TY  - JOUR
AU  - Cheah, Hoay Yan
AU  - Sarenac, Olivera
AU  - Arroyo, Juan J.
AU  - Vasić, Marko
AU  - Lozić, Maja
AU  - Glumac, Sofija
AU  - Hoe, See Ziau
AU  - Hindmarch, Charles Colin Thomas
AU  - Murphy, David
AU  - Kiew, Lik Voon
AU  - Lee, Hong Boon
AU  - Vicent, Maria J.
AU  - Chung, Lip Yong
AU  - Japundžić-Žigon, Nina
PY  - 2017
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1056
AB  - Conjugation of Doxorubicin (DOX) to N-(2-hydroxypropyl) methylacrylamide copolymer (HPMA) has significantly reduced the DOX-associated cardiotoxicity. However, the reports on the impact of HPMA-DOX conjugates on the cardiovascular system such as blood pressure (BP) and heart rate (HR) were in restrained animals using tail cuff and/or other methods that lacked the resolution and sensitivity. Herein, we employed radiotelemetric-spectral-echocardiography approach to further understand the in vivo cardiovascular hemodynamics and variability post administration of free DOX and HPMA-DOX. Rats implanted with radio-telemetry device were administered intravenously with DOX (5mg/kg), HPMA-DOX (5mg DOX equivalent/kg) and HPMA copolymer and subjected to continuous cardiovascular monitoring and echocardiography for 140 days. We found that DOX-treated rats had ruffled fur, reduced body weight (BW) and a low survival rate. Although BP and HR were normal, spectral analysis indicated that their BP and HR variabilities were reduced. All rats exhibited typical signs of cardiotoxicity at histopathology. In contrast, HPMA-DOX rats gained weight over time and survived. Although BP, HR and related variabilities were unaffected, the left ventricular end diastolic volume (EDV) of these rats, as well as of the HPMA copolymer-treated rats, was found increased at the end of observation period. Additionally, HPMA copolymer caused microscopic injury of the heart tissue. All of these suggest the necessity of caution when employing HPMA as carrier for prolonged drug delivery. The current study also indicates the potential of radiotelemetric-spectral-echocardiography approach for improved preclinical cardiovascular risk assessment of polymer-drug conjugate and other nano-sized-drug constructs.
PB  - Taylor & Francis Ltd, Abingdon
T2  - Nanotoxicology
T1  - Hemodynamic effects of HPMA copolymer based doxorubicin conjugate: A randomized controlled and comparative spectral study in conscious rats
EP  - 222
IS  - 2
SP  - 210
VL  - 11
DO  - 10.1080/17435390.2017.1285071
ER  - 

@article{
author = "Cheah, Hoay Yan and Sarenac, Olivera and Arroyo, Juan J. and Vasić, Marko and Lozić, Maja and Glumac, Sofija and Hoe, See Ziau and Hindmarch, Charles Colin Thomas and Murphy, David and Kiew, Lik Voon and Lee, Hong Boon and Vicent, Maria J. and Chung, Lip Yong and Japundžić-Žigon, Nina",
year = "2017",
abstract = "Conjugation of Doxorubicin (DOX) to N-(2-hydroxypropyl) methylacrylamide copolymer (HPMA) has significantly reduced the DOX-associated cardiotoxicity. However, the reports on the impact of HPMA-DOX conjugates on the cardiovascular system such as blood pressure (BP) and heart rate (HR) were in restrained animals using tail cuff and/or other methods that lacked the resolution and sensitivity. Herein, we employed radiotelemetric-spectral-echocardiography approach to further understand the in vivo cardiovascular hemodynamics and variability post administration of free DOX and HPMA-DOX. Rats implanted with radio-telemetry device were administered intravenously with DOX (5mg/kg), HPMA-DOX (5mg DOX equivalent/kg) and HPMA copolymer and subjected to continuous cardiovascular monitoring and echocardiography for 140 days. We found that DOX-treated rats had ruffled fur, reduced body weight (BW) and a low survival rate. Although BP and HR were normal, spectral analysis indicated that their BP and HR variabilities were reduced. All rats exhibited typical signs of cardiotoxicity at histopathology. In contrast, HPMA-DOX rats gained weight over time and survived. Although BP, HR and related variabilities were unaffected, the left ventricular end diastolic volume (EDV) of these rats, as well as of the HPMA copolymer-treated rats, was found increased at the end of observation period. Additionally, HPMA copolymer caused microscopic injury of the heart tissue. All of these suggest the necessity of caution when employing HPMA as carrier for prolonged drug delivery. The current study also indicates the potential of radiotelemetric-spectral-echocardiography approach for improved preclinical cardiovascular risk assessment of polymer-drug conjugate and other nano-sized-drug constructs.",
publisher = "Taylor & Francis Ltd, Abingdon",
journal = "Nanotoxicology",
title = "Hemodynamic effects of HPMA copolymer based doxorubicin conjugate: A randomized controlled and comparative spectral study in conscious rats",
pages = "222-210",
number = "2",
volume = "11",
doi = "10.1080/17435390.2017.1285071"
}

Cheah, H. Y., Sarenac, O., Arroyo, J. J., Vasić, M., Lozić, M., Glumac, S., Hoe, S. Z., Hindmarch, C. C. T., Murphy, D., Kiew, L. V., Lee, H. B., Vicent, M. J., Chung, L. Y.,& Japundžić-Žigon, N.. (2017). Hemodynamic effects of HPMA copolymer based doxorubicin conjugate: A randomized controlled and comparative spectral study in conscious rats. in Nanotoxicology
Taylor & Francis Ltd, Abingdon., 11(2), 210-222.
https://doi.org/10.1080/17435390.2017.1285071

Cheah HY, Sarenac O, Arroyo JJ, Vasić M, Lozić M, Glumac S, Hoe SZ, Hindmarch CCT, Murphy D, Kiew LV, Lee HB, Vicent MJ, Chung LY, Japundžić-Žigon N. Hemodynamic effects of HPMA copolymer based doxorubicin conjugate: A randomized controlled and comparative spectral study in conscious rats. in Nanotoxicology. 2017;11(2):210-222.
doi:10.1080/17435390.2017.1285071 .

Cheah, Hoay Yan, Sarenac, Olivera, Arroyo, Juan J., Vasić, Marko, Lozić, Maja, Glumac, Sofija, Hoe, See Ziau, Hindmarch, Charles Colin Thomas, Murphy, David, Kiew, Lik Voon, Lee, Hong Boon, Vicent, Maria J., Chung, Lip Yong, Japundžić-Žigon, Nina, "Hemodynamic effects of HPMA copolymer based doxorubicin conjugate: A randomized controlled and comparative spectral study in conscious rats" in Nanotoxicology, 11, no. 2 (2017):210-222,
https://doi.org/10.1080/17435390.2017.1285071 . .