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  • br DelivDrug Advdiseases as articlethiscitePlease addr j

    2020-08-30


    .DelivDrug.Advdiseases, as:articlethiscitePlease 010.01.2019.addr.1016/j.org/10.https://doi,.Rev sensitive-CathepsinShankar,.RandNicolas.JDheer,.D
    otherandtherapycancerforsystemsdeliverydrugnanoscale
    Table 2
    List 丝裂霉素 C Cathepsin B-cleavable prodrugs evaluated in clinical trials.
    Entry Name Composition Spacer Linker Clinical Trial status Company Refs
    1 PK1; FCE28068 PHPMA copolymer-Doxorubicine Gly-Phe-Leu-Gly Amide Phase II Pfizer Inc., Cancer Research [196,225]
    (discontinued) Campaign, UK
    2 PK2; FCE28069 PHPMA-Dox-Galatosamine Gly-Phe-Leu-Gly Amide Phase I/II Pfizer Inc., Cancer Research [226,227]
    (discontinued) Campaign, UK
    3 PNU166945/HPMA-Ptx PHPMA copolymer- Paclitaxel Gly-Phe-Leu-Gly Ester Phase I Pharmacia [206]
    (discontinued)
    4 PNU166148/HPMA-CPT/MAG-CPT PHPMA copolymer-Camptothecin Glycine residue/ Glycylaminohexanoyl Ester Phase I Pharmacia [207]
    spacer
    (discontinued)
    5 CT-2103/PGA-Ptx-XYOTAXTM/OPAXIO® Polyglutamate-Paclitaxel L-glutamic acid Ester Phase II/III Cell Therapeutics Inc. [199–205] 6 CT-2106/PGA-CPT Polyglutamate-Camptothecin L-glutamic acid Ester Phase II Cell Therapeutics Inc. [228–230]
    discontinued
    7 AP5280 PHPMA copolymer- Carboplatinate Gly-Phe-Leu-Gly Aminomalonate Phase I Access Pharmaceuticals Inc. [208,209] 8 AP5346/ ProlindacTM PHPMA copolymer-DACH Oxiplatinate GGG-carboxylate-Pt coordination Aminomalonate Phase II Access Pharmaceuticals Inc. [210] 9 EZ-246/PEG-CPT/Pegamotecan/ProthecanTM PEG-Camptothecin Glycine Ester Phase II Enzon Pharmaceuticals, Inc. [216,217]
    discontinued
    10 NK911 PEG-aspartic acid-Doxorubicinmicelle Aspartic acid Amide Phase II National Cancer Institute Japan [97,218,219] 11 P-Dox PHPMA copolymer-Dox Gly-Phe-Leu-Gly Amide Preclinical – [211,212] 12 P-(GFLG)-Dox-Ab PHPMA copolymer-Dox-abraxane Gly-Phe-Leu-Gly Amide Preclinical – [213] 13 P-(GFLG-Dox)-Ga IN PHPMA copolymer-Dox-N-acylated Gly-Phe-Leu-Gly Amide Preclinical – [214]
    galactosamine
    14 P-(GFLG-Dox)-Lac PHPMA copolymer-Dox-Lactose Gly-Phe-Leu-Gly Amide Preclinical
    [214] 15 HMW1D PHPMA copolymer-Dox (high molecular Gly-Phe-Leu-Gly Amide Preclinical – [215]
    weight)
    16 TET1D PHPMA copolymer-Dox (non-targeted) Gly-Phe-Leu-Gly Amide Preclinical – [215] 17 DOXO-EMCH (INNO-206) EMC-Arg-Arg-Ala-Leu-Ala-Leu-Dox Ala-Leu-Ala-Leu Maleimide Preclinical CytRx Corporation [231] 18 EMC-Phe-Lys-PABC-Dox PHPMA copolymer-Phe-Lys-PABC-Dox Phe-Lys Amide Preclinical KTB Tumorforschungs GmbH [223] 19 PG-Phe-Lys-Dox Hyperbranched polyglycerol-Phe-Lys-Dox Phe-Lys Amide Preclinical KTB Tumorforschungs GmbH [224] 20 DE-310 Carboxymethyldextran-exatecan Gly-Phe-Leu-Gly Amide Phase I Daiichi Pharmaceutical Co. Ltd. [221] 21 Delimotecan (MEN 4901/T-0128) Carboxymethyldextran-camptothecin Triglycine Ester Phase I Mitsubishi Tanabe/Menarini [222]
    also entered clinical trials (Table 2). For instance, XYOTAX (based on polyglutamate) has shown encouraging results in phase III trials in women with non-small-cell lung cancer [199–205]. Among the differ-ent PHPMA clinical candidates, PNU166945 is based on Ptx for the treat-ment of advanced breast cancer and PNU166148 is based on camptothecin for the treatment of metastatic solid tumors but both were stopped in Phase I trials because of severe neurotoxicity and lack of anticancer action, respectively [206,207]. Also, AP5280 prodrug has been introduced for PHPMA-carboplatinate and entered clinical phase
    II trial whereas PHPMA-oxiplatinate (ProLindac, also named AP5346) was in clinical phase II trial against ovarian cancer [208–210]. PHPMA polymer conjugated to Dox using GFLG linker has also been attempted with protein-bound Ptx (abraxane), carbohydrate residues such as ga-lactosamine, lactose and also amino acids like phenylalaninelysine (Phe-Lys), and are currently in preclinical studies [211–214].On the contrary, high molar mass PHPMA was investigated to enhance the an-ticancer efficacy which also reached preclinical settings [215]. A second series of blockbuster polymers that entered clinical trials are PEG-based conjugates, namely, EZ-246 conjugated to camptothecin but its phase II
    trials has been stopped due to lack of efficacy. However, NK911 in the form of PEGylated micelles with aspartic acid and Dox had showed promising efficacy against various solid malignancies likely thanks to the EPR effect and is currently in phase II [216–219]. Carboxymethyldextrans another synthetic polymer forming prodrugs with exatecan and camptothecin [220], and which entered Phase I clin-ical trials, showed prominent results especially against colon cancer [221,222]. Polyglutamate has been conjugated using Ptx by Cell Thera-peutics Inc. company and is currently in Phase II trials [199,200]. Other Cathepsin-sensitive drug delivery systems are under preclinical investi-gations, including polymeric dendritic systems containing Dox (KTB Tumorforschungs GmbH company) [223,224].