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 C 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 C 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.

Improving Drug Delivery of Micellar Paclitaxel against Non‐Small Cell Lung Cancer by Coloading Itraconazole as a Micelle Stabilizer and a Tumor Vascular Manipulator

“…The particle morphology and particle size distribution of PM and PIM were compared using transmission electron microscopy (TEM) and dynamic light scattering (DLS) (Figure A), which were apparently similar despite the doubled drug payload within the PIM. However, IM was a milky suspension with visible large micelle agglomerates (size > 200 nm) at the same 4 mg mL −1 ITA concentration as PIM (Figure S2, Supporting Information) . According to our previously study, we believe the hetero‐intermolecular interactions (e.g., π–π stacking, H‐bonding) between PTX and ITA are the critical factors contributing to the formation of a miscible system, inhibit crystallization of both ITA and PTX, and enhance the colloidal stability of the micelles …”

“…It is well recognized that PDX model is able to faithfully represent the molecular diversity, cellular heterogeneity, and histology of human cancer, thus the tumor inhibition effects in PDX models are clinically relevant. After weekly intravenously injection for four weeks, except that IM monotherapy increased the tumor growth, all other treatments demonstrated complete tumor growth inhibition until ≈15 d after last dosing. After that however, rapid tumor recurrence and growth occurred in all but PIM‐treated groups, while no tumor recurrence was observed in the PIM group at least ≈50 d after the termination of treatment, accompanied with stable body weight increase of the treated animals during the whole study time frame ( Figure A–D).…”

“…It has been demonstrated that low dose of bevacizumab may induce tumor blood vessel normalization thus facilitate the delivery of antitumor agents and reduction of hypoxia . In fact, combination therapy of PTX and ITA has also shown synergistic anticancer effects against various cancers, including NSCLC and epithelial ovarian cancer …”

Paclitaxel and Itraconazole Co‐Encapsulated Micelle Prolongs the Survival of Spontaneous LSL‐KrasG12D/+, LSL‐Trp53R172H/+, Pdx‐1‐Cre Genetically Engineered Mouse Model of Pancreatic Cancer

“…[29] Briefly, after a single administration of PM, IM, PM/IM, and PIM, the tumors of KPC mice were removed at 2 and 24 h, respectively, and extracted with organic solvents to obtain the supernatant containing the analytes. [29] Briefly, after a single administration of PM, IM, PM/IM, and PIM, the tumors of KPC mice were removed at 2 and 24 h, respectively, and extracted with organic solvents to obtain the supernatant containing the analytes.…”

“…[29] Due to the existence of strong intermolecular interactions between PTX, ITA, and the hydrophobic core of the micelle, PIM (PTX 2 mg mL −1 , ITA 2 mg mL −1 ) had excellent colloidal stability and appeared to be clear and transparent with narrow particle size distribution ( Figure 1C and Figure S1C Figure S1A, Supporting Information). The PIM has been prepared and characterized as described previously.…”