Toxicity of Polyalkyl Cyanoacrylate Nanoparticles

Toxicity of PACA nanoparticles varies depending on the alkyl chain length in the polymer. Incubation of hepatocytes with 1% poly(methyl cyanoacrylate) nanoparticles resulted in complete perforation of cell membranes.106,107 However, PIBCA nanoparticles showed no signs of toxicity at the same concentration. This toxicity is probably due to the presence of nanoparticle degradation products in the cytoplasm following their phagocytosis. The low toxicity of isobutyl product is due to its slower degradation than the methyl product. The toxicity and safety data on PBCA nano-particles is somewhat contradictory. Kante et al.106 found LD50 of 230 mg/kg of PBCA nanoparticles injected intravenously in mice. Olivier et al.108 observed a 30-40% mortality rate in mice after the injection of 166 mg/kg of PBCA nanoparticles; some animals died even at low doses. Meanwhile, Simeonova et al.,109 in an investigation of the immunomodulating properties of PBCA nanoparticles in mice, did not report any signs of toxicity at doses as high as 200 mg/kg. A much higher LD50 of 585 mg/kg was found for nanoparticles made of a similar polymer PHCA.110 Gelperina et al.111 reported no mortality in rats even after administering up to 400 mg/kg of empty PBCA nanoparticles.

The implantation into the tissue of monomers, which polymerize within the body in orthopedic surgery and percutaneous minimally invasive radiological procedures, was performed earlier. The polymerization was mostly exothermic, and is associated with the toxicity to the tissue.112,113 The use of n-butylcyanoacrylate in the endovascular treatment of arteriovenous malformations has been well documented.113,114 Implantation of n-butyl-2-cyanoacrylate (NBCA) has resulted in a good occlusive effect on the parenchyma of highly vascular tumors, with extensive intralesional necrosis. The antitumor effect of the NBCA at the implant surface on adjacent tumors appeared limited.115 Histopathological examination of a surgically removed malignant pelvic para-ganglioma after a percutaneous injection of NBCA, three days after the NBCA injection, revealed variable degrees of tumoral necrosis.116 Areas surrounding small volumes of NBCA at the periphery of the tumor showed practically no necrosis, whereas regions inside the tumor plastified with NBCA presented greater degrees of necrosis, especially toward the center of the tumoral mass (Figure 15.3). However, no necrosis was found at a macroscopic level outside the implant, indicating that the NBCA allowed for the destruction of tumor tissue within the heavily plastified areas. The carcinogenic potential of cyanoacrylate adhesive and isobutyl-2-cyanoacrylate were also reported respectively by Matsumoto117 and Samson and Marshal.118 Induction of malignant fibrous histiocytoma in female Fisher rats by implantation of foreign bodies was studied by Hatanaka et al.119 Five kinds of foreign bodies (silicone, cellulose, polyvinyl chloride, and zirconia and alkyl-alpha cyanoacrylate) were implanted into the subcutaneous tissue of female Fisher rats. The tumors developed in almost all the cases was composed of a mixture of cells that resembled fibroblast,

FIGURE 15.3 Uptake by rat brain of i.v. injected doxorubicin loaded to polysorbate 80-coated nanoparticles. Doxorubicin levels in rat brain (mg/g) versus time (min). C Doxorubicin (5 mg/kg) in saline. $ Doxorubicin (5 mg/kg) bound to nanoparticles overcoated with 1% polysorbate 80. (From Gulyaev, A. E. et al., Pharm. Res., 16, 1564, 1999. With permission.)

Time [min]

FIGURE 15.3 Uptake by rat brain of i.v. injected doxorubicin loaded to polysorbate 80-coated nanoparticles. Doxorubicin levels in rat brain (mg/g) versus time (min). C Doxorubicin (5 mg/kg) in saline. $ Doxorubicin (5 mg/kg) bound to nanoparticles overcoated with 1% polysorbate 80. (From Gulyaev, A. E. et al., Pharm. Res., 16, 1564, 1999. With permission.)

Golgi apparatus, histiocytes, myofibroblasts, and immature mesenchymal cells. A rat malignant fibrous histiocytoma transplanted into the subcutaneous tissue of the syngeneic female Fisher rats grew and metastasized to the lungs. Canter et al.120 reported the consecutive pathological findings of a patient who underwent surgery for facial hemangioma after percutaneous injection of NBCA for devascularization of a lesion. The patient underwent additional surgery one month and six months after the initial operation for the removal of the residual NBCA cast from the injection site. Acute inflammatory findings after injection of NBCA and the development of a chronic granulomatous foreign-body reaction support the histological findings of experimental animal studies and postmortem examinations of humans. Though the alkylcyanoacrylates of smaller alkyl chain lengths exhibited considerable toxicity, the alkylcyanoacrylates of larger chain lengths such as isohexylcyanoacrylate nanoparticles resulted in negligible toxicity121 and drove them to their clinical trials.

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