Mostafa Sadoqi

Biodistribution of indocyanine green-loaded nanoparticles with surface modifications of PEG and folic acid

PURPOSE To establish the biodistribution profile of the PLGA nanoparticles with dual surface modifications of PEG and folic acid (FA) in mice xenografted with MDA-MB-231 human breast cancer cells with high expression of folate receptor (FR); and to illustrate that the modified nanoparticles can target the loaded indocyanine green (ICG) to the tumor with high FR expression. METHODS ICG-loaded nanoparticles were prepared with PLGA (non-modified nanoparticles, NM-NP) or mPEG-PLGA and FA-PLGA (dual modified nanoparticles, DM-NP). Biodistribution of the ICG-loaded nanoparticles (1.25 mg/kg) after i.v. injection was investigated on athymic mice transplanted with MDA-MB-231 tumor. RESULTS ICG concentration in plasma from the DM-NP group was significantly (p<0.05) higher than the NM-NP group from 90 min to the end of the study (12 h). After 4 h, the drug concentration in the tumor tissue from the DM-NP started to be significantly (p<0.05) higher than the NM-NP until 12 h. Compared to the NM-NP, the DM-NP increased the AUC(0-12 h) in plasma by 245% and the AUC(0-12 h) in tumor by 194%, while decreased the AUC(0-12 h) in liver by 13%. CONCLUSION The accumulation of DM-NP into the tumor was significantly higher than NM-NP due to the long circulation and FR-mediated uptake.

The formulation, characterization and in vivo evaluation of a magnetic carrier for brain delivery of NIR dye

This work reports the targeting of the near infrared (NIR) dye indocyanine green (ICG) to the brain using composite nanoparticles. Thermal decomposition of iron pentacarbonyl was used to synthesize monodisperse oleic acid coated magnetic nanoparticles (OAMNP). Synthesized OAMNP and ICG were encapsulated in a poly (lactide-co-glycolide) matrix using an emulsion evaporation method. Different batches containing OAMNP:PLGA ratios (1:4, 1:2 and 3:4) were prepared with ICG (group B-1, 2, 3) and without ICG (group A-1, 2, 3) loading. All the formulations were characterized in terms of morphology, particle size, zeta potential, magnetic content, ICG encapsulation efficiency and the spectral properties of ICG. The optimized formulation showed an encapsulation efficiency of 56 +/- 4.6% for ICG and 57 +/- 1.37% for OAMNP. The biodistribution and brain targeting study involved three groups of six animals, each with 0.4 mg kg(-1) equivalent of ICG, given as neat ICG solution, composite nanoparticles without the aid of a magnetic field, and composite nanoparticles under the influence of a magnetic field (8000 G) to groups 1, 2 and 3 respectively. The tissue analysis and microscopy images revealed a significantly higher brain concentration of ICG (p < 0.05) for group 3 than the two control groups. These results are encouraging for the brain delivery of hydrophilic dyes/drugs using this method for biomedical applications.

Revisiting the role of nanoparticles as modulators of drug resistance and metabolism in cancer

ABSTRACT Introduction: Drug resistance is the major obstacle impeding the efficacy of chemotherapeutic agents. Although numerous drug delivery techniques have been developed to combat drug resistance, their limitations of non-specific targeting and inconsistent bioavailability has led to the search of novel delivering strategies, such as nanoparticles. Areas covered: Nanoparticles for anti-cancer drug delivery are microscopic preparations encapsulating a chemotherapeutic and a chemosensitizer into a rationally designed drug delivery vehicle. Nano-strategies directed against multi-drug resistance (MDR) can be categorized into those inhibiting the drug efflux pumps, those effective against the cellular factors of drug resistance, and the combinational based strategies. Here, we review the most recent literature to reposition nanoparticles as chemotherapeutics and inhibitors of MDR. Expert Opinion: Novelty in anti-cancer drug delivery has led to the formulation of chemotherapeutics and MDR inhibitors as nano-preparations, which are multi-functional and have better tumor cell-targeting effects. Their characteristics of size and surface attachments make them readily diffusible through the tumor vasculature and increase their retention time as well. With a better understanding of the molecular mechanisms of drug resistance, more potent and multi-targeted nano-preparations can be formulated in the near future.

Resonant transmission of light through ZnO nanowaveguides in a silver film

Zinc oxide (ZnO) nanowaveguides of 40 nm in diameter are fabricated by embedding ZnO nanowires vertically grown on a glass substrate in a silver film. Resonant transmission through these nanowaveguides is observed for incident wavelengths around 500 nm. As the ZnO nanowaveguide diameter increases, the transmission resonance shifts toward longer wavelengths with increased amplitude. We attribute the observed resonant transmission to the unique material combination used enabling the excitation of localized surface plasmons.

Assessing the binding of cholinesterase inhibitors by docking and molecular dynamics studies

In this report we assessed by docking and molecular dynamics the binding mechanisms of three FDA-approved Alzheimer drugs, inhibitors of the enzyme acetylcholinesterase (AChE): donepezil, galantamine and rivastigmine. Dockings by the softwares Autodock-Vina, PatchDock and Plant reproduced the docked conformations of the inhibitor-enzyme complexes within 2Å of RMSD of the X-ray structure. Free-energy scores show strong affinity of the inhibitors for the enzyme binding pocket. Three independent Molecular Dynamics simulation runs indicated general stability of donepezil, galantamine and rivastigmine in their respective enzyme binding pocket (also referred to as gorge) as well as the tendency to form hydrogen bonds with the water molecules. The binding of rivastigmine in the Torpedo California AChE binding pocket is interesting as it eventually undergoes carbamylation and breaks apart according to the X-ray structure of the complex. Similarity search in the ZINC database and targeted docking on the gorge region of the AChE enzyme gave new putative inhibitor molecules with high predicted binding affinity, suitable for potential biophysical and biological assessments.

Targeted polymeric magnetic nanoparticles for brain imaging

The purpose of this study was to develop targeted polymeric magnetic nanoparticle system for brain imaging. Near infrared dye indocyanine green (ICG) or p-gycoprotein substrate rhodamine 123 (Rh123) were encapsulated along with oleic acid coated magnetic nanoparticles (OAMNP) in a matrix of poly(lactide-co-glycolide) (PLGA) and methoxy poly(ethyleneglycol)-poly(lactide) (Met-PEG-PLA). The nanoparticles were evaluated for morphology, particle size, dye content and magnetite content. The in vivo biodistribution study was carried out using three groups of six male Sprague Dawley rats each. Group I received a saline solution containing the dye, group II received dye-loaded polymeric magnetic nanoparticles without the aid of a magnetic field, and group III received dye-loaded polymeric magnetic nanoparticles with a magnet (8000 G) placed on the head of the rat. After a preset exposure period, the animals were sacrificed and dye concentration was measured in the brain, liver, kidney, lungs and spleen homogenates. Brain sections were fixed, cryotomed and visualized using fluorescence microscopy. The particles were observed to be spherical and had a mean size of 220 nm. The encapsulation efficiency for OAMNP was 57%, while that for ICG was 56% and for Rh123 was 45%. In the biodistribution study, while the majority of the dose for all animals was found in the liver, kidneys and spleen, group III showed a significantly higher brain concentration than the other two groups (p < 0.001). This result was corroborated by the fluorescence microscopy studies, which showed enhanced dye penetration into the brain tissue for group III. Further studies need to be done to elucidate the exact mechanism responsible for the increased brain uptake of dye to help us understand if the magnetic nanoparticles actually penetrate the blood brain barrier or merely deliver a massive load of dye just outside it, thereby triggering passive diffusion into the brain parenchyma. These results reinforce the potential use of polymeric magnetically-targeted nanoparticles in active brain targeting and imaging.

Novel multifunctional near-infrared fluorescent nanoparticles: integrating nanotechnology and biophotonics

The objective of this study is to engineer a novel nanoparticlulate system for use in early tumor diagnosis. Indocyanine green (ICG)-loaded biodegradable nanoparticles were prepared by using biodegradable polymer, poly(DL-lactic-co-glycolic acid) (PLGA). The ICG entrapment, nanoparticle size, shape, zeta potential the release of ICG from nanoparticles was determined. Also, the effect of ICG entrapment on fluorescence spectra of ICG was measured. The engineered nanoparticles were nearly spherical in shape and efficiently entrapped ICG. The release profile of the nanoparticles was exponential. The entrapment of ICG in nanoparticles caused reduction in its peak fluorescence intensity and shifted its wavelength of peak fluorescence to higher values.

Long circulating near infrared fluorescent nanoparticles for diagnosis and photodynamic therapy of cutaneous cancers

Indocyanine green (ICG) is a near-infrared fluorescence contrast agent, which has enormous potential in early tumor diagnosis and therapy. The objective of this study is to develop biodegradable nanoparticles entrapping ICG and to characterize its intracellular uptake and photodynamic activity in different cancer cell lines. Nanoparticles entrapping ICG were engineered, characterized and the intracellular uptake of ICG was investigated in B16-F10 and C-33A cancer cell lines. The photodynamic activity of ICG-loaded nanoparticles was also investigated. The nanoparticles enhanced the intracellular uptake of ICG and showed significant photodynamic activity, especially at very low ICG concentrations. These preliminary studies indicate the potential of efficient tumor cell delivery and tumoricidal effect of ICG when incorporated in nanoparticles.

Novel near-infrared nanoparticlulate biomarker: preparation and stability studies

Degradation of Indocyanine green (ICG) in aqueous media, limits its application in early tumor diagnosis and therapy. Thus, the objective of this study is to develop biodegradable nanoparticles entrapping ICG and to establish its effectiveness in providing overall stability to ICG. Nanoparticles entrapping ICG were engineered and characterized. The degradation kinetics of ICG in the nanoparticles was investigated in aqueous media. The degradation of ICG in aqueous nanoparticle suspension followed first-order kinetics. Nanoparticles enhanced aqueous, photo and thermal-stability of ICG.

Spatial sensitivity profiles by time-resolved fluorescence Monte Carlo simulation

Many investigations in the literature have studied the migration of photons in fluorescent and non-fluorescent applications, both in the steady-state and time-resolved, within a tissue-simulating medium. However, none have addressed the specific issue of quantified the subsequent migration path of the emitted photons. This is important since fluorescent spectroscopy has been gaining acceptance as an important diagnostic tool. In this paper we show the migration patterns of fluorescent photons with respect to time in a scattering medium such as tissue. The images produced are of the paths of the emission photons that reach the detector. We are able to observe how they migrate at different times. We investigate the effect of the absorption and scattering coefficients on the migration patterns, and how it could give us information about methods to detect inhomogeneities in the medium. The images produced give us information about the accuracy of the estimation of the optical properties in particular medium. Finally, we study how the detector position and absorption and scattering coefficients affect the source of the photons that reach the detector. We discover that during the rising time of the temporal spectrum most of the detected fluorescent photons are being generated very close to the source and the path followed by these photons are localized near the detector. Therefore, we could explore this for the best orientation and location of the detector and source positions to locate inhomogenieties and also source of fluorescence photons within the medium.