title: Co-loaded paclitaxel/rapamycin liposomes: Development, characterization and in vitro and in vivo evaluation for breast cancer therapy.
abstract: Paclitaxel and rapamycin have been reported to act synergistically to treat breast cancer. Albeit paclitaxel is available for breast cancer treatment, the most commonly used formulation in the clinic presents side effects, limiting its use. Furthermore, both drugs present pharmacokinetics drawbacks limiting their in vivo efficacy and clinic combination. As an alternative, drug delivery systems, particularly liposomes, emerge as an option for drug combination, able to simultaneously deliver co-loaded drugs with improved therapeutic index. Therefore, the purpose of this study is to develop and characterize a co-loaded paclitaxel and rapamycin liposome and evaluate it for breast cancer efficacy both in vitro and in vivo. Results showed that a SPC/Chol/DSPE-PEG (2000) liposome was able to co-encapsulate paclitaxel and rapamycin with suitable encapsulation efficiency values, nanometric particle size, low polydispersity and neutral zeta potential. Taken together, FTIR and thermal analysis evidenced drug conversion to the more bioavailable molecular and amorphous forms, respectively, for paclitaxel and rapamycin. The pegylated liposome exhibited excellent colloidal stability and was able to retain drugs encapsulated, which were released in a slow and sustained fashion. Liposomes were more cytotoxic to 4T1 breast cancer cell line than the free drugs and drugs acted synergistically, particularly when co-loaded. Finally, in vivo therapeutic evaluation carried out in 4T1-tumor-bearing mice confirmed the in vitro results. The co-loaded paclitaxel/rapamycin pegylated liposome better controlled tumor growth compared to the solution. Therefore, we expect that the formulation developed herein might be a contribution for future studies focusing on the clinical combination of paclitaxel and rapamycin.
authors.affiliation: College of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Avenida do Cafe s/n, 14040-903 Ribeirao Preto, SP, Brazil; College of Pharmacy, The Ohio State University, Columbus, 500W 12th Ave, Columbus, OH 43210, United States.
authors.forename: Josimar O
authors.initials: JO
authors.lastname: Eloy
authors.affiliation: College of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Avenida do Cafe s/n, 14040-903 Ribeirao Preto, SP, Brazil; College of Pharmacy, The Ohio State University, Columbus, 500W 12th Ave, Columbus, OH 43210, United States.
authors.forename: Raquel
authors.initials: R
authors.lastname: Petrilli
authors.affiliation: College of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Avenida do Cafe s/n, 14040-903 Ribeirao Preto, SP, Brazil.
authors.forename: José Fernando
authors.initials: JF
authors.lastname: Topan
authors.affiliation: School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Avenida Bandeirantes s/n, 14040-040 Ribeirao Preto, SP, Brazil.
authors.forename: Heriton Marcelo Ribeiro
authors.initials: HMR
authors.lastname: Antonio
authors.affiliation: College of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Avenida do Cafe s/n, 14040-903 Ribeirao Preto, SP, Brazil.
authors.forename: Juliana Palma Abriata
authors.initials: JPA
authors.lastname: Barcellos
authors.affiliation: School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Avenida Bandeirantes s/n, 14040-040 Ribeirao Preto, SP, Brazil.
authors.forename: Deise L
authors.initials: DL
authors.lastname: Chesca
authors.affiliation: School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Avenida Bandeirantes s/n, 14040-040 Ribeirao Preto, SP, Brazil.
authors.forename: Luciano Neder
authors.initials: LN
authors.lastname: Serafini
authors.affiliation: School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Avenida Bandeirantes s/n, 14040-040 Ribeirao Preto, SP, Brazil.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tiezzi
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, 500W 12th Ave, Columbus, OH 43210, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: College of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Avenida do Cafe s/n, 14040-903 Ribeirao Preto, SP, Brazil. Electronic address: jmarchet@usp.br.
authors.forename: Juliana Maldonado
authors.initials: JM
authors.lastname: Marchetti
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D008081:Liposomes / Q000737:chemistry*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D020123:Sirolimus / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017550:Spectroscopy, Fourier Transform Infrared; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D008081:Liposomes; D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols; D017239:Paclitaxel; D020123:Sirolimus
keywords: Breast cancer; Co-loading; Liposomes; Paclitaxel; Rapamycin
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