothesized that because they contain water-soluble HCT, HCT-DTX-NCs would have increased particle size and in vitro drug release, and well maintained stability compared with DTX-NCs. We also hypothesized that HCT-DTX-NCs would exhibit higher uptake by, and toxicity toward, HER2-receptor-bearing cells. The DTX-NCs and HCT-DTX-NCs exhibited pebble-shaped morphologies with mean sizes of 472.8±138.1nm and 526.4±130.4nm, respectively. The zeta-potentials of DTX-NCs and HCT-DTX-NCs were -9.6±2.81mV and +10.4±2.87mV, respectively. The drug release profiles from HCT-DTX-NCs were more rapid than those from DTX-NCs and DTX. Both the DTX-NCs and HCT-DTX-NCs exhibited good stability in PBS (pH 7.4) at 4°C for 4 weeks. Moreover, HCT-DTX-NCs were associated with significantly greater uptake by, and cytotoxicity toward, MCF-7 cells, than DTX-NCs and DTX. In conclusion, HCT-adsorbed DTX-NCs exhibited good cellular uptake and cytotoxicity and may be useful anti-cancer treatments.

Use of acidifier and solubilizer in tadalafil solid dispersion to enhance the in vitro dissolution and oral bioavailability in rats

The purpose of this study is to improve the solubility, in vitro dissolution, and oral bioavailability in rats of tadalafil (TDF) by using SD technique with a weak acid and a copolymer. TDF-SD was prepared via solvent evaporation, coupled with the incorporation of an acidifier and solubilizer. Tartaric acid enhanced the solubility of TDF over 5-fold in DW, and Soluplus® enhanced the solubility of TDF over 8.7-fold and 19.2-fold compared to that of TDF (pure) in DW and pH 1.2 for 1h, respectively. The optimal formulation of TDF-SD3 was composed of TDF vs Tartaric acid vs Soluplus® vs Aerosil=1:1:3:3. The in vitro dissolution rate of TDF-SD3 in DW, pH 1.2 and pH 6.8 buffer (51.5%, 53.3%, and 33.2%, respectively) was significantly higher than that of the commercial product (Cialis®) powder (16.5%, 15.2%, and 14.8%, respectively). TDF was completely transformed to an amorphous form as shown in SEM, DSC and PXRD data. The stability of TDF-SD3 included drug contents and in vitro dissolution for 1 month were similar to those of Cialis®, and the amorphous form of TDF-SD3 was well maintained for 6 months. The TDF-SD3 formulation improved the relative bioavailability (BA) and peak plasma concentration (Cmax) compared to that of Cialis® powder after oral administration in rats as 117.3% and 135.7%, respectively. From the results, we found that the acidifier increased the wettability of TDF, and the solubilizer improved solubility through hydrogen bonding with TDF, thereby increasing the solubility, dissolution and oral bioavailability of TDF in TDF-SD3.

Sustained release docetaxel-incorporated lipid nanoparticles with improved pharmacokinetics for oral and parenteral administration

Abstract The aim of this study was to develop docetaxel-incorporated lipid nanoparticles (DTX-NPs) to improve the pharmacokinetic behaviour of docetaxel (DTX) after oral and parenteral administration via sustained release. DTX-NPs were prepared by nanotemplate engineering technique with palmityl alcohol as a solid lipid and Tween-40/Span-40/Myrj S40 as a surfactants mixture. Spherical DTX-NPs below 100 nm were successfully prepared with a narrow particle size distribution, 96% of incorporation efficiency and 686 times increase in DTX solubility. DTX-NPs showed a sustained release over 24 h in phosphate-buffered saline and simulated gastric and intestinal fluids, while DTX-micelles released DTX completely within 12 h. The half-maximal inhibitory concentration (IC50) of DTX-NPs against human breast cancer MCF-7 cells was 1.9 times lower than that of DTX-micelles and DTX solution. DTX-NPs demonstrated 3.7- and 2.8-fold increase in the area under the plasma concentration–time curve compared with DTX-micelles after oral and parenteral administration, respectively.