Targeted prodrug treatment of HER-2-positive breast tumor cells using trastuzumab and paclitaxel linked by A-Z-CINN Linker.
Targeting drugs for delivery and release has the potential to increase the efficacy of treatment. A bifunctional linker, A-Z-CINN Linker was used to create a targeted prodrug, A-Z-CINN 310. A-Z-CINN Linker links to a potent chemotherapeutic agent, paclitaxel, via an energy-reversible ester bond and also binds a targeting agent, the monoclonal antibody trastuzumab (Herceptin). This study demonstrates the effectiveness of a single-treatment use of A-Z-CINN 310 in decreasing tumor volume and tumor cell density of human HER-2-positive BT-474 mammary tumor cells implanted in scid mice, compared to treatment with simultaneously administered trastuzumab and paclitaxel and with saline control. After treatment with A-Z-CINN 310, some mice received light exposure at 6 h for 5 min adjacent to the tumor to cause light-accelerated release of paclitaxel. Changes in tumor volume were measured for 28 days following treatment; changes in histology were measured at 31 days. Animals treated with A-Z-CINN 310, then light, showed dose-dependent decreases in tumor volume and tumor cell density which were more rapid and extensive than those seen with A-Z-CINN 310 without light or a 10-fold higher concentration of co-administered trastuzumab plus paclitaxel. This suggests that targeted delivery of paclitaxel using A-Z-CINN 310 kills tumor cells by localized release of paclitaxel at the tumor site, which can be accelerated by light treatment. These results indicate that a targeted prodrug therapy containing trastuzumab as the targeting agent and A-Z-CINN-paclitaxel as the prodrug results in a conjugate that is more effective in killing tumor cells than equivalent concentrations of co-administered trastuzumab and paclitaxel. Targeting of a drug can reduce the dose needed for effective therapy and can increase local bioavailability. This makes targeted therapy using an A-Z-CINN prodrug delivery system feasible for treating both primary and metastatic tumors.
Gilbert
Carl W
CW
AuraZyme Pharmaceuticals, Inc., 1655 Roberts Boulevard, Kennesaw, GA 30144, USA. gilbert.carl@aurazyme.com
McGowan
Eleanor B
EB
Seery
Gerald B
GB
Black
Kirby S
KS
Pegram
Mark D
MD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D005260:Female; D018734:Genes, erbB-2; D006868:Hydrolysis; D018796:Immunoconjugates / Q000737:chemistry / Q000627:therapeutic use*; D008027:Light; D051379:Mice; D016513:Mice, SCID; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011355:Prodrugs / Q000138:chemical synthesis / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects; D013997:Time Factors; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D017239:Paclitaxel; D011355:Prodrugs; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C481001:A-Z-CINN 310