title: An iTEP-salinomycin nanoparticle that specifically and effectively inhibits metastases of 4T1 orthotopic breast tumors.
abstract: Cancer stem cell (CSC) inhibitors are a new category of investigational drugs to treat metastasis. Salinomycin (Sali) is one of most studied CSC inhibitors and has reached clinical tests. Several drug carriers have been developed to improve efficacy of Sali. However, Sali has not been shown to inhibit metastasis from orthotopic tumors, the gold standard for metastasis. To fill this gap, we developed an immune-tolerant, elastin-like polypeptide (iTEP)-based nanoparticle (iTEP-Sali-ABA NP) that released 4-(aminomethyl)benzaldehyde-modified Sali (Sali-ABA) under acidic conditions. We found that the NP increased the area under the curve (AUC) of Sali-ABA by 30-fold and the tumor accumulation by 3.4-fold. Furthermore, no metastasis was detected in any of the mice given the NP. However, all the mice died of primary tumor burdens. To overcome primary tumor growth and improve the overall survival, we applied a combination therapy consisting of the iTEP-Sali-ABA NP and iTEP NP-delivered paclitaxel. This therapy effectively retarded primary tumor growth, and most importantly, improved the overall survival. In conclusion, delivery of Sali-ABA by the NP, alone or in combination with paclitaxel, was more effective than free Sali-ABA in decreasing metastasis and increasing survival. This iTEP-Sali-ABA NP represents a novel and clinically promising therapy to combat metastasis.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei 430071, China.
authors.forename: Guiquan
authors.initials: G
authors.lastname: Xia
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Shuyun
authors.initials: S
authors.lastname: Dong
authors.affiliation: School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei 430071, China.
authors.forename: Zhaong-Xing
authors.initials: ZX
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: Mingnan.chen@utah.edu.
authors.forename: Mingnan
authors.initials: M
authors.lastname: Chen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001547:Benzaldehydes / Q000138:chemical synthesis / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004549:Elastin / Q000737:chemistry*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000737:chemistry*; D011714:Pyrans / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014018:Tissue Distribution; D000095662:Polyether Polyketides
chemical_list: D001547:Benzaldehydes; D004549:Elastin; D017239:Paclitaxel; D010455:Peptides; D011714:Pyrans; C005176:4-dimethylaminomethylbenzaldehyde; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: Breast cancer; Cancer stem cell; Immune-tolerant elastin-like polypeptides (iTEP) nanoparticle; Metastasis; Salinomycin