Bispecific antibody complex pre-targeting and targeted delivery of polymer drug conjugates for imaging and therapy in dual human mammary cancer xenografts: Targeted polymer drug conjugates for cancer diagnosis and therapy

Ban An Khaw, Keyur S. Gada, Vishwesh Patil, Rajiv Panwar, Savitri Mandapati, Arash Hatefi, Stan Majewski, Andrew Weisenberger

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Introduction: Doxorubicin, a frontline chemotherapeutic agent, limited by its cardiotoxicity and other tissue toxicities, was conjugated to N-terminal DTPA-modified polyglutamic acid (D-Dox-PGA) to produce polymer pro-drug conjugates. D-Dox-PGA or Tc-99 m labeled DTPA-succinyl-polylysine polymers (DSPL) were targeted to HER2-positive human mammary carcinoma (BT-474) in a double xenografted SCID mouse model also hosting HER2-negative human mammary carcinoma (BT-20). Methods: After pretargeting with bispecific anti-HER2-affibody-anti-DTPA-Fab complexes (BAAC), anti-DTPA-Fab or only phosphate buffered saline, D-Dox-PGA or Tc-99 m DSPL were administered. Positive therapeutic control mice were injected with Dox alone at maximum tolerated dose (MTD). Results: Only BT-474 lesions were visualized by gamma imaging with Tc-99 m-DSPL; BT-20 lesions were not. Therapeutic efficacy was equivalent in mice pretargeted with BAAC/targeted with D-Dox-PGA to mice treated only with doxorubicin. There was no total body weight (TBW) loss at three times the doxorubicin equivalent MTD with D-Dox-PGA, whereas mice treated with doxorubicin lost 10 % of TBW at 2 weeks and 16 % after the second MTD injection leading to death of all mice. Conclusions: Our cancer imaging and pretargeted therapeutic approaches are highly target specific, delivering very high specific activity reagents that may result in the development of a novel theranostic application. HER/2 neu specific affibody-anti-DTPA-Fab bispecific antibody pretargeting of HER2 positive human mammary xenografts enabled exquisite targeting of polymers loaded with radioisotopes for molecular imaging and doxorubicin for effective therapy without the associating non-tumor normal tissue toxicities.

Original languageEnglish (US)
Pages (from-to)1603-1616
Number of pages14
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume41
Issue number8
DOIs
StatePublished - Aug 2014

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging

Keywords

  • Affibody
  • Bispecific-antibody
  • Doxorubicin
  • HER2/neu
  • Polymer drug conjugates

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