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Self‐Assembly of an Amphiphilic Janus Camptothecin–Floxuridine Conjugate into Liposome‐Like Nanocapsules for More Efficacious Combination Chemotherapy in Cancer
Author(s) -
Liang Xiaolong,
Gao Chuang,
Cui Ligang,
Wang Shumin,
Wang Jinrui,
Dai Zhifei
Publication year - 2017
Publication title -
advanced materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 10.707
H-Index - 527
eISSN - 1521-4095
pISSN - 0935-9648
DOI - 10.1002/adma.201703135
Subject(s) - camptothecin , nanocapsules , floxuridine , amphiphile , liposome , conjugate , drug delivery , materials science , drug , combinatorial chemistry , pentaerythritol , drug carrier , lipophilicity , pharmacology , chemistry , nanotechnology , biophysics , stereochemistry , organic chemistry , cancer , nanoparticle , fluorouracil , medicine , copolymer , biology , polymer , mathematical analysis , mathematics , fire retardant
The combination of camptothecin (CPT) and fluoropyrimidine derivatives acts synergistically at a 1:1 molar ratio. Practically, the greatest challenge is the development of a single liposomal formulation that can both encapsulate and maintain this drug combination at an exact 1:1 ratio to achieve coordinated pharmacokinetics. Consequently, a new type of liposome‐like nanocapsule (NC) is developed from a highly symmetric Janus camptothecin–floxuridine conjugate (JCFC) amphiphile, which is synthesized by coupling two hydrophobic CPT molecules and two hydrophilic floxuridine (FUDR) molecules to multivalent pentaerythritol via a hydrolyzable ester linkage. JCFC NCs possess remarkably high drug‐loading contents, and no premature release because of the highly stable co‐delivery of the drug combination without the need for any carrier. It is shown that JCFC NCs consistently provide synergy and avoid antagonism in a broad panel of tumor cell lines. In vivo delivery of JCFC NCs leads to longer blood retention half‐life, higher tumorous accumulation and cellular uptake of drugs, and greatly enhanced efficacy in murine tumor models compared to CPT, FUDR, and CPT + FUDR. This liposomal strategy can be extended to other hydrophilic and hydrophobic anticancer drugs that are coupled to pentaerythritol to self‐assemble into nanocapsules for drug self‐delivery, pointing to potential clinical translation in near future.