Investigational New Drugs

, Volume 25, Issue 4, pp 313–326

A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance

  • Gene L. BidwellIII
  • Aisha N. Davis
  • Izabela Fokt
  • Waldemar Priebe
  • Drazen Raucher
PRECLINICAL STUDIES

DOI: 10.1007/s10637-007-9053-8

Cite this article as:
Bidwell, G.L., Davis, A.N., Fokt, I. et al. Invest New Drugs (2007) 25: 313. doi:10.1007/s10637-007-9053-8

Summary

The ability of cancer cells to become simultaneously resistant to different drugs, a trait known as multidrug resistance, remains a major obstacle for successful anticancer therapy. One major mechanism of resistance involves cellular drug efflux by expression of P-glycoprotein (P-gp), a membrane transporter with a wide variety of substrates. Anthracyclines are especially prone to induction of resistance by the P-gp mechanism. P-gp mediated resistance is often confronted by use of P-gp inhibitors, synthesis of novel analogs, or conjugating drugs to macromolecular carriers in order to circumvent the efflux mechanism. In this report, the effect of free and Elastin-like polypeptide (ELP) bound doxorubicin (Dox) on the viability of sensitive (MES-SA and MCF-7) and multidrug resistant (MES-SA/Dx5 and NCI/ADR-RES) human carcinoma cells was studied in vitro. The resistant MES-SA/Dx5 cells demonstrated about 70 times higher resistance to free Dox than the sensitive MES-SA cells, and the NCI/ADR-RES cells were about 30 fold more resistant than the MCF-7 cells. However, the ELP-bound Dox was equally cytotoxic in both sensitive and resistant cell lines. The ELP-bound Dox was shown to accumulate in MES-SA/Dx5 cells, as opposed to free Dox, which was rapidly pumped out by the P-gp transporter. Since ELP is a thermally responsive carrier, the effect of hyperthermia on the cytotoxicity of the ELP-Dox conjugate was investigated. Both cytotoxicity and apoptosis were enhanced by hyperthermia in the Dox resistant cells. The results suggest that ELP-Dox conjugates may provide a means to thermally target solid tumors and to overcome drug resistance in cancer cells.

Keywords

Elastin-like polypeptide Doxorubicin Multidrug resistance Drug delivery Thermal targeting 

Abbreviations

ABC

ATP binding cassette

AUC

area under curve

BSA

bovine serum albumin

Dnr

daunorubicin

Dox

doxorubicin

ELP

elastin-like polypeptide

EPR

enhanced permeability and retention

HPLC

high pressure liquid chromatography

HPMA

N-(2-hydroxypropyl)methacrylamide

MDR

multidrug resistance

PBS

phosphate buffered physiological saline

PE

phycoerythrin

PFA

paraformaldehyde

P-gp

P-glycoprotein

Tt

transition temperature

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Gene L. BidwellIII
    • 1
  • Aisha N. Davis
    • 1
  • Izabela Fokt
    • 2
  • Waldemar Priebe
    • 2
  • Drazen Raucher
    • 1
  1. 1.Department of BiochemistryUniversity of Mississippi Medical CenterJacksonUSA
  2. 2.The University of Texas M. D. Anderson Cancer CenterHoustonUSA