title: Colocalized delivery of rapamycin and paclitaxel to tumors enhances synergistic targeting of the PI3K/Akt/mTOR pathway.
abstract: Ongoing clinical trials target the aberrant PI3K/Akt/mammalian target of rapamycin (mTOR) pathway in breast cancer through administration of rapamycin, an allosteric mTOR inhibitor, in combination with paclitaxel. However, synergy may not be fully exploited clinically because of distinct pharmacokinetic parameters of drugs. This study explores the synergistic potential of site-specific, colocalized delivery of rapamycin and paclitaxel through nanoparticle incorporation. Nanoparticle drug loading was accurately controlled, and synergistic drug ratios established in vitro. Precise drug ratios were maintained in tumors 48 hours after nanoparticle administration to mice, at levels twofold greater than liver and spleen, yielding superior antitumor activity compared to controls. Simultaneous and preferential in vivo delivery of rapamycin and paclitaxel to tumors yielded mechanistic insights into synergy involving suppression of feedback loop Akt phosphorylation and its downstream targets. Findings demonstrate that a same time, same place, and specific amount approach to combination chemotherapy by means of nanoparticle delivery has the potential to successfully translate in vitro synergistic findings in vivo. Predictive in vitro models can be used to determine optimum drug ratios for antitumor efficacy, while nanoparticle delivery of combination chemotherapies in preclinical animal models may lead to enhanced understanding of mechanisms of synergy, ultimately opening several avenues for personalized therapy.
authors.affiliation: Department of Nanomedicine, The Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Elvin
authors.initials: E
authors.lastname: Blanco
authors.affiliation: Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sangai
authors.affiliation: Department of Nanomedicine, The Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Suhong
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Nanomedicine, The Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Hsiao
authors.affiliation: Department of Nanomedicine, The Houston Methodist Research Institute, Houston, Texas, USA; Escuela de Biotecnología y Alimentos y Escuela de Medicina, Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, Mexico.
authors.forename: Guillermo U
authors.initials: GU
authors.lastname: Ruiz-Esparza
authors.affiliation: Department of Nanomedicine, The Houston Methodist Research Institute, Houston, Texas, USA; Escuela de Biotecnología y Alimentos y Escuela de Medicina, Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, Mexico.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Gonzalez-Delgado
authors.affiliation: Department of Nanomedicine, The Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Francisca E
authors.initials: FE
authors.lastname: Cara
authors.affiliation: Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Granados-Principal
authors.affiliation: Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Evans
authors.affiliation: Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Argun
authors.initials: A
authors.lastname: Akcakanat
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Do
authors.affiliation: Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA; Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address: fmeric@mdanderson.org.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Department of Nanomedicine, The Houston Methodist Research Institute, Houston, Texas, USA. Electronic address: mferrari@tmhs.org.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases