Celecoxib normalizes the tumor microenvironment and enhances small nanotherapeutics delivery to A549 tumors in nude mice

Abstract

Barriers presented by the tumor microenvironment including the abnormal tumor vasculature and interstitial matrix invariably lead to heterogeneous distribution of nanotherapeutics. Inspired by the close association between cyclooxygenase-2 (COX-2) and tumor-associated angiogenesis, as well as tumor matrix formation, we proposed that tumor microenvironment normalization by COX-2 inhibitors might improve the distribution and efficacy of nanotherapeutics for solid tumors. The present study represents the first time that celecoxib, a special COX-2 inhibitor widely used in clinics, was explored to normalize the tumor microenvironment and to improve tumor nanotherapeutics delivery using a human-derived A549 tumor xenograft as the solid tumor model. Immunofluorescence staining of tumor slices demonstrated that oral celecoxib treatment at a dose of 200 mg/kg for two weeks successfully normalized the tumor microenvironment, including tumor-associated fibroblast reduction, fibronectin bundle disruption, tumor vessel normalization, and tumor perfusion improvement. Furthermore, it also significantly enhanced the in vivo accumulation and deep penetration of 22-nm micelles rather than 100-nm nanoparticles in tumor tissues by in vivo imaging and distribution experiments and improved the therapeutic efficacy of paclitaxel-loaded micelles in tumor xenograft-bearing mouse models in the pharmacodynamics experiment. As celecoxib is widely and safely used in clinics, our findings may have great potential in clinics to improve solid tumor treatment.

Association of anti‐inflammatory and antiangiogenic therapies negatively influences prostate cancer progression in TRAMP mice

“…In agreement, according to Zhang et al, 78 celecoxib administration promoted significant normalization of stromal microenvironment in solid xenograft tumors, including CAF population reduction, tumor vessel maturation, and perfusion improvement. In addition, taking into account that the immune system is able to influence fibroblast phenotype, 11 potential interferences on the inflammation process provided by anti-inflammatory drugs are expected to disturb CAF differentiation.…”

Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope

“…Although efficient in promoting the tumor accumulation, the clinical application of such strategies is hampered by safety concerns, high costs, and the intrinsic instability of biologic drugs. To tackle these limitations, delivery improvement of these agents and/or the use of alternative cost-effective and well-tolerated small molecules (e.g., the already available Celecoxib) are under investigation [109]. Additionally, another relevant drawback of TME alteration is the possible promotion of tumor progression and invasiveness [31].…”

Modification with CREKA Improves Cell Retention in a Rat Model of Myocardial Ischemia Reperfusion

“…The gene expression levels of M1 markers (IL‐6, iNOS) and M2 markers (IL‐10, Arg1) were measured by polymerase chain reaction (PCR). Overall, total RNA of macrophages cocultured with CREKA‐MSCs or MSCs was extracted and reversed according to the manufacturer's instructions . PCR was performed on Corbett Research Rotor‐Gene RG‐3000 PCR System (Qiagen) using a QuantiTect SYBR Green PCR kit (Qiagen, Valencia, CA).…”