Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zhang, F; Wang, X; Xu, X; Li, M; Zhou, J; Wang, W.
Reconstituted high density lipoprotein mediated targeted co-delivery of HZ08 and paclitaxel enhances the efficacy of paclitaxel in multidrug-resistant MCF-7 breast cancer cells.
Eur J Pharm Sci. 2016; 92(36):11-21
Doi: 10.1016/j.ejps.2016.06.017
Web of Science
PubMed
FullText
FullText_MUG
- Führende Autor*innen der Med Uni Graz
- Zhang Fangrong
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- Abstract:
- In the past decades, reconstituted high density lipoprotein (rHDL) has been successfully developed as a drug carrier since the enhanced HDL-lipids uptake is demonstrated in several human cancers. In this paper, rHDL, for the first time, was utilized to co-encapsulate two hydrophobic drugs: an anticancer drug, paclitaxel (PTX), and a new reversal agent for P-gp (P-glycoprotein)-mediated multidrug resistance (MDR) of cancer, N-cyano-1-[(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide (HZ08). We proposed this drug co-delivery strategy to reverse PTX resistance. The study aimed to develop a biomimetic nanovector, reconstituted high density lipoprotein (rHDL), mediating targeted PTX-HZ08 delivery for cancer therapy. Using sodium cholate dialysis method, we successfully formulated dual-agent co-delivering rHDL nanoparticles (PTX-HZ08-rHDL NPs) with a typical spherical morphology, well-distributed size (~100nm), high drug encapsulation efficiency (approximately 90%), sustained drug release properties and exceptional stability even after storage for 1month or incubation in 10% fetal bovine serum (FBS) DMEM for up to 2days. Results demonstrated that PTX-HZ08-rHDL NPs significantly enhanced anticancer efficacy in vitro, including higher cytotoxicity and better ability to induce cell apoptosis against both PTX-sensitive and -resistant MCF-7 human breast cancer cell lines (MCF-7 and MCF-7/PTX cells). Mechanism studies demonstrated that these improvements could be correlated with increased cellular uptake of PTX mediated by scavenger receptor class B type I (SR-BI) as well as prolonged intracellular retention of PTX due to the HZ08 mediated drug-efflux inhibition. In addition, in vivo investigation showed that the PTX-HZ08-rHDL NPs were substantially safer, have higher tumor-targeted capacity and have stronger antitumor activity than the corresponding dosage of paclitaxel injection. These findings suggested that rHDL NPs could be an ideal tumor-targeted nanovector for simultaneous transfer of insoluble anticancer drug and drug resistance reversal agents. The PTX-HZ08-rHDL NPs co-delivery system might be a new promising strategy to overcome tumor drug resistance. Copyright © 2016 Elsevier B.V. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Antineoplastic Agents, Phytogenic - administration & dosage
- Antineoplastic Agents, Phytogenic - chemistry
- Antineoplastic Agents, Phytogenic - pharmacology
- Antineoplastic Agents, Phytogenic - therapeutic use
- Breast Neoplasms - drug therapy
- Breast Neoplasms - pathology
- Cell Survival - drug effects
- Drug Delivery Systems -
- Drug Liberation -
- Drug Resistance, Neoplasm - drug effects
- Female -
- Humans -
- Isoquinolines - administration & dosage
- Isoquinolines - chemistry
- Isoquinolines - pharmacology
- Isoquinolines - therapeutic use
- Lipoproteins, HDL - administration & dosage
- Lipoproteins, HDL - chemistry
- Lipoproteins, HDL - pharmacology
- Lipoproteins, HDL - therapeutic use
- MCF-7 Cells -
- Mice, Inbred BALB C -
- Mice, Nude -
- Nanoparticles - administration & dosage
- Nanoparticles - chemistry
- Nanoparticles - therapeutic use
- Paclitaxel - administration & dosage
- Paclitaxel - chemistry
- Paclitaxel - pharmacology
- Paclitaxel - therapeutic use
- Tumor Burden - drug effects
- Find related publications in this database (Keywords)
- Reconstituted high density lipoprotein
- Paclitaxel
- HZ08
- Multidrug resistance
- Co-delivery