title: Dual-targeted and pH-sensitive Doxorubicin Prodrug-Microbubble Complex with Ultrasound for Tumor Treatment.
abstract: In this study, we investigated the potential of a dual-targeted pH-sensitive doxorubicin prodrug-microbubble complex (DPMC) in ultrasound (US)-assisted antitumor therapy. The doxorubicin prodrug (DP) consists of a succinylated-heparin carrier conjugated with doxorubicin (DOX)viahydrazone linkage and decorated with dual targeting ligands, folate and cRGD peptide. Combination of microbubble (MB) and DP, generatedviaavidin-biotin binding, promoted intracellular accumulation and improved therapeutic efficiency assisted by US cavitation and sonoporation. Aggregates of prepared DP were observed with an inhomogeneous size distribution (average diameters: 149.6±29.8 nm and 1036.2±38.8 nm, PDI: 1.0) while DPMC exhibited a uniform distribution (average diameter: 5.804±2.1 μm), facilitating its usage for drug delivery. Notably, upon US exposure, DPMC was disrupted and aggregated DP dispersed into homogeneous small-sized nanoparticles (average diameter: 128.6±42.3 nm, PDI: 0.21). DPMC could target to angiogenic endothelial cells in tumor regionviaαvβ3-mediated recognition and subsequently facilitate its specific binding to tumor cells mediatedviarecognition of folate receptor (FR) after US exposure.In vitroexperiments showed higher tumor specificity and killing ability of DPMC with US than free DOX and DP for breast cancer MCF-7 cells. Furthermore, significant accumulation and specificity for tumor tissues of DPMC with US were detected usingin vivofluorescence and ultrasound molecular imaging, indicating its potential to integrate tumor imaging and therapy. In particular, through inducing apoptosis, inhibiting cell proliferation and antagonizing angiogenesis, DPMC with US produced higher tumor inhibition rates than DOX or DPMC without US in MCF-7 xenograft tumor-bearing mice while inducing no obvious body weight loss. Our strategy provides an effective platform for the delivery of large-sized or aggregated particles to tumor sites, thereby extending their therapeutic applicationsin vivo.
authors.affiliation: Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China;; Guangdong Provincial Key laboratory of cancer immunotherapy research, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wanxian
authors.initials: W
authors.lastname: Luo
authors.affiliation: Imaging center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Wen
authors.affiliation: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Guangdong Provincial Key laboratory of cancer immunotherapy research, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Tang
authors.affiliation: Guangdong Provincial Key laboratory of cancer immunotherapy research, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wang
authors.affiliation: Guangdong Provincial Key laboratory of cancer immunotherapy research, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jihui
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Liling
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Guangdong Provincial Key laboratory of cancer immunotherapy research, Cancer Research Institute, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yingjia
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D051379:Mice; D045423:Microbubbles; D058990:Molecular Targeted Therapy / Q000379:methods*; D053758:Nanoparticles / Q000008:administration & dosage; D061848:Optical Imaging; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013010:Sonication / Q000379:methods*; D016896:Treatment Outcome; D014463:Ultrasonography
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D011355:Prodrugs; D004317:Doxorubicin
keywords: Doxorubicin prodrug; Dual-targeted; Microbubble complex; Ultrasound.; pH-sensitive