Poly(3-hydroxi-butyrate-co-3-hydroxy-valerate) (PHB-HV) microparticles loaded with holmium acetylacetonate as potential contrast agents for magnetic resonance images

Abstract

Introduction

Biodegradable polymers that contain radioactive isotopes such as Holmium 166 have potential applications as beta particle emitters in tumor tissues. Also, Ho(III) is paramagnetic, which makes it suitable as a contrast agent for magnetic resonance (MR) images.

Methods

Holmium acetylacetonate (Ho(acac)₃) loaded poly(3-hydroxy-butyrate-co-3-hydroxy-valerate) microspheres, with 5% or 8% of 3-hydroxy-valerate (HV), were prepared by emulsification/evaporation process within 20–53 μm size. Microspheres characterization was done using scanning electron microscopy, energy-dispersive X-ray, and infrared spectroscopies. The release of holmium(III) in sodium phosphate buffer (pH 7.4) was followed for 9 days with inductively coupled plasma. Finally, T₂ and T₂* magnetic resonance images (MRI) were acquired and compared with the MRI of the inclusion complex of holmium acetylacetonate in some β-cyclodextrins.

Results

Holmium acetylacetonate loading, evaluated by thermogravimetry, was up to 20 times higher for copolymer with 5% of HV. It was shown that microspheres loaded with Ho(acac)₃ exhibited an accumulation of Ho(III) on their surfaces but were stable over time, as no expressive release of holmium(III) was detected in 9-day exposition to sodium phosphate buffer. Holmium acetylacetonate in both microspheres or inclusion complexes was very efficient in obtaining T₂ and T₂* weighted images in magnetic resonance, thus, might be used as contrast agents.

Conclusion

This is the first description of the use of inclusion complexes of holmium acetylacetonate in biodegradable polymers as contrast agents. New investigations are underway to evaluate the resistance of PHB-HV polymer microparticles to nuclear activation to assess their potential for use as radiopharmaceuticals for the treatment of liver cancer.

Keywords:

• holmium acetylacetonate
• PHB-HV microparticles
• microspheres
• MRI

Acknowledgments

The authors would like to thank the Radiopharmacy Department (DIRF/IPEN/CNEN) for financial support of this study.

This study was also funded by the Brazilian National Research Council (CNPq) (grants: DT306980/2015-0, DT310247/2013-6, DT310227/2010-0, 560423/2010-1, 550598/2010-3, and DT 315236/2018-3) and FAPESP, São Paulo, Brazil (grant: 2015/26058-0).

Abbreviations

CLSM, confocal laser scanning microscopy; EDS, energy-dispersive X-ray; HP-β-CD, hydroxyl-propyl-β-cyclodextrin; Ho(acac)₃, holmium(III) acetylacetonate; Ho(acac)₃-MS, holmium(III) acetylacetonate microspheres; ICP, inductively coupled plasma; PHB-HV, Poly(3-hydroxi-butyrate-co-3-hydroxy-valerate); MRI, magnetic resonance images; MS, microspheres; PHB, poly(3-hydroxy-butyrate); SEM, scanning electron microscopy; XRD, X-ray diffraction.

Disclosure

The authors report no conflicts of interest in this work.