title: Hemodynamic effects of HPMA copolymer based doxorubicin conjugate: A randomized controlled and comparative spectral study in conscious rats.
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 (5 mg/kg), HPMA-DOX (5 mg 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.
authors.affiliation: a Department of Pharmacology, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia.
authors.forename: Hoay Yan
authors.initials: HY
authors.lastname: Cheah
authors.affiliation: b Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine , University of Belgrade , Republic of Serbia.
authors.forename: Olivera
authors.initials: O
authors.lastname: Šarenac
authors.affiliation: c Polymer Therapeutics Lab , Centro de Investigación Príncipe Felipe , Valencia , Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Arroyo
authors.affiliation: b Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine , University of Belgrade , Republic of Serbia.
authors.forename: Marko
authors.initials: M
authors.lastname: Vasić
authors.affiliation: b Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine , University of Belgrade , Republic of Serbia.
authors.forename: Maja
authors.initials: M
authors.lastname: Lozić
authors.affiliation: b Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine , University of Belgrade , Republic of Serbia.
authors.forename: Sofija
authors.initials: S
authors.lastname: Glumac
authors.affiliation: d Department of Physiology, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia.
authors.forename: See Ziau
authors.initials: SZ
authors.lastname: Hoe
authors.affiliation: d Department of Physiology, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia.|e Department of Biomedical and Molecular Sciences , School of Medicine, Queen's, University , Kingston, ON , Canada , UK.
authors.forename: Charles Colin Thomas
authors.initials: CC
authors.lastname: Hindmarch
authors.affiliation: f Molecular Neuroendocrinology Research Group , The Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol , Bristol , England, UK.
authors.forename: David
authors.initials: D
authors.lastname: Murphy
authors.affiliation: a Department of Pharmacology, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia.
authors.forename: Lik Voon
authors.initials: LV
authors.lastname: Kiew
authors.affiliation: g Department of Pharmacy, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia.
authors.forename: Hong Boon
authors.initials: HB
authors.lastname: Lee
authors.affiliation: c Polymer Therapeutics Lab , Centro de Investigación Príncipe Felipe , Valencia , Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Vicent
authors.affiliation: g Department of Pharmacy, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia.
authors.forename: Lip Yong
authors.initials: LY
authors.lastname: Chung
authors.affiliation: b Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine , University of Belgrade , Republic of Serbia.
authors.forename: Nina
authors.initials: N
authors.lastname: Japundžić-Žigon
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D066126:Cardiotoxicity; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004452:Echocardiography; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D007275:Injections, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D009206:Myocardium / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D013686:Telemetry
chemical_list: D000178:Acrylamides; C482378:N-(2-hydroxypropyl)methacrylamide co-polymer-doxorubicin conjugate; D004317:Doxorubicin; C032976:N-(2-hydroxypropyl)methacrylamide
keywords: Nanomaterials; cardiotoxicity; echocardiography; polymer carriers; telemetry