title: In vitro demonstration of enhanced prostate cancer toxicity: pretargeting with Bombesin bispecific complexes and targeting with polymer-drug-conjugates.
abstract: BACKGROUND
  Bombesin has been used to target Bombesin receptor, a growth receptor, which is over-expressed in many cancers, including prostate cancer. Polymer-anti-neoplastic-drug-conjugates (PDC) were also developed to reduce non-specific toxicity and increase tumor toxicity utilizing the enhanced permeability and retention effect, benefitting treatment of large tumors with well-established vasculature.
  
  
  OBJECTIVE
  If PDCs were delivered by targeted delivery to cancer cells, tumor toxicity would be enhanced and non-specific toxicity decreased.
  
  
  METHODS
  Cardiocyte toxicity was assessed in H9c2 cardiocytes with doxorubicin (Dox) or N-terminal DTPA-modified-Doxorubicin-loaded-polyglutamic acid polymers (D-Dox-PGA). Therapeutic efficacy of targeted D-Dox-PGA after pretargeting with Bombesin-conjugated anti-DTPA-antibody Bispecific Complexes (Bom-BiSpCx) was compared to that of Dox in PC3 cells. Bom-BiSpCx was generated by thioether bond between Bombesin to Anti-DTPA antibody.
  
  
  RESULTS
  D-Dox-PGA was demonstrated to have less cardiocyte toxicity (IC50 = 20 µg/ml) than free Dox (1.55 µg/ml, p < 0.001). However, after pre-targeting of human prostate cancer PC3 cells with Bom-BiSpCx and targeting with D-Dox-PGA, IC50 (13.2 µg/ml) was about two times less than that of Dox (28.5 µg/ml, p < 0.0001).
  
  
  CONCLUSIONS
  Targeted delivery of PDCs having lower cardiocyte toxicity enabled higher efficiency cancer cell therapy.
  
  
  CONCLUSIONS
  This study may allow development of very efficient targeted prostate cancer pro-drug therapy.
authors.affiliation: Bouve College of Health Sciences, School of Pharmacy, Northeastern University , Boston , USA .
authors.forename: Vishwesh
authors.initials: V
authors.lastname: Patil
authors.forename: Keyur
authors.initials: K
authors.lastname: Gada
authors.forename: Rajiv
authors.initials: R
authors.lastname: Panwar
authors.forename: Stan
authors.initials: S
authors.lastname: Majewski
authors.forename: Yared
authors.initials: Y
authors.lastname: Tekabe
authors.forename: Alexandra
authors.initials: A
authors.lastname: Varvarigou
authors.forename: Ban-An
authors.initials: BA
authors.lastname: Khaw
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D018033:Antibodies, Bispecific / Q000276:immunology; D001839:Bombesin / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D004369:Pentetic Acid / Q000276:immunology; D011099:Polyglutamic Acid / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D018004:Receptors, Bombesin / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D018033:Antibodies, Bispecific; D004337:Drug Carriers; D018004:Receptors, Bombesin; D011099:Polyglutamic Acid; D004369:Pentetic Acid; D004317:Doxorubicin; D001839:Bombesin