Nanocrystal Technology as a Strategy to Improve Drug Bioavailability and Antitumor Efficacy for the Cancer Treatment.

BACKGROUND AND OBJECTIVE: Nanocrystal technology is an effective approach which can increase the dissolution rate of poorly water-soluble drugs by raising their saturation solubility, thus improving the drug bioavailability. With the development of nanocrystals, its preparation approaches have gradually matured, which can be generally divided into Bottom-up, Top-down and Combinative technologies. METHODS: A systematic literature review in the field of nanocrystal technology for the cancer treatment was scanned and collected data was detailedly analyzed and summarized. RESULTS: Over the past decade, several anticancer drug nanocrystals have been explored and evaluated in preclinical studies and clinical trials. This review mainly covers the utilizations of the nanocrystal technology in enhancing the saturation solubility of anticancer drugs associated with the increased bioavailability and anticancer efficacy. Preparation methods and characterizations of nanocrystals are also introduced in brief. In addition, one critical step in the formation of drug nanocrystals is selecting suitable stabilizers for the system. Many types of research are heading towards the role of the stabilizers in the final nanocrystals formulation. So we summed up several commonly used stabilizers in order to give a reference to the further study. At last, we discussed some considerations raised by the application of nanocrystal drugs for cancer treatment. CONCLUSION: This review is likely to enable a detailed insight on nanocrystal technology as a strategy to improve drug bioavailability and antitumor efficacy for the cancer treatment and be of particular interest to pharmaceutical industry.

Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia.

Currently, conventional therapies for acute myeloid leukemia (AML) have high failure and relapse rates. Thus, developing new strategies is crucial for improving the treatment of AML. With the clinical success of anti-CD19 chimeric antigen receptor (CAR) T cell therapies against B-lineage malignancies, many studies have attempted to translate the success of CAR T cell therapy to other malignancies, including AML. This review summarizes the current advances in CAR T cell therapy against AML, including preclinical studies and clinical trials, and discusses the potential AML-associated surface markers that could be used for further CAR technology. Finally, we describe strategies that might address the current issues of employing CAR T cell therapy in AML.

Asialoglycoprotein receptor-targeted liposomes loaded with a norcantharimide derivative for hepatocyte-selective targeting.

In order to overcome the shortcomings associated with the clinical application of norcantharidin (NCTD), including intense irritation and a short half-life, and to obtain a hepatocyte-selective liposome system with high encapsulation efficiency (EE) and low leakage, we synthesized a C14 alkyl chain norcantharimide derivative of NCTD (2-tetradecylhexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione, N-14NCTDA). Asialoglycoprotein receptor-targeted, galactosylated liposomes loaded with N-14NCTDA (GAL-Lipo) were prepared by the lipid film hydration method. GAL-Lipo with a satisfactory particle size of approximately 120nm has a higher encapsulation efficiency of more than 98.0%, which is markedly increased compared with NCTD loaded liposomes (EE%=47.6%). In addition, GAL-Lipo remained stable for at least 1 month at 4°C. In cytotoxicity assays, GAL-Lipo demonstrated stronger cytotoxicity effects (IC50=24.58µmolL-1) on Hep G2 cells than free N-14NCTDA (100µmol/L) and conventional liposomes (Con-Lipo, 39.49µmol/L) without the GAL modification. GAL-Lipo can continuously accumulate in Hep G2 cells and be internalized into cells via two pathways, namely caveolin-dependent endocytosis and clathrin-dependent asialoglycoprotein receptors (ASGP-R) mediated endocytosis and produces considerably more significant cellular apoptosis. The results of vivo toxicity studies showed that GAL-Lipo dramatically reduced renal toxicity. In addition, GAL-Lipo has a markedly improved pharmacokinetic profile in vivo and a longer circulation time (AUC=6.700±2.964mgL-1h, t1/2z=1.347±0.519h) than Con-Lipo (AUC=2.319±0.121mgL-1h, t1/2z=0.413±0.238h). In conclusion, N-14NCTDA with an ideal logP is a better alternative for the treatment of primary hepatic carcinoma. GAL-Lipo offers an attractive strategy to specifically target hepatocytes via caveolin-dependent and clathrin-dependent asialoglycoprotein receptor-mediated endocytosis resulting in higher anticancer activity and fewer side-effects.

Clarithromycin ion pair in a liposomal membrane to improve its stability and reduce its irritation caused by intravenous administration.

OBJECTIVE: The aim of this study was to improve the drug loading (DL) and stability of clarithromycin (CLA)-loaded liposomes, and reduce the irritation caused by intravenous administration of CLA. METHODS: A CLA-cholesteryl hemisuccinate (CHEMS) ion pair (CIP) was prepared by the solvent evaporation method and confirmed by fourier transform infrared spectroscopy, (1)H-nuclear magnetic resonance, differential scanning calorimetry and X-ray powder diffraction. Subsequently, CIP liposomes (CIP-Lip) were prepared by the thin-film dispersion method and evaluated in terms of their size, zeta-potential, in vitro release, stability, in vitro antimicrobial activity and irritation. RESULTS: The CIP-Lip exhibited a homogeneous round shape, and their size, ζ-potential, encapsulation efficiency (EE) and DL were 71.89 ± 2.6 nm, -9.91 ± 0.82 mV, 95.1 ± 1.5% and 7.8 ± 0.3%, respectively. The physical appearance and drug content of CIP-Lip over a three-month storage remained almost unchanged. The release of CLA in CIP-Lip was pH-dependent, with a more rapid release at pH 6.0 than at pH 7.4. Although the in vitro antimicrobial activity of CIP-Lip was comparable with free CLA, the irritation produced by CIP-Lip was significantly reduced compared with CLA solution. CONCLUSIONS: These findings suggest that CIP-Lip is a promising intravenous drug delivery system, especially on account of its high DL and reduced irritation.

Impact of electrolytes on double emulsion systems (W/O/W) stabilized by an amphiphilic block copolymer.

In this work, the block copolypeptide surfactant, poly(l-lysine·HBr)40-b-poly(racemic-leucine)20, was synthesized and characterized, then used to build water-in-oil-in-water (W/O/W) double emulsions. Double emulsions are usually prepared by a two-step emulsification process and commonly stabilized using a combination of hydrophilic and hydrophobic surfactants. Herein, we report a one-step phase inversion process to produce water-in-oil-in-water (W/O/W) double emulsions stabilized by a synthetic diblock copolymer and electrolyte. It was found that the O/W ratio and the type of electrolyte had a marked effect on the formation and type of the double emulsions. Moreover, double emulsions containing an NaCl isotonic solution were stable for at least two months, whereas those using glucose as a substitute for NaCl showed a clear compartmental change. The mechanism behind this was related to the electrostatic interaction between the anion of the electrolyte and the cation of the polylysine residues, which affected the HLB value and curvature. This novel finding is very interesting in terms of both scientific research and practical applications.