Chalermchai Khemtong

Nanonization strategies for poorly water-soluble drugs.

Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor(®) EL). In this review, several major nanonization techniques that seek to overcome these limitations for drug solubilization are presented. Strategies including drug nanocrystals, nanoemulsions and polymeric micelles are reviewed. Finally, perspectives on existing challenges and future opportunities are highlighted.

MRI-Visible Micellar Nanomedicine for Targeted Drug Delivery to Lung Cancer Cells

Polymeric micelles are emerging as a highly integrated nanoplatform for cancer targeting, drug delivery and tumor imaging applications. In this study, we describe a multifunctional micelle (MFM) system that is encoded with a lung cancer-targeting peptide (LCP), and encapsulated with superparamagnetic iron oxide (SPIO) and doxorubicin (Doxo) for MR imaging and therapeutic delivery, respectively. The LCP-encoded MFM showed significantly increased alpha(v)beta(6)-dependent cell targeting in H2009 lung cancer cells over a scrambled peptide (SP)-encoded MFM control as well as in an alpha(v)beta(6)-negative H460 cell control. (3)H-Labeled MFM nanoparticles were used to quantify the time- and dose-dependent cell uptake of MFM nanoparticles with different peptide encoding (LCP vs SP) and surface densities (20% and 40%) in H2009 cells. LCP functionalization of the micelle surface increased uptake of the MFM by more than 3-fold compared to the SP control. These results were confirmed by confocal laser scanning microscopy, which further demonstrated the successful Doxo release from MFM and accumulation in the nucleus. SPIO clustering inside the micelle core resulted in high T(2) relaxivity (>400 Fe mM(-1) s(-1)) of the resulting MFM nanoparticles. T(2)-weighted MRI images showed clear contrast differences between H2009 cells incubated with LCP-encoded MFM over the SP-encoded MFM control. An ATP activity assay showed increased cytotoxicity of LCP-encoded MFM over SP-encoded MFM in H2009 cells (IC(50) values were 28.3 +/- 6.4 nM and 73.6 +/- 6.3 nM, respectively; p < 0.005). The integrated diagnostic and therapeutic design of MFM nanomedicine potentially allows for image-guided, target-specific treatment of lung cancer.

Polymeric nanomedicine for cancer MR imaging and drug delivery

Multifunctional nanomedicine is emerging as a highly integrated platform that allows for molecular diagnosis, targeted drug delivery, and simultaneous monitoring and treatment of cancer. Advances in polymer and materials science are critical for the successful development of these multi-component nanocomposites in one particulate system with such a small size confinement (<200 nm). Currently, several nanoscopic therapeutic and diagnostic systems have been translated into clinical practice. In this feature article, we will provide an up-to-date review on the development and biomedical applications of nanocomposite materials for cancer diagnosis and therapy. An overview of each functional component, i.e. polymer carriers, MR imaging agents, and therapeutic drugs, will be presented. Integration of different functional components will be illustrated in several highlighted examples to demonstrate the synergy of the multifunctional nanomedicine design.

Zinc ferrite nanoparticles as MRI contrast agents

Mixed spinel hydrophobic ZnxFe1-xO x Fe2O3 (up to x = 0.34) nanoparticles encapsulated in polymeric micelles exhibited increased T2 relaxivity and sensitivity of detection over clinically used Feridex.

β-lapachone micellar nanotherapeutics for non-small cell lung cancer therapy

Lung cancer is the leading cause of cancer-related deaths with current chemotherapies lacking adequate specificity and efficacy. Beta-lapachone (beta-lap) is a novel anticancer drug that is bioactivated by NAD(P)H:quinone oxidoreductase 1, an enzyme found specifically overexpressed in non-small cell lung cancer (NSCLC). Herein, we report a nanotherapeutic strategy that targets NSCLC tumors in two ways: (a) pharmacodynamically through the use of a bioactivatable agent, beta-lap, and (b) pharmacokinetically by using a biocompatible nanocarrier, polymeric micelles, to achieve drug stability, bioavailability, and targeted delivery. Beta-lap micelles produced by a film sonication technique were small ( approximately 30 nm), displayed core-shell architecture, and possessed favorable release kinetics. Pharmacokinetic analyses in mice bearing subcutaneous A549 lung tumors showed prolonged blood circulation (t(1/2), approximately 28 h) and increased accumulation in tumors. Antitumor efficacy analyses in mice bearing subcutaneous A549 lung tumors and orthotopic Lewis lung carcinoma models showed significant tumor growth delay and increased survival. In summary, we have established a clinically viable beta-lap nanomedicine platform with enhanced safety, pharmacokinetics, and antitumor efficacy for the specific treatment of NSCLC tumors.

