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Malarmugila Manimaran,1,* Yin Yin Teo,2 James Chen Yong Kah,3 Adilet Beishenaliev,1 Yean Leng Loke,2 Yiing Yee Foo,1 Shiow-Fern Ng,4 Chin Fei Chee,5 Sek Peng Chin,6 Farid Nazer Faruqu,1 Chia-Yu Chang,7 Misni Misran,2 Lip Yong Chung,6 Bey Fen Leo,8,* Shih-Hwa Chiou,9,10 Chia-Ching Chang,7,11– 13 Sun Tee Tay,14 Lik Voon Kiew1,7 1Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; 2Department of Chemistry, Faculty of Science, Universiti Malaya, Kuala Lumpur, Malaysia; 3Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore; 4Centre for Drug Delivery Technology and Vaccine, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia; 5Nanotechnology Catalysis Research Centre, Universiti Malaya, Kuala Lumpur, Malaysia; 6Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia; 7Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan, Republic of China; 8Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; 9Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China; 10Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China; 11Department of Electrophysics, National Yang Ming Chiao Tung University, Hsinchu, Taiwan, Republic of China; 12Center for Intelligent Drug Systems and Smart Bio-devices, National Yang Ming Chiao Tung University, Hsinchu, Taiwan, Republic of China; 13Institute of Physics, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China; 14Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia*These authors contributed equally to this workCorrespondence: Chia-Ching Chang; Lik Voon Kiew, Email ccchang01@nycu.edu.tw; lvkiew@um.edu.myIntrod

Stephanie Sally Fong,1,* Yiing Yee Foo,1,* Wen Shang Saw,2 Bey Fen Leo,3 Yin Yin Teo,4 Ivy Chung,1 Boon Tong Goh,5 Misni Misran,4 Toyoko Imae,6 Chia-Ching Chang,7– 11 Lip Yong Chung,2 Lik Voon Kiew1,7 1Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia; 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Malaya, Kuala Lumpur, 50603, Malaysia; 3Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia; 4Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, 50603, Malaysia; 5Low Dimensional Materials Research Center, Department of Physics, Faculty of Science, University of Malaya, Kuala Lumpur, 50603, Malaysia; 6Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, 10607, Taiwan; 7Department of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan; 8Center for Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, 30050, Taiwan; 9Department of Electrophysics, National Yang Ming Chiao Tung University, Hsinchu, 30010, Taiwan; 10Institute of Physics, Academia Sinica, Nankang, Taipei, Taiwan; 11Taiwan-Malaysia Semiconductor and Biomedical Oversea Science and Technology Innovation Center, National Yang Ming Chiao Tung University, Hsinchu, 30010, Taiwan*These authors contributed equally to this workCorrespondence: Lik Voon KiewDepartment of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, MalaysiaTel +603-79675720Email lvkiew@um.edu.myChia-Ching ChangDepartment of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, 30068, TaiwanTel +886-3-57131633Email ccchang01@nycu.edu.twPurpose: The use of nanocarriers to improve the deliv

Hann-Juang Chai,1 Lik-Voon Kiew,1 Yunni Chin,1 Anwar Norazit,2 Suzita Mohd Noor,2 Yoke-Lin Lo,3,4 Chung-Yeng Looi,1 Yeh-Siang Lau,1 Tuck-Meng Lim,5 Won-Fen Wong,6 Nor Azizan Abdullah,1 Munavvar Zubaid Abdul Sattar,7 Edward J Johns,8 Zamri Chik,1 Lip-Yong Chung3 1Department of Pharmacology, 2Department of Biomedical Science, 3Department of Pharmacy, Faculty of Medicine, University of Malaya, 4School of Pharmacy, International Medical University, Kuala Lumpur, 5Department of Chemical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Kampar, 6Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 7School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Malaysia; 8Department of Physiology, University College Cork, Cork, Republic of Ireland Background and purpose: Poly-L-glutamic acid (PG) has been used widely as a carrier to deliver anticancer chemotherapeutics. This study evaluates PG as a selective renal drug carrier.Experimental approach: 3H-deoxycytidine-labeled PGs (17 or 41 kDa) and 3H-deoxycytidine were administered intravenously to normal rats and streptozotocin-induced diabetic rats. The biodistribution of these compounds was determined over 24 h. Accumulation of PG in normal kidneys was also tracked using 5-(aminoacetamido) fluorescein (fluoresceinyl glycine amide)-labeled PG (PG-AF). To evaluate the potential of PGs in ferrying renal protective anti-oxidative stress compounds, the model drug 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) was conjugated to 41 kDa PG to form PG-AEBSF. PG-AEBSF was then characterized and evaluated for intracellular anti-oxidative stress efficacy (relative to free AEBSF).Results: In the normal rat kidneys, 17 kDa radiolabeled PG (PG-Tr) presents a 7-fold higher, while 41 kDa PG-Tr shows a 15-fold higher renal accumulation than the free radiolabel after 24 h post injection. The accumulation of PG-AF was primarily found in the renal tubular ­tissu

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.