Hailing Zhang

Thermosensitive liposome formulated indocyanine green for near-infrared triggered photodynamic therapy: in vivo evaluation for triple-negative breast cancer.

ABSTRACTPurposeThe focus of this research was to formulate and evaluate a theranostic liposomal delivery system using indocyanine green (ICG) as a photosensitizer, triggered by near infrared (NIR) irradiation, for in vivo photodynamic therapy (PDT) of breast cancer.MethodsCytotoxicity of PDT using liposomal ICG (LPICG) as well as free ICG (FRICG) was evaluated in the human MDA-MB-468 triple-negative breast cancer (TNBC) cell line. NIR irradiation-induced increase in temperature was also monitored both in vitro and in vivo. Quantitative pharmacokinetic profile and fluorescence imaging-based biodistribution patterns of both formulations were obtained using the human TNBC xenograft model in nude mice. Overall safety, tolerability, and long-term anti-tumor efficacy of LPICG versus FRICG-mediated PDT was evaluated.ResultsSignificant loss of cell viability was achieved following photoactivation of LPICG via NIR irradiation. Temperatures of irradiated LPICG increased with increasing concentrations of loaded ICG, which correlated with significant rise of temperature compared to PBS in vivo (p < 0.01). Pharmacokinetic assessment revealed a significant increase in systemic distribution and circulation half-life of LPICG, and NIR fluorescence imaging demonstrated enhanced accumulation of liposomes within the tumor region. Tumor growth in mice treated with LPICG followed by NIR irradiation was significantly reduced compared to those treated with FRICG, saline, and irradiation alone.ConclusionsIn vivo photodynamic therapy using LPICG demonstrated targeted biodistribution and superior anti-tumor efficacy in a human TNBC xenograft model compared to FRICG. In addition, this unique delivery system exhibited a promising role in NIR image-guided delivery and real-time biodistribution monitoring of formulation with ICG serving as the fluorescent probe.

Indocyanine green loaded liposome nanocarriers for photodynamic therapy using human triple negative breast cancer cells

BACKGROUND The goal of the current research is to evaluate the potential of photodynamic therapy (PDT) in the treatment of triple negative breast cancer (TNBC) with the development of a theranostic thermosensitive liposome platform to deliver indocyanine green (ICG) as the near-infrared (NIR) photosensitizer excited by an 808 nm diode laser. METHODS In the PDT protocol, an optimized thermosensitive liposome formulation is investigated to formulate ICG as the photosensitizer, which is exited by laser light at the wavelength of 808 nm delivered by a fiber-coupled laser system. ICG in both free solution and thermosensitive liposomal formulation were evaluated as the NIR photosensitizer and compared in the PDT treatment on a panel of triple negative breast cancer cell lines along with the nontumorigenic mammary epithelial cell line MCF-10A. In addition to cytotoxicity, and clonogenic survival assessment, the role of DNA double strand break damage was evaluated. RESULTS Both MTT and clonogenic assays revealed that PDT using ICG inhibited the growth of several TNBC cell lines as well as the non-tumorigenic human breast epithelial cell line MCF-10A; and the liposomal formulation of ICG did not compromise the in vitro treatment potency, though free ICG performed slightly more effective in certain cell lines, but was not statistically significant. Cell viability was dose dependent in regards to ICG concentration and irradiation energy. Interestingly, PDT using the described protocol was more potent to inhibit the growth of MDA-MB-468 and HCC-1806 cells, coinciding with the observation that these cells are more sensitive toward DNA damaging agents. In comparison, cell lines HCC-70, BT-549, and MCF-10A were found to have less of an inhibitory effect. Furthermore, substantial DNA double strand breaks (DSBs) were observed 30 min after the PDT treatment via a γ-H2AX staining assay. PDT induced DNA damage has the potential to lead to mutagenicity, which may have various responses depending on the repair capabilities of the cells. CONCLUSION Our results suggest that PDT using indocyanine green loaded liposomes were effective in inhibiting tumor cell growth to varying extents with higher responses observed for MDA-MB-468 and HCC-1806 cells.

Molecular Dynamics Simulations of Glycocholate—Oleic Acid Mixed Micelle Assembly

We have applied a molecular dynamics (MD) method to investigate the aggregation behavior and physicochemical properties of bile salt as well as bile salt/fatty acid mixed micelles. Local atomic density profiles from the center of the micelles confirm that the self-assembly of the trihydroxy bile salt, glycocholate, is largely driven by hydrophobic aggregation of the nonpolar beta-faces of the steroid backbones. Additional association occurs between neighboring monomers through hydrogen-bonding interactions. The average micellar aggregation number for glycocholate at 37 degrees C with a background salt concentration of 150 mM is shown to be 8.5 molecules per micelle, while the critical micelle concentration (cmc) is 3.1 mM. The good agreement of these results with experimental values illustrates that a MD approach is useful to study mixed micelles of bile salts and fatty acids, critical to the understanding of oral lipid-based formulations. The aggregation behavior and colloidal structure of such micelles are simulated and presented in this article.

Solubilizing efficiency and in vitro cytotoxicity of Peptoad G

A novel non-ionic surfactant, peptoad G, is evaluated for its solubilizing capacity and cytotoxicity in order to explore its possible use in aqueous formulation of hydrophobic drugs. Solubility studies were carried out using ten model hydrophobic drugs, and cytotoxicity of the surfactant was evaluated in three different cell lines using the MTT assay. It was shown that peptoad G enhances the solubility of the ten model drugs to different extents, ranging from 20- to 1100-fold, which correlated with the number of hydrogen-bonding sites on the drug molecules. The in vitro cytotoxicity studies revealed comparable cytotoxicity of peptoad G to that of cremophor EL. The results suggest peptoad G possesses potential as an alternative to conventional solubilizers in hydrophobic drug formulations.

Understanding pharmacokinetic food effects using molecular dynamics simulation coupled with physiologically based pharmacokinetic modeling

In this study, a molecular dynamics (MD) method is assessed as a new front‐end tool for deriving relevant drug‐micelle partitioning rates for use in conjunction with a compartmental‐style gastrointestinal absorption model. A refined mechanistic approach for handling micelle‐associated vs unbound drug is presented and examined in terms of its utility for projecting human oral pharmacokinetic food/formulation effects. Similar to predecessor oral absorption models, the intestinal drug absorption rate is formulated as a function of the combined permeability through the unstirred water layer and the epithelial membrane, however, an additional diffusion coefficient adjustment is applied to account for the viscosity changes of the postprandial small intestine. Bulk passage of drug particles through the GI tract is simulated by compartmental transit through a network of nine compartments comprising the stomach, small intestine and colon. The tandem MD simulation/compartmental absorption algorithm is applied to identify factors influencing the fed vs fasted absorption ratios of a structurally diverse set of orally administered drugs. The data illustrate the interplay and apparent compromise between micelle solubilization and permeability. Copyright