title: Tunable release of chemotherapeutic and vascular disrupting agents from injectable fiber fragments potentiates combination chemotherapy.
abstract: Cancer progression and metastasis relies much on vasculature networks in tumor microenvironment, and the combination treatment with chemotherapeutic drugs and vascular disrupting agents represents apparent clinical benefits. In the current study, fiber fragments with loadings of hydroxycamptothecin (HCPT) or combretastatin A-4 (CA4) were proposed for tumor inhibition and blood vessel disruption after local administration in tumors. To address challenges in balancing the disruption of tumor vessels and intratumoral uptake of chemotherapeutic agents, this study is focus on release tuning of HCPT and CA4 from the fiber fragment mixtures. Hydroxypropyl-β-cyclodextrin (HPCD) was blended at ratios from 0 to 10% into CA4-loaded fiber fragments (Fc) to modulate CA4 release durations from 0.5 to 24days, and HCPT-loaded fiber fragments (Fh) indicated a sustained release for over 35days. In vitro cytotoxicity tests indicated a sequential inhibition on the endothelial and tumor cell growth, and the growth inhibition of tumor cells was more significant after treatment with mixtures of Fh and Fc containing 2% HPCD (Fc2) than that of other mixtures. In an orthotopic breast tumor model, compared with those of free CA4, or Fc with a fast or slow release of CA4, Fh/Fc mixtures with CA4 release durations from 2 to 12days indicated a lower tumor growth rate, a prolonged animal survival, a lower vessel density in tumors, and a less significant tumor metastasis. In addition, the tumor cell proliferation rate, hypoxia-inducible factor-1α expression within tumors, and the number of surface metastatic nodules in lungs were significantly lower after treatment with Fh/Fc2 mixtures with a CA4 release duration of 5days than those of other mixtures. It demonstrates the advantages of fiber fragment mixtures in independently modulating the release of multiple drugs and the essential role of release tuning of chemotherapeutic drugs and vascular disrupting agents in improving the therapeutic efficacy.
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China; Department of Public Health, Chengdu Medical College, Chengdu 610500, PR China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Luo
authors.affiliation: Emergency Department, Chengdu Military General Hospital, Chengdu 610083, PR China.
authors.forename: Guisen
authors.initials: G
authors.lastname: Xu
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
authors.forename: Jiaojun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
authors.forename: Maohua
authors.initials: M
authors.lastname: Chen
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China. Electronic address: xhli@swjtu.edu.cn.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001632:Bibenzyls / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D065546:Drug Liberation; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects; D047392:beta-Cyclodextrins / Q000008:administration & dosage
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001632:Bibenzyls; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C040105:combretastatin; D002166:Camptothecin
keywords: Antitumor efficacy; Blood vessel disruption; Injectable fiber fragment; Metastasis inhibition; Release duration