Safety evaluation of 32P-chromic phosphate-poly L lactic acid particles interstitially implanted into livers of Beagle dogs

Abstract

Aims: The aim of this study was to investigate the safety and toxicity of biodegradable (32)P-chromic phosphate-poly L lactic acid ((32)P-CP-PLLA) particles interstitially implanted into Beagle dog livers.

Methods: Eighteen healthy Beagle dogs were randomly divided into 6 groups (n=3), and were treated with drugs of different formulations or doses, as well as controls. At different time points after surgery, the experimental dogs were weighed. Detection of indicators of blood chemistry and liver fibrosis, SPECT bremsstrahlung imaging, computed tomography, histological examination, continuous blood measurement, and counting of urine and fecal radioactivity were performed for these dogs.

Results: SPECT imaging showed that after implantation of radioactive particles into livers, radioactivity continuously accumulated in the implanted sites, while no radioactivity imaging was found in the nonimplantation sites. The mean absorbance doses in the implantation sites were 89.8-178.7 Gy. Local spherical lesions were observed in tissues. The average effective half-life time of (32)P-CP-PLLA was 11.8 days. Within 4 weeks after surgery, slight or moderate swelling and degradation of liver cells were detected, while in 8 weeks after surgery, they are normal. For the blood chemistry, liver fibrosis, and other indicators, no significant differences were found between the control groups and particle implantation groups (F=1.378, p=0.232).

Conclusions: (32)P-CP-PLLA particles have advantages including good targeting, immobile, being degradable in vivo, easy to be protected, and so on. It is suitable for treating solid tumors with blood supply. (32)P-CP-PLLA particles are a kind of safe, novel, radioactive implantation drug.

FIG. 1.

Upper row: 3 months after ³²P-CP-PLLA particle implantation into Beagle dog liver, CT imaging showed limited damage foci in the implantation site. The foci images consisted of slightly low-dense center and circular high-dense area. Edemas were found in peripheral area. The neighboring liver tissues were normal. Damage foci sizes are related to doses and scopes of implantation. (A) 185 MBq 8.2×9.4 mm; (B) 370 MBq 9.2×13.5 mm; (C) 740 MBq 15.2×18.2 mm. The damage foci are indicated with arrows. Lower row: Beagle dogs were sacrificed 3 months after surgery. Upon liver implantation of corresponding doses of particles, damage foci in the gross specimen were eye viewed. (D) 1.4×0.9 cm; (E) 1.3×1.3 cm; (F) 2.1×1.5 cm. ³²P-CP-PLLA, ³²P–chromic phosphate–poly L lactic acid.

FIG. 2.

SPECT three-dimensional fault and ECT/CT image fusion of Beagle dogs postsurgery: (a) dogs in control group with intravenous injection of ⁹⁹Tc^m–phytate, followed by liver imaging. The dogs were normal (a1 prone position), with evenly distributed radioactivity. (b) Dogs in particle groups had only spherical radioactivity accumulation in particle implantation sites, with sharp edges. No radioactive accumulation was found in other organs. (c) Dogs in colloid groups had whole liver and spleen (c3) imaging. Radioactivity in livers was not evenly distributed. In injection sites, radioactivity accumulated as lumps, with unclear edges.