Encapsulation of cisplatin in long-circulating and pH-sensitive liposomes improves its antitumor effect and reduces acute toxicity

Abstract

Elaine A Leite,1,2 Cristina M Souza,3 Álvaro D Carvalho-Júnior,1,2 Luiz GV Coelho,4 Ângela MQ Lana,5 Geovanni D Cassali,3 Mônica C Oliveira11Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; 2Departamento de Farmácia, Faculdade de Ciências Biológicas e da Saúde, Universidade Federal dos Vales do Jequitinhonha e Mucuri, Diamantina, Minas Gerais, Brazil; 3Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; 4Departamento de Clínica Médica, Instituto Alfa de Gastroenterologia, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; 5Departamento de Zootecnia, Escola de Veterinária, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, BrazilAbstract: Cisplatin (CDDP) is one of the most effective and potent anticancer drugs used as first-line chemotherapy against several solid tumors. However, the severe side effects and its tendency to provoke chemoresistance often limit CDDP therapy. To avoid these inconveniences, the present study's research group developed long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP). The present study aimed to evaluate the antitumor effect and toxicity of SpHL-CDDP, as compared with that of free CDDP, and long-circulating and non-pH-sensitive liposomes containing CDDP (NSpHL-CDDP), after their intravenous administration in solid Ehrlich tumor-bearing mice. Antitumor activity was evaluated by analysis of tumor volume and growth inhibition ratio, serum vascular endothelial growth factor (VEGF) levels, and histomorphometric and immunohistochemical studies. Body weight variation and the histological examination of bone marrow and kidneys were used as toxicity indicators. A significant reduction in the tumor volume and a higher tumor growth inhibition ratio was observed after SpHL-CDDP treatment, compared with free CDDP and NSpHL-CDDP treatments. In addition, complete remission of the tumor was detected in 18.2% of the mice treated with SpHL-CDDP (16 mg/kg). As such, the administration of SpHL-CDDP, as compared with free CDDP and NSpHL-CDDP, led to a decrease in the area of necrosis and in the percentage of positive CDC 47 tumor cells. A significant reduction in the VEGF serum level was also observed after SpHL-CDDP treatment, as compared with free-CDDP treatment. SpHL-CDDP administered in a two-fold higher dose than that of free CDDP presented a loss in body weight and changes in the hematopoietic tissue morphology, which proved to be similar to that of free CDDP. No changes could be verified in the renal tissue after any formulations containing CDDP had been administered. These findings showed that SpHL-CDDP allowed for the administration of higher doses of CDDP, significantly improving its antitumor effect.Keywords: antitumor effect, toxicity, angiogenesis, Ehrlich tumor