Purpose. This research was designed to investigate the protective effect of rifampicin (RIF) loaded by N-(2-hydroxypropyl) methylacrylamide- (HPMA-) polylactic acid (PLA) nanopolymer on macrophages infected with Mycobacterium tuberculosis (MTB). Methods. We first induced H37Rv to infect macrophages to build a cell model. Then, the HPMA-PLA nanopolymer loaded with RIF was prepared to treat MTB-infected macrophages. The macrophage activity was tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the nitric oxide (NO) in cells was measured through Griess reagent, and the bacterial activity of MTB was observed via the colony-forming unit (CFU) assay. The inflammation-related factors in cells were detected via the enzyme-linked immunosorbent assay (ELISA), the apoptosis of macrophages was examined via flow cytometry, and the expression of apoptosis-related proteins was determined by western blot (WB). Results. HPMA-PLA had no obvious toxicity to macrophages. The expression of NO and inflammatory factors in macrophages infected with MTB increased significantly, but the apoptosis rate was not significantly different from that of uninfected cells. However, after treatment with HPMA-PLA-RIF or free RIF, the inflammatory reaction of infected cells was inhibited, the expression of NO was decreased, the apoptosis rate was increased, and the bacterial activity in cells was decreased, with statistically significant differences; moreover, HPMA-PLA-RIF was more effective than free RIF. Conclusions. HPMA-PLA-RIF has a high protective effect on macrophages infected with MTB, with high safety. Its protective mechanism is at least partly through inhibiting the production of NO and inflammatory response, which can inhibit bacterial activity and induce cell apoptosis.

16 Mar 2018·Journal of Drug TargetingQ3 · MEDICINE

A novel α_Vβ₃ligand-modified HPMA copolymers for anticancer drug delivery

Q3 · MEDICINE

Article

Author: Huang, Yuan ; Li, Lian ; Liu, Yuanyuan ; Sun, Wei ; Li, Lijia ; Zhou, Zhou ; Wang, Fengling

The integrin α_Vβ₃ receptor emerged as one of the most promising targets owing to its high expression on the surface of various malignant tumour cells and tumour angiogenesis endothelial cells, but with little expression in mature endothelial cells and the majority of normal cells. Here, we report a new targeting ligand FQSIYPpIK (FQS) with high affinity to integrin α_Vβ₃ receptor. To take the advantage of the particular interaction between FQS and integrin α_Vβ₃ receptor, FQS was linked to N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers. A model drug doxorubicin (DOX) was simultaneously conjugated to the same HPMA copolymers via pH-sensitive hydrazone linkages (FQS-HPMA-DOX). In in vitro study, FQS-HPMA-DOX could be internalised into α_Vβ₃ receptor-overexpressed B16F10 cells via a highly specific ligand - receptor pathway (5.0 times and 4.5 times higher cellular internalisation than HPMA-DOX and a scrambled peptide (s)-FQS (sequence: SYFIPKQIp)-modified copolymers ((s)-FQS-HPMA-DOX)). It is worth noting that compared with the classical α_Vβ₃ ligand cRGDfK-modified HPMA copolymers (cRGDfK-HPMA-DOX), FQS-HPMA-DOX also showed superior targeting efficiency. In in vivo study in the B16F10 melanoma bearing mice model showed the antitumour efficiency of FQS-HPMA-DOX (83.9%) were significantly higher than HPMA-DOX (44.9%) and cRGDfK-HPMA-DOX (77.5%). These results suggest that FQS peptide can act as an effective targeting ligand for the delivery of therapeutic agents.

07 Feb 2017·NanotoxicologyQ3 · MEDICINE

Hemodynamic effects of HPMA copolymer based doxorubicin conjugate: A randomized controlled and comparative spectral study in conscious rats

Q3 · MEDICINE

Article

Author: Glumac, Sofija ; Cheah, Hoay Yan ; Japundžić-Žigon, Nina ; Murphy, David ; Lozić, Maja ; Lee, Hong Boon ; Hoe, See Ziau ; Arroyo, Juan J. ; Kiew, Lik Voon ; Vasić, Marko ; Hindmarch, Charles Colin Thomas ; Chung, Lip Yong ; Vicent, María J. ; Šarenac, Olivera

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.

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