Drug Delivery in Cancer with Poly Alkyl Cyanoacrylate Nanoparticles 15261 Targeting to Cancer Cells and Tissues

Increase in the antitumoral activity of many anti-cancer drugs was also observed when loaded in polyisohexylcyanoacrylate nanoparticles. A study123 conducted with doxorubicin-loaded polyiso-hexylcyanoacrylate nanoparticles administered i.v. to the C57BL/6 mice consisting of metastases induced by i.v. inoculation of reticulosarcoma M5076 cell suspension showed a dramatic increase in the antitumoral activity of the drug. Doxorubicin measurements in healthy hepatic or neoplastic tissue, carried out with histological examinations using TEM, demonstrated that the hepatic tissue is an efficient reservoir of the drug when it was injected in association with nanoparticles. Accumulation of doxorubicin-associated nanoparticles suggests that the Kupffer cells created a gradient of drug concentration for a massive and prolonged diffusion of the free drug toward the neoplastic tissue. The negatively charged mitoxantrone PBCA nanoparticles (DHAQ-PBCA-NP) prepared by

EP method124 following intravenous administration were concentrated mainly in liver tumors. The accumulation of DHAQ-PBCA-NP was higher in the liver tumors than in the liver tissue. Yang et al.125 compared antitumor activity of mitoxantrone (DHAQ) and mitoxantrone-polybutyl cyanoa-crylate-nanosphere (DHAQ-PBCA-NS) against experimental liver tumor H22 in mice. The results of antitumor activity determination of both drugs with different treatment schedules showed DHAQ-PBCA-NS to present higher activity than DHAQ; DHAQ-PBCA-NS is possessed of liver-targeting property.

Soma et al.126 demonstrated that the Doxorubicin-loaded PACA nanoparticles are more efficient than free drugs in mice bearing hepatic metastasis of the M5076 tumor. High phagocytic activity of Kupffer cells in the liver played the role of drug reservoir after nanoparticle phagocytosis. The study also assessed the role of macrophages in mediating the cytotoxicity of doxorubicin-loaded nanoparticles on M5076 cells. After the phagocytosis of the doxorubicin-loaded nanoparticles, J774.A1 cells were able to release the active drug, allowing it to exert its cytotoxicity against M5076 cells. Intracellular accumulation and DNA binding of doxorubicin encapsulated in PIHCA nanospheres and of daunorubicin bound to polyglutamic acid (DGA) in comparison with free Dox and daunorubicin was studied by Bogush et al.127 using methods involving interaction between an anthracycline and cellular DNA to understand how the drug reaches its nuclear targets. The results showed that the intracellular accumulation and DNA binding of Dox-loaded nanospheres and DGA are reduced by 30-40% in comparison with those obtained for free doxorubicin and daunorubicin, respectively.

Studies by Bennis et al.128 on the cytotoxicity and accumulation of doxorubicin encapsulated in PIHCA nanospheres in a model of doxorubicin-resistant rat glioblastoma variants revealed that the cytotoxicity differed with the degree of resistance to this drug. The nanoparticle associated Dox was more cytotoxic than the free Dox, whereas co-administration of drug-free nanoparticles with free Dox did not significantly modify the cytotoxicity of Dox. However, Simeonova and Antcheva129 reported that the cytotoxic activities of drug-free PBCA nanoparticles free of vinblastine, vinblas-tine-loaded nanoparticles (by incorporation and adsorption processes), and a mixture of vinblastine-free and drug-free PBCA nanoparticles, when compared in vitro on human erythroleukemic K-562 cells, showed enhanced cytotoxicity when vinblastine was either adsorbed on PBCA or mixed with them rather than free. When vinblastine was incorporated into the polymer matrix of nanoparticles, a lag period and a postponed cytotoxic effect on K-562 cells was observed. Preclinical studies121 in 21 patients with refractory solid tumors also confirmed an increase in doxorubicin cytotoxicity and a decrease in cardiotoxicity when incorporated into biodegradable PIHCA by modifying tissue distribution. In clinical studies130 conducted on 21 patients with Stages III-IV maxillary tumors, antitumor drugs deposited with a cyanoacrylate adhesive solution showed immediate and late results of therapy. This evidence of deposition of the drug and its regulated elimination from the composition helps create a high concentration of the agent at the operation site where the tumor elements remained after surgery.

Pan et al.131 demonstrated the higher efficacy of 5-FU when loaded into PBCA nanocapsules with a diameter of 338 nm, compared to the free drug in S180, HepS, and EAC tumors.

The in vitro and in vivo antihepatoma effects of the liver-targeted drug delivery system lyophi-lized aclacinomycin-A loaded polyisobutylcyanoacrylate nanoparticle (ACM-IBC-NP) was found to be significantly concentration dependent.132 The antihepatoma activity of lyophilized ACM-IBC-NP was higher than that of the aclacinomycin-A. Similarly, actinomycin-D absorbed into polymethylcyanoacrylate nanoparticles showed increased efficiency against an experimental tumor in comparison to the free drug.133

The antitumor efficacy of a medical-grade cyanoacrylate adhesive MK-8-based composition with prospidin has been studied by Chissov et al.,134 and the kinetics of the drug elimination have been followed up in a rat model. The findings showed a prolongation of the relapse-free period and a longer survival of the experimental animals. Clinical trials of the composition carried out in 70 patients with esophageal carcinomas showed local disseminated forms in 52 patients. Application of the adhesive composition has not increased the rate of postoperative complications; in some cases, the life span of patients after palliative surgery was considerably longer. In a study by Perez et al.135 using an N-butyl-2-cyano acrylate-based tissue adhesive, Tisuacryl, as a nonsuture method for closing wounds in oral surgery involving apicectomy, molar extractions, and mucogingival grafting, the adhesive was well tolerated by the tissue and permitted immediate hemostasis and normal healing of incisions.

Association of 5-FU to PBCA nanoparticles also showed enhanced efficacy against Crocker sarcoma S 180 and a higher toxicity of the drug, as measured by induced leukopenia, body weight loss, and premature death.31 The efficacy was further increased by an increase in the polymer-to-drug ratio. The nanoparticles yielded a prolonged persistence of the 5-FU in all organs examined, including the tumor.

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