Publication Archives

2006

In-Vivo Efficacy of Novel Paclitaxel Nanoparticles in Paclitaxel-Resistant Human Colorectal Tumors

JM Koziara, TR Whisman, MT Tseng, and RJ Mumper. I

J. Controlled Rel. (2006) May 30;112(3):312-9. Epub 2006 Apr 19.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.

Colloidal carriers have been shown to improve tumor therapy by increased drug delivery into tumor sites resulting directly from the enhanced permeability and retention effect (EPR). However, the clinical outcome of tumor therapy is often limited due to multidrug resistance. Several different types of resistance exist with expression of p-glycoprotein being the most commonly described. Paclitaxel entrapped in emulsifying wax nanoparticles (PX NPs) was shown to overcome drug resistance in a human colon adenocarcinoma cell line (HCT-15). In the present studies, the in-vivo efficacy of PX NPs in a HCT-15 mouse xenograft model was demonstrated. Significant inhibition in tumor growth was observed in mice receiving PX NPs treatment. Additionally, mice dosed with Taxol also demonstrated slower tumor growth; however, the efficacy of the Taxol treatment was shown in the in-vitro HUVEC model to be due to the antiangiogenic effect of paclitaxel. It was concluded that the enhanced efficacy of PX NPs over Taxol in the xenograft model was due to both overcoming paclitaxel resistance and an antiangiogenic effect.

Publication Types:Comparative Study

PMID: 16626835 [PubMed - indexed for MEDLINE]

Biocompatible Nanotemplate-Engineered Nanoparticles Containing Gadolinium: Stability and Relaxivity of a Potential MRI Contrast Agent.

D Zhu, RD White, PA Hardy, N Weerapreeyakul, K Sutthanut, and M Jay.

J Nanosci Nanotech, (2006) 6:996-1003.

Department of Pharmaceutical Sciences, University of Kentucky, Lexington 40536-0082, USA.

In this article, we use a nanotemplate engineering approach to prepare biodegradable nanoparticles composed of FDA-approved materials and possessing accessible gadolinium (Gd) atoms and demonstrate their potential as a Magnetic Resonance Imaging (MRI) contrast agent. Nanoparticles containing dimyristoyl phosphoethanolamine diethylene triamine penta acetate (PE-DTPA) were prepared using 3.5 mg of Brij 78, 2.0 mg of emulsifying wax and 0.5 mg of PE-DTPA/ml from a microemulsion precursor. After the addition of GdCl3, the presence of Gd on the surface of nanoparticles was characterized using inductively coupled plasma atomic emission spectroscopy and Scanning Transmission Electron Microscopy (STEM). The in vitro relaxivities of the PE-DTPA-Gd nanoparticles in different media were assessed at different field strengths. The conditional stability constant of Gd binding to the nanoparticles was determined using competitive spectrophotometric titration. Transmetallation kinetics of the gadolinium ion from PE-DTPA-Gd nanoparticles with zinc as the competing ionic was measured using the relaxivity evolution method. Nanoparticles with a diameter of approximately 130 nm possessing surface chelating functions were made from GRAS (Generally Regarded As Safe) materials. STEM demonstrated the uniform distribution of Gd3+ on the surface of the nanoparticles. The thermodynamic binding constant for Gd3+ to the nanoparticles was approximately 10(18) M(-1) and transmetallation studies with Zn2+ yielded kinetic constants K1 and K(-1) of 0.033 and 0.022 1/h, respectively, with an equilibrium constant of 1.5. A payload of approximately 10(5) Gd/nanoparticle was achieved; enhanced relaxivities were observed, including a pH dependence of the transverse relaxivity (r2). Nanoparticles composed of materials that have been demonstrated to be hemocompatible and enzymatically metabolized and possessing accessible Gd ions on their surface induce relaxivities in the bulk water signal that make them potentially useful as next-generation MRI tumor contrast enhancement agents.

PMID: 16736756 [PubMed - indexed for MEDLINE]

The Blood-Brain Barrier and Brain Drug Delivery.

JM Koziara, PR Lockman, DD Allen, and RJ Mumper.

Invited Review for the Journal of Nanoscience and Nanotechnology. Special Issue: "Nanotechnology in Advanced Drug Delivery." (2006) 6:2712-2735.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0082, USA.

The present report encompasses a thorough review of drug delivery to the brain with a particular focus on using drug carriers such as liposomes and nanoparticles. Challenges in brain drug delivery arise from the presence of one of the strictest barriers in vivo-the blood-brain barrier (BBB). This barrier exists at the level of endothelial cells of brain vasculature and its role is to maintain brain homeostasis. To better understand the principles of brain drug delivery, relevant knowledge of the blood-brain barrier anatomy and physiology is briefly reviewed. Several approaches to overcome the BBB have been reviewed including the use of carrier systems. In addition, strategies to enhance brain drug delivery by specific brain targeting are discussed.

Publication Types:Review

PMID: 17048477 [PubMed - indexed for MEDLINE]

Suspensions of Fluor-Containing Nanoparticles for Quantifying b- Emitting Radionuclides in Non-Hazardous Media.

D Zhu, Z Mu, C Mooty, M Kovarik and M Jay.

J Pharm. Innovation. (2006) 1:76-82 .

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The Metabolism of Fatty Alcohols in Lipid Nanoparticles by Alcohol Dehydrogenase.

Dong X, Mumper RJ.

Drug Dev. Ind. Pharm. (2006) 32:973-980.

Fatty alcohols are commonly used in lipid-based drug delivery systems including parenteral emulsions and solid lipid nanoparticles (NPs). The purpose of these studies was to determine whether horse liver alcohol dehydrogenase (HLADH), a NAD-dependent enzyme, could metabolize the fatty alcohols within the NPs and thus serve as a mechanism to degrade these NPs in the body. Solid nanoparticles (<100 nm) were engineered from oil-in-water microemulsion precursors using emulsifying wax NF as the oil phase and polyoxyethylene 20-stearyl ether (Brij 78) as the surfactant. Emulsifying wax contains both cetyl and stearyl alcohols. NPs were incubated with the enzyme and NAD+ at 37 degrees C for up to 48 h, and the concentrations of fatty alcohols were quantitatively determined over time by gas chromatography (GC). The concentrations of cetyl alcohol and stearyl alcohol within the NPs decreased to only 10-20% remaining after 15-24 h of incubation. In parallel, NP size, turbidity and the fluorescence intensity of NADH all increased over time. It was concluded that horse liver alcohol dehydrogenase/NAD+ was able to metabolize the fatty alcohols within the NPs, suggesting that NPs made of fatty alcohols may be metabolized in the body via endogenous alcohol dehydrogenase enzyme systems.

PMID: 16954110 [PubMed - indexed for MEDLINE]

HIV-1 Tat-Coated Nanoparticles Result in Enhanced Humoral Immune Responses and Neutralizing Anitbodies Compared to Alum Adjuvant

Patel J, Galey D, Jones J, Ray P, Woodward JG, Nath A, Mumper RJ.

Vaccine. 2006 Apr 24;24(17):3564-73. Epub 2006 Feb 17.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.

HIV-1 Tat has been identified as an attractive target for vaccine development and is currently under investigation in clinical trials as both a therapeutic and preventative vaccine for HIV-1. It is well known that protein based vaccines produce poor immune responses by themselves and therefore require adjuvants to
enhance immune responses. We have previously reported on the use of anionic nanoparticles (NPs) for enhancing cellular and humoral immune responses to Tat (1-72). The purpose of this study was to further evaluate the immune response of HIV-1 Tat (1-72) coated on anionic nanoparticles compared to alum using various doses of Tat (1-72). Nanoparticles were effective at generating comparable antibody titers at both 1 and 5 microg doses of Tat (1-72), whereas the antibody titers significantly decreased at the lower dose of Tat (1-72) using alum. Anti-sera from Tat (1-72) immunized mice reacted greatest to the N-terminal and
basic regions of Tat, with the NP groups showing stronger reactivity to these regions compared to alum. Moreover, the anti-sera from all Tat (1-72) immunized groups contained Tat-neutralizing antibodies and were able to significantly inhibit Tat-mediated long terminal repeat (LTR) transactivation.

Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

PMID: 16516358 [PubMed - indexed for MEDLINE]