title: Simultaneous delivery of siRNA and paclitaxel via a "two-in-one" micelleplex promotes synergistic tumor suppression.
abstract: Combination of two or more therapeutic strategies with different mechanisms can cooperatively prohibit cancer development. Combination of chemotherapy and small interfering RNA (siRNA)-based therapy represents an example of this approach. Hypothesizing that the chemotherapeutic drug and the siRNA should be simultaneously delivered to the same tumoral cell to exert their synergistic effect, the development of delivery systems that can efficiently encapsulate two drugs and successfully deliver payloads to targeted sites via systemic administration has proven to be challenging. Here, we demonstrate an innovative "two-in-one" micelleplex approach based on micellar nanoparticles of a biodegradable triblock copolymer poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) to systemically deliver the siRNA and chemotherapeutic drug. We show clear evidence that the micelleplex is capable of delivering siRNA and paclitaxel simultaneously to the same tumoral cells both in vitro and in vivo. We further demonstrate that systemic administration of the micelleplex carrying polo-like kinase 1 (Plk1) specific siRNA and paclitaxel can induce a synergistic tumor suppression effect in the MDA-MB-435s xenograft murine model, requiring a thousand-fold less paclitaxel than needed for paclitaxel monotherapy delivered by the micelleplex and without activation of the innate immune response or generation of carrier-associated toxicity.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, P.R. China.
authors.forename: Tian-Meng
authors.initials: TM
authors.lastname: Sun
authors.forename: Jin-Zhi
authors.initials: JZ
authors.lastname: Du
authors.forename: Yan-Dan
authors.initials: YD
authors.lastname: Yao
authors.forename: Cheng-Qiong
authors.initials: CQ
authors.lastname: Mao
authors.forename: Shuang
authors.initials: S
authors.lastname: Dou
authors.forename: Song-Yin
authors.initials: SY
authors.lastname: Huang
authors.forename: Pei-Zhuo
authors.initials: PZ
authors.lastname: Zhang
authors.forename: Kam W
authors.initials: KW
authors.lastname: Leong
authors.forename: Er-Wei
authors.initials: EW
authors.lastname: Song
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry; D004357:Drug Synergism; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000378:metabolism* / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D004337:Drug Carriers; D008823:Micelles; D017239:Paclitaxel; D011108:Polymers; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1