title: Synergistic anti-tumor activity through combinational intratumoral injection of an in-situ injectable drug depot.
abstract: Here, we describe combinational chemotherapy via intratumoral injection of doxorubicin (Dox) and 5-fluorouracil (Fu) to enhance the efficacy and reduce the toxicity of systemically administered Fu and Dox in cancer patients. As the key concept in this work, mixture formulations of Dox-loaded microcapsules (Dox-M) and Fu-loaded Pluronic(®) hydrogels (Fu-HP) or Fu-loaded diblock copolymer hydrogels (Fu-HC) have been employed as drug depots. The in vitro and in vivo drug depot was designed as a formulation of Dox-M dispersed inside an outer shell of Fu-HP or Fu-HC after injection. The Dox-M/Fu-HP and Dox-M/Fu-HC formulations are free flowing at room temperature, indicating injectability, and formed a structural gelatinous depot in vitro and in vivo at body temperature. The Fu-HP, Fu-HC, Dox-M/Fu-HP, Dox-M/Fu-HC, and Dox-M formulations were easily injected into tumor centers in mice using a needle. Dox-M/Fu-HC produced more significant inhibitory effects against tumor growth than that by Dox-M/Fu-HP, while Fu-HP, Fu-HC and Dox-M had the weakest inhibitory effects of the tested treatments. The in vivo study of Dox and Fu biodistribution showed that high Dox and Fu concentrations were maintained in the target tumor only, while distribution to normal tissues was not observed, indicating that Dox and Fu concentrations below their toxic plasma concentrations should not cause significant systemic toxicity. The Dox-M/Fu-HP and Dox-M/Fu-HC drug depots described in this work showed excellent performance as chemotherapeutic delivery systems. The results reported here indicate that intratumoral injection using combination chemotherapy with Dox-M/Fu-HP or Dox-M/Fu-HC could be of translational research by enhancing the synergistic inhibitory effects of Dox and Fu on tumor growth, while reducing their systemic toxicity in cancer patients.
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-759, Republic of Korea.
authors.forename: Da Yeon
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-759, Republic of Korea.
authors.forename: Doo Yeon
authors.initials: DY
authors.lastname: Kwon
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-759, Republic of Korea.
authors.forename: Jin Seon
authors.initials: JS
authors.lastname: Kwon
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-759, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-759, Republic of Korea.
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-759, Republic of Korea.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Oh
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-759, Republic of Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-759, Republic of Korea.
authors.forename: Byoung Hyun
authors.initials: BH
authors.lastname: Min
authors.affiliation: Departments of Biomedical Engineering and Pharmaceutics, Purdue University, IN 47907-1791, USA.
authors.forename: Kinam
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-759, Republic of Korea. Electronic address: moonskim@ajou.ac.kr.
authors.forename: Moon Suk
authors.initials: MS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D020100:Hydrogels / Q000737:chemistry; D015552:Injections, Intralesional; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy*; D011108:Polymers / Q000737:chemistry; D012212:Rheology; D014018:Tissue Distribution; D014783:Viscosity
chemical_list: D000970:Antineoplastic Agents; D020100:Hydrogels; D011108:Polymers; D004317:Doxorubicin; D005472:Fluorouracil
keywords: 5-Fluorouracil; Doxorubicin; Injectable depot; Intratumoral injection; Tumors