Colocalized Delivery of Rapamycin and Paclitaxel to Tumors Enhances Synergistic Targeting of the PI3K/Akt/mTOR Pathway

被引:56
|
作者
Blanco, Elvin [1 ]
Sangai, Takafumi [2 ]
Wu, Suhong [1 ]
Hsiao, Angela [1 ]
Ruiz-Esparza, Guillermo U. [1 ,3 ,4 ]
Gonzalez-Delgado, Carlos A. [1 ,3 ,4 ]
Cara, Francisca E. [1 ]
Granados-Principal, Sergio [5 ]
Evans, Kurt W. [2 ,6 ]
Akcakanat, Argun [2 ]
Wang, Ying [7 ]
Do, Kim-Anh [8 ]
Meric-Bernstam, Funda [2 ,6 ]
Ferrari, Mauro [1 ]
机构
[1] Houston Methodist Res Inst, Dept Nanomed, Houston, TX 77030 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA
[3] Inst Tecnol & Estudios Super Monterrey, Escuela Biotecnol & Alimentos, Monterrey, Mexico
[4] Inst Tecnol & Estudios Super Monterrey, Escuela Med, Monterrey, Mexico
[5] Houston Methodist Hosp, Houston Methodist Canc Ctr, Houston, TX USA
[6] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA
[7] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA
[8] Univ Texas Houston, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA
关键词
MAMMALIAN TARGET; BREAST-CANCER; PHASE-II; MTOR; AKT; MICELLES; AGENTS; DOXORUBICIN; EVEROLIMUS; MUTATIONS;
D O I
10.1038/mt.2014.27
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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.
引用
收藏
页码:1310 / 1319
页数:10
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