Abstract #4308: Noninvasive monitoring of drug release from PLGA nanoparticles
Authors: Igor Jacobs, Yoshinori Onuki, Dmitri Artemov, Nicole Benoit, Yoshinori Kato
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Purpose: Efficient drug release from nanocarriers is one of the critical factors for the success of nanocarrier-based targeted cancer chemotherapy. Therefore, the development of a noninvasive release monitoring technique has clinical significance in cancer therapy. Concept: Intact nanocarriers encapsulating the fluorinated anticancer agent 5-fluorouracil (5-FU), a positive (GdDTPA), and a negative (SPIO) MRI contrast agent exhibit a broad resonance line for an anticancer agent in 19F MR spectroscopy as well as negative contrast enhancement in MRI due to the T2 / T2 * effect of the negative contrast agent. Upon the release, free anticancer agent has a narrow resonance line, and free positive contrast agent generates positive contrast enhancement in areas beyond the diffusion range of a negative contrast agent, thus serving as surrogate marker of the drug release. Methods: 5-FU and poly(D,L-lactide- co -glycolide) (PLGA, LA/GA=50/50) were used as an anticancer agent and a main component of nanocarrier, respectively. GdDTPA and superparamagnetic iron oxide (SPIO) nanoparticles were used as a positive and a negative MRI contrast agent, respectively. PLGA nanoparticles encapsulating 5-FU, GdDTPA, and SPIO were prepared using a double emulsion solvent evaporation method. The size distribution and 5-FU contents of PLGA nanoparticles were characterized with dynamic laser-light scattering and high-performance liquid chromatography, respectively. Orthotopic xenograft tumor models were grown in female SCID mice by injecting 3×106 of human breast carcinoma MCF-7 cells into the mammary fat pad of the animal. All MR studies were carried out on a horizontal bore Bruker Biospec 9.4T spectrometer. The anesthetized mouse was catheterized via tail vein, and MR images and spectroscopies were acquired pre- and post-administration of PLGA nanoparticles. Quantitative T1 maps were constructed using custom-written software in the IDL programming environment. Results/Discussion: Hydrodynamic size and \#950;-potential of PLGA nanoparticles were about 200 nm, and about -2 mV, respectively. In vivo MR results demonstrated that decreases in T1 of the tumor were observed following i.v. administration of 5-FU/GdDTPA/SPIO-loaded PLGA nanoparticles, while 5-FU could not be detected with MR spectroscopy in vivo , which is attributable to the intrinsic low sensitivity of MR spectroscopy compared to MRI. As both agents are low molecular weight and highly hydrophilic molecules, GdDTPA can be used as a surrogate marker of 5-FU and other low molecular weight hydrophilic agents for noninvasive monitoring of drug release by MRI, and this technique can lead to more effective strategies for targeted cancer chemotherapy. Acknowledgment: Supported by NIH grant R21 EB008162 (YK). Special thanks to Ms. Lan Wu for her technical assistance.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4308.