An in vitro demonstration of overcoming drug resistance in SKOV3 TR and MCF7 ADR with targeted delivery of polymer pro-drug conjugates

Drug resistance is a common phenomenon that occurs in cancer chemotherapy. Delivery of chemotherapeutic agents as polymer pro-drug conjugates (PPDCs) pretargeted with bispecific antibodies could circumvent drug resistance in cancer cells. To demonstrate this approach to overcome drug resistance, Pac...

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Bibliographic Details
Published inJournal of drug targeting Vol. 25; no. 5; pp. 436 - 450
Main Authors Bhattarai, Prashant, Vance, Dylan, Hatefi, Arash, Khaw, Ban An
Format Journal Article
LanguageEnglish
Published England Taylor & Francis 28.05.2017
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Summary:Drug resistance is a common phenomenon that occurs in cancer chemotherapy. Delivery of chemotherapeutic agents as polymer pro-drug conjugates (PPDCs) pretargeted with bispecific antibodies could circumvent drug resistance in cancer cells. To demonstrate this approach to overcome drug resistance, Paclitaxel (Ptxl)-resistant SKOV3 TR human ovarian- and doxorubicin (Dox)-resistant MCF7 ADR human mammary-carcinoma cell lines were used. Pre-targeting over-expressed biotin or HER2/neu receptors on cancer cells was conducted by biotinylated anti-DTPA or anti-HER2/neu affibody - anti-DTPA Fab bispecific antibody complexes. The targeting PPDCs are either D-Dox-PGA or D-Ptxl-PGA. Cytotoxicity studies demonstrate that the pretargeted approach increases cytotoxicity of Ptxl or Dox in SKOV3 TR or MCF7 ADR resistant cell lines by 5.4 and 27 times, respectively. Epifluorescent microscopy - used to track internalization of D-Dox-PGA and Dox in MCF7 ADR cells - shows that the pretargeted delivery of D-Dox-PGA resulted in a 2- to 4-fold increase in intracellular Dox concentration relative to treatment with free Dox. The mechanism of internalization of PPDCs is consistent with endocytosis. Enhanced drug delivery and intracellular retention following pretargeted delivery of PPDCs resulted in greater tumor cell toxicity in the current in vitro studies.
Bibliography:Arash Hatefi–Associate Professor, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University.
Ban An Khaw – Professor, Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University.
Dylan Vance-Undergraduate, Department Biology, College of Sciences, Northeastern University
Equal contribution to the manuscript.
Prashant Bhattarai – PhD candidate, Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University
ISSN:1061-186X
1029-2330
DOI:10.1080/1061186X.2016.1271421