Hyperpolarized 15 N-pyridine Derivatives as pH-Sensitive MRI Agents

Highly sensitive MR imaging agents that can accurately and rapidly monitor changes in pH would have diagnostic and prognostic value for many diseases. Here, we report an investigation of hyperpolarized 15N-pyridine derivatives as ultrasensitive pH-sensitive imaging probes. These molecules are easily polarized to high levels using standard dynamic nuclear polarization (DNP) techniques and their 15N chemical shifts were found to be highly sensitive to pH. These probes displayed sharp 15N resonances and large differences in chemical shifts (Δδ >90 ppm) between their free base and protonated forms. These favorable features make these agents highly suitable candidates for the detection of small changes in tissue pH near physiological values.

Polymeric micelle nanoparticles for photodynamic treatment of head and neck cancer cells

Objective: To encapsulate 5,10,15,20-tetrakis(meso-hydroxyphenyl)porphyrin (mTHPP), a photosensitizer, into polymeric micelles; characterize the micelles; and test in vitro photodynamic therapy efficacy against human head and neck cancer cells. Study Design: A nanoparticle design, fabrication, and in vitro testing study. Setting: Polymer chemistry laboratory. Subjects and Methods: Micelles encapsulating mTHPP were produced, and micellar size was measured. Ultraviolet visible spectra and fluorescence spectroscopy were used to characterize the mTHPP-loaded micelles. In vitro cell culture using HSC-3 and HN-5 cancer cells was performed to test the photodynamic therapy efficacy of the micelles using confocal microscopy and method of transcriptional and translational (MTT) assay. Results: mTHPP was encapsulated with high loading efficiency (> 85%) and density (up to 17%) into micelles. Micelle size was 30.6 ± 3.3 nm by transmission electron microscopy and 30.8 ± 0.6 nm by dynamic light scattering. The absorption maximum for each sample was 418 nm, and fluorescent spectroscopy revealed quenching with maximal fluorescence at five percent loading. Significant cytotoxicity was observed with confocal microscopy when HSC-3 cells were treated with 10 percent mTHPP micelles, with 100 percent cytotoxicity within the zone of laser light exposure at 420 nm. Phototoxicity and dark toxicity against HSC-3 and HN-5 cells measured using the MTT assay with five and 10 percent loaded mTHPP micelles demonstrated greater than 90 percent cytotoxicity with photodynamic therapy and less than 10 percent dark toxicity at a micelle concentration of 25 μg/mL for both cell lines. Conclusion: Micelles were able to encapsulate and solubilize mTHPP at high loading densities with uniform size distribution. These micelles exhibit fluorescence and photodynamic therapy mediated cytotoxicity against head and neck cancer cells in vitro.

In vivo angiogenesis imaging of solid tumors by αvβ3-targeted, dual-modality micellar nanoprobes

The objective of this study was to develop and evaluate an αv β 3-specific nanoprobe consisting of fluorescent superparamagnetic polymeric micelles (FSPPM) for in vivo imaging of tumor angiogenesis. Spherical micelles were produced using poly(ethylene glycol)-b-poly(d,l-lactide) co-polymers conjugated with tetramethylrhodamine, a fluorescent dye, and loaded with superparamagnetic iron oxide nanoparticles. The resulting micelle diameter was 50–70 nm by dynamic light scattering and transmission electron microscopy measurements. Micelles were encoded with an αv β 3-specific peptide, cyclic RGDfK, and optimized for maximum fluorescence and targeting in αv β 3-overexpressing cells in vitro. In mice, cRGD-FSPPM-treated animals showed αv β 3-specific FSPPM accumulation in human lung cancer subcutaneous tumor xenografts. Together with the histological validation, the three-dimensional gradient echo magnetic resonance imaging (MRI) data provide high spatial resolution mapping and quantification of angiogenic vasculature in an animal tumor model using targeted, ultrasensitive MRI nanoprobes.

Hyperpolarized 13C NMR detects rapid drug-induced changes in cardiac metabolism

The diseased myocardium lacks metabolic flexibility and responds to stimuli differently compared with healthy hearts. Here, we report the use of hyperpolarized 13C NMR spectroscopy to detect sudden changes in cardiac metabolism in isolated, perfused rat hearts in response to adrenergic stimulation.

Synthesis and catalytic activity of a poly(N,N-dialkylcarbodiimide)/palladium nanoparticle composite: a case in the Suzuki coupling reaction using microwave and conventional heatingElectronic supplementary information (ESI) available: experimental details and UV?vis spectrum. See http://www.rsc.org/suppdata/cc/b3/b313210m/

Poly(N,N-dialkylcarbodiimide) was found to be an effective polymeric ligand system for preparing and stabilizing palladium nanoparticles (1-5 nm). The composite material prepared in situ was found to be a robust catalyst for the Suzuki coupling reaction under microwave or regular heating.