Intratumoral Injection of Anlotinib Hydrogel Combined With Radiotherapy Reduces Hypoxia in Lewis Lung Carcinoma Xenografts: Assessment by Micro Fluorine-18-fluoromisonidazole Positron Emission Tomography/Computed Tomography Hypoxia Imaging

Abstract

Hypoxia is a common feature of solid tumors that increases tumor invasiveness and resistance to radiotherapy (RT) and chemotherapy. Local application of anlotinib (AL) might increase the regulation of new blood vessel growth and improve tumor hypoxia in RT. Therefore, it is essential to fully understand the drug delivery system of AL. Herein, we applied hypoxia imaging using micro fluorine-18-fluoromisonidazole positron emission tomography/computed tomography (micro 18F-FMISO PET/CT) to assess responses to intratumoral injections of an AL hydrogel (AL-HA-Tyr) combined with RT in mice bearing Lewis lung carcinoma (LLC). We formed AL-HA-Tyr by encapsulating AL with hyaluronic acid-tyramine (HA-Tyr) conjugates via the oxidative coupling of tyramine moieties catalyzed by H2O2 and horseradish peroxidase. AL-HA-Tyr restrained the proliferation of human umbilical endothelial cells (HUVECs) in colony formation assays in vitro (p < 0.001). We established a subcutaneous LLC xenograft model using C57BL/6J mice that were randomly assigned to six groups that were treated with AL, HA-Tyr, AL-HA-Tyr, RT, and RT+AL-HA-Tyr, or untreated (controls). Tumor volume and weight were dynamically measured. Post treatment changes in hypoxia were assessed in some mice using micro 18F-FMISO PET/CT, and survival was assessed in others. We histopathologically examined toxicity in visceral tissues and Ki-67, VEGF-A, γ-H2AX, and HIF-1α expression using immunohistochemistry. Direct intratumoral injections of AL-HA-Tyr exerted anti-tumor effects and improved hypoxia like orally administered AL (p > 0.05), but reduced visceral toxicity and prolonged survival. The uptake of 18F-FMISO did not significantly differ among the AL, AL-HA-Tyr, and RT+AL-HA-Tyr treated groups. Compared with the other agents, RT+AL-HA-Tyr decreased HIF-1α, Ki67, and VEGF-A expression, and