Tumor Progression of Non-Small Cell Lung Cancer Controlled by Albumin and Micellar Nanoparticles of Itraconazole, a Multitarget Angiogenesis Inhibitor.

Abstract

Itraconazole (ITA), an old and widely prescribed antifungal drug with excellent safety profile, has more recently been demonstrated to be a multitarget antiangiogenesis agent affecting multiple angiogenic stimulatory signals and pathways, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, and mammalian target of rapamycin (mTOR). In this study, we developed two nanoparticle formulations, i.e., polymer micelles (IP2K) and albumin nanoparticles (IBSA), to solubilize the extremely hydrophobic and insoluble ITA to allow intravenous administration and pharmacokinetics (PK)/pharmacodynamics (PD) comparisons. Although none of the formulations showed strong antiproliferation potency against non-small cell lung cancer (NSCLC) cells in vitro, when administrated at the equivalent ITA dose to a NSCLC patient-derived xenograft (PDX) model, IBSA retarded while IP2K accelerated the tumor growth. We attributed the cause of this paradox to formulation-dependent PK and vascular manipulation: IBSA demonstrated a more sustained PK with a Cmax of 60-70% and an AUC ∼2 times of those of IP2K, and alleviated the tumor hypoxia presumably through vascular normalization. In contrast, the high Cmax of IP2K elevated tumor hypoxia through a strong angiogenesis inhibition, which could have aggravated cancer aggressiveness and accelerated tumor growth. Furthermore, IBSA induced minimal hepatic and hematologic toxicities compared to IP2K and significantly enhanced the in vivo tumor inhibition activity of paclitaxel albumin nanoparticles when used in combination. These findings suggest that formulation and pharmacokinetics are critical aspects to be considered when designing the ITA angiogenesis therapy, and IBSA could potentially be assessed as a novel and safe multitarget angiogenesis therapy to be used in combination with other anticancer agents.

• Authors: Ling Zhang, Zhengsheng Liu, Kuan Yang, Chao Kong, Chun Liu, Huijun Chen, Jinfeng Huang, Feng Qian
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 14 Issue 12 Pg. 4705-4713 (12 04 2017) ISSN: 1543-8392 [Electronic] United States
• PMID: 29068216 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Albumins
• Angiogenesis Inhibitors
• Antineoplastic Agents
• Micelles
• monomethoxypolyethyleneglycol-polylactide block copolymer
• Itraconazole
• Polyethylene Glycols
• Paclitaxel

Topics

• Albumins (chemistry)
• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Progression
• Humans
• Injections, Intravenous
• Itraconazole (pharmacology, therapeutic use)
• Lung (drug effects, pathology)
• Lung Neoplasms (drug therapy, pathology)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Micelles
• Nanoparticles (chemistry)
• Paclitaxel (pharmacology, therapeutic use)
• Polyethylene Glycols (chemistry)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays