title: Codelivery of doxorubicin-containing thermosensitive hydrogels incorporated with docetaxel-loaded mixed micelles enhances local cancer therapy.
abstract: Doxorubicin (DOX) thermosensitive hydrogels (TSHs) incorporated with docetaxel (DOC)-loaded mixed micelles were developed to co-deliver these two drugs through a TSH system, DH700kMF-13.5/M-DocLF, to improve local cancer therapy and reduce side effects. First, Pluronics-based DOC-loaded mixed micelles were developed and optimized. The optimal formulation designated as M-DocLF was composed of 1mg/g docetaxel, 15mg/g Pluronic F127 (PF127), and 45mg/g Pluronic L121 (PL121). Rheological tests showed that DH700kMF-13.5/M-DocLF was an injectable flowing solution, which formed a nonflowing gel at body temperature. After intratumoral (IT) or peritumoral (PT) administration, DH700kMF-13.5/M-DocLF demonstrated efficient growth inhibition of CT-26 tumors in a Balb/c mice model. The tumor inhibitory rate after IT administration of DH700kMF-13.5/M-DocLF was 92.4%, followed by 85.8%, 75.6%, 62.9%, 50.6%, and 49.5% for DH700kMF-15, free DOX, F-13.5/M-DocLF, Tynen (DOC solution), and M-DocLF, respectively. Furthermore, PT administration of DH700kMF-13.5/M-DocLF resulted in similar efficacies. Pharmacokinetic and biodistribution studies showed that after subcutaneous (SC) and IT administration of the designated formulations, smaller amounts of DOX and DOC were absorbed from the local SC or tumor sites into systemic circulation, probably reducing their systemic toxicity. Tumor retention of DOX and DOC in biodistribution studies further revealed that co-delivery of these two drugs in DH700KMF-13.5/M-DocLF potentially enhanced the efficacy of tumor inhibition. In conclusion, our in situ injectable DOX and DOC TSH is a potential dual drug delivery system, which can enhance the efficacy of cancer chemotherapy with minimal side effects and reduced chemoresistance.
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan; Clinical Research Center and Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Ming-Thau
authors.initials: MT
authors.lastname: Sheu
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
authors.forename: Hua-Jing
authors.initials: HJ
authors.lastname: Jhan
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Su
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
authors.forename: Ling-Chun
authors.initials: LC
authors.lastname: Chen
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
authors.forename: Chia-En
authors.initials: CE
authors.lastname: Chang
authors.affiliation: Center for General Education, Hsuan Chuang University, Hsinchu, Taiwan; Graduate Institute of Biomedical Materials and Tissue Engineering, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Der-Zen
authors.initials: DZ
authors.lastname: Liu
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan. Electronic address: hsiuoho@tmu.edu.tw.
authors.forename: Hsiu-O
authors.initials: HO
authors.lastname: Ho
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D005079:Excipients / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D007267:Injections; D008297:Male; D008807:Mice, Inbred BALB C; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020442:Poloxamer / Q000737:chemistry; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics; D013696:Temperature; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D005079:Excipients; D020100:Hydrogels; D008823:Micelles; D043823:Taxoids; D020442:Poloxamer; D000077143:Docetaxel; D004317:Doxorubicin
keywords: Co-delivery; Docetaxel; Doxorubicin; Intratumoral; Micelles; Thermosensitive hydrogel