title: Synergistic antitumor activity of a self-assembling camptothecin and capecitabine hybrid prodrug for improved efficacy.
abstract: The direct use of anticancer drugs to create their own nanostructures is an emerging concept in the field of drug delivery to obtain nanomedicines of high drug loading and high reproducibility, and the combination use of two or more drugs has been a proven clinical strategy to enhance therapeutic outcomes. We report here the synthesis, assembly and cytotoxicity evaluation of self-assembling hybrid prodrugs containing both camptothecin (CPT) and a capecitabine (Cap) analogue. CPT and Cap molecules were conjugated onto a short β-sheet-forming peptide (Sup35) to yield three different self-assembling prodrugs (dCPT-Sup35, CPT-Cap-Sup35 and dCap-Sup35). We found that the chemical structure of conjugated drugs could strongly influence their assembled morphology as well as their structural stability in aqueous solution. With a decrease in number of CPT units, the resulting nanostructures exhibited a morphological transformation from nanofibers (dCPT-Sup35) to filaments (CPT-Cap-Sup35) then to spherical particles (dCap-Sup35). Notably, the hybrid CPT-Cap prodrug showed a synergistic effect and significantly enhanced potency against three esophageal adenocarcinoma cell lines compared with the two homo-prodrugs (dCPT-Sup35 and dCap-Sup35) as well as free parent drugs (CPT, 5-Fu and CPT/5-FU mixture (1:1)). We believe this work represents a conceptual advancement in integrating two structurally distinct drugs of different action mechanisms into a single self-assembling hybrid prodrug to construct self-deliverable nanomedicines for more effective combination chemotherapy.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Eastern Road, Zhengzhou 450052, Henan, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Ma
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Cheetham
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Eastern Road, Zhengzhou 450052, Henan, China.
authors.forename: Weifang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Yuzhu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Eastern Road, Zhengzhou 450052, Henan, China. Electronic address: quanchengk0371@sina.com.
authors.forename: QuanCheng
authors.initials: Q
authors.lastname: Kan
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Eastern Road, Zhengzhou 450052, Henan, China; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore, MD 21231, USA. Electronic address: hcui6@jhu.edu.
authors.forename: Honggang
authors.initials: H
authors.lastname: Cui
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry; D002166:Camptothecin / Q000008:administration & dosage* / Q000737:chemistry; D000069287:Capecitabine / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D065546:Drug Liberation; D006801:Humans; D046529:Microscopy, Electron, Transmission; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D000069287:Capecitabine; D002166:Camptothecin
keywords: Camptothecin; Capecitabine; Chemotherapy; Drug conjugate; Drug delivery