BACKGROUND: Topical chemotherapy of skin cancers is a promising strategy for reduction of side effects and for improvement of patient compliance. The combination of the chemotherapeutic 5-fluouracil (5-FU) and the anti- EGFR antibody cetuximab is a strategy to inhibit tumor growth. Their skin penetration, however, is hampered by their high hydrophilicity, which could be improved by encapsulation in delivery systems. Furthermore, it is a challenge to encapsulate hydrophilic drugs. The conjugation of an antibody to a liposome, maintaining its activity, is also a difficult task. OBJECTIVE: Thus, we aimed to develop 5-FU liposomes and cetuximab-conjugated liposomes (immunoliposomes) of 5- FU to improve drug cytotoxicity against skin cancer cells. METHOD: We characterized them by particle size, zeta potential, loading efficiency and antibody integrity. To optimize the loading efficiency of 5-FU, a series of liposomes were prepared, using different methods and drug-to-lipid ratios. RESULTS: Liposomes containing DSPC and Chol at drug-to-lipid ratio 0.1 prepared by the thin lipid hydration method resulted in the best 5-FU encapsulation and were chosen to conjugate with cetuximab. Cetuximab was directly coupled to preformed liposomes using DSPE-mPEG2000-Mal as an anchor. In A431 skin carcinoma cells, at 72 h, 5-FU liposomes showed a 5-fold lower IC50 than 5-FU solution. Additionally, 5-FU immunoliposomes resulted in a 4-fold lower cetuximab IC50 than cetuximab solution, demonstrating synergism with a combination index lower than 1 and potential to improve 5-FU and cetuximab cytotoxicity. CONCLUSION: Liposomes and immunoliposomes containing 5-FU were developed and cetuximab remained active as demonstrated in cell culture studies.
BACKGROUND: Topical chemotherapy of skin cancers is a promising strategy for reduction of side effects and for improvement of patient compliance. The combination of the chemotherapeutic 5-fluouracil (5-FU) and the anti- EGFR antibody cetuximab is a strategy to inhibit tumor growth. Their skin penetration, however, is hampered by their high hydrophilicity, which could be improved by encapsulation in delivery systems. Furthermore, it is a challenge to encapsulate hydrophilic drugs. The conjugation of an antibody to a liposome, maintaining its activity, is also a difficult task. OBJECTIVE: Thus, we aimed to develop 5-FU liposomes and cetuximab-conjugated liposomes (immunoliposomes) of 5- FU to improve drug cytotoxicity against skin cancer cells. METHOD: We characterized them by particle size, zeta potential, loading efficiency and antibody integrity. To optimize the loading efficiency of 5-FU, a series of liposomes were prepared, using different methods and drug-to-lipid ratios. RESULTS: Liposomes containing DSPC and Chol at drug-to-lipid ratio 0.1 prepared by the thin lipid hydration method resulted in the best 5-FU encapsulation and were chosen to conjugate with cetuximab. Cetuximab was directly coupled to preformed liposomes using DSPE-mPEG2000-Mal as an anchor. In A431skin carcinoma cells, at 72 h, 5-FU liposomes showed a 5-fold lower IC50 than 5-FU solution. Additionally, 5-FU immunoliposomes resulted in a 4-fold lower cetuximab IC50 than cetuximab solution, demonstrating synergism with a combination index lower than 1 and potential to improve 5-FU and cetuximabcytotoxicity. CONCLUSION: Liposomes and immunoliposomes containing 5-FU were developed and cetuximab remained active as demonstrated in cell culture studies.
Authors: Seung Jin Lee; Seog Young Kim; Jin Hwa Chung; Seung Jun Oh; Jin Sook Ryu; Yong Sang Hong; Tae Won Kim; Dae Hyuk Moon Journal: Biochem Pharmacol Date: 2010-08-17 Impact factor: 5.858
Authors: Vladimir Ratushny; Igor Astsaturov; Barbara A Burtness; Erica A Golemis; Joshua S Silverman Journal: Cell Signal Date: 2009-03-01 Impact factor: 4.315
Authors: Ana M T D P V Cabral; Ana C G Fernandes; Neuza A M Joaquim; Francisco Veiga; Sara P C Sofio; Isabel Paiva; Miguel A Esteso; M Melia Rodrigo; Artur J M Valente; Ana C F Ribeiro Journal: Toxics Date: 2022-06-01