title: Real-time near-infrared bioimaging of a receptor-targeted cytotoxic dendritic theranostic agent.
abstract: Efficient and site-specific delivery of anticancer drugs to tumors is important in the development of effective cancer chemotherapy. As an undecapeptide of the tachykinin neuropeptide family, the substance P (SP)/neurokinin-1 receptor (NK1R) system has been identified as a promising ligand-receptor pair in tumor-specific drug delivery. However, the rational design of suitable theranostic agents with high drug loading capacity and tumor targeting for cancer patients remains a great challenge. Herein, we report a dendritic strategy that utilizes the two amine functionalities of lysine to create branch points that allow conjugation of the anticancer drug 5-fluorouracil (5-FU) to the tumor-targeting ligand substance P, along with an additional near-infrared (NIR) squaraine dye, to construct a theranostic dendritic agent, P-FU 4. This cytotoxic theranostic agent, containing four carboxyl-modified 5-FU molecules, has several desirable advantages: i) the ability to self-assemble into nanoparticles; ii) enhanced cytotoxicity with high drug loading capacity (16%) and a specific receptor-targeted interaction with NK1R through the SP moiety; and iii) a high NIR squaraine fluorescence efficiency due to the specific dendron isolation, avoiding aggregation-mediated quenching. As demonstrated in this report, the cytotoxic activity of P-FU 4 is dose-dependent against the tested cancer cells. The improved drug loading capacity with dendritic branching distinctly enhanced cytotoxicity to tumor cells but had little effect on the viability of normal cells. P-FU 4 was preferentially taken up by tumor cells through a receptor-mediated interaction, which was monitored by effective NIR fluorescence with high tissue penetration. Studies using a mouse model revealed that P-FU 4 can significantly inhibit tumor progression, with a tumor-inhibition rate of 60.2%. The receptor-targeted cytotoxic dendritic theranostic agent is highly preferable to standard chemotherapeutic treatments and decreases the negative side effects of medications on healthy cells, which establishes its utility in drug delivery and cancer chemotherapy.
authors.affiliation: Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Shanghai Key Laboratory of Functional Materials Chemistry, Collaborative Innovation Centre for Coal Based Energy (i-CCE), School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Junchen
authors.initials: J
authors.lastname: Wu
authors.affiliation: Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Shanghai Key Laboratory of Functional Materials Chemistry, Collaborative Innovation Centre for Coal Based Energy (i-CCE), School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Yuren
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Shanghai Key Laboratory of Functional Materials Chemistry, Collaborative Innovation Centre for Coal Based Energy (i-CCE), School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Shang
authors.initials: S
authors.lastname: Li
authors.affiliation: Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Shanghai Key Laboratory of Functional Materials Chemistry, Collaborative Innovation Centre for Coal Based Energy (i-CCE), School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Dahui
authors.initials: D
authors.lastname: Qu
authors.affiliation: Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Shanghai Key Laboratory of Functional Materials Chemistry, Collaborative Innovation Centre for Coal Based Energy (i-CCE), School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China. Electronic address: whzhu@ecust.edu.cn.
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Zhu
authors.affiliation: Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Shanghai Key Laboratory of Functional Materials Chemistry, Collaborative Innovation Centre for Coal Based Energy (i-CCE), School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: He
authors.initials: H
authors.lastname: Tian
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003199:Computer Systems; D003503:Cyclobutanes / Q000737:chemistry*; D050091:Dendrimers / Q000737:chemistry; D005260:Female; D005456:Fluorescent Dyes; D005472:Fluorouracil / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D007259:Infrared Rays; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism; D010636:Phenols / Q000737:chemistry*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013373:Substance P / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000068936:Theranostic Nanomedicine / Q000379:methods; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D003503:Cyclobutanes; D050091:Dendrimers; D005456:Fluorescent Dyes; D053769:Nanocapsules; D058726:Nanoconjugates; D010636:Phenols; D018040:Receptors, Neurokinin-1; C480596:squaraine; D013373:Substance P; D005472:Fluorouracil
keywords: 5-fluorouracil; Anticancer; Near-infrared imaging; Neurokinin-1 receptor; Substance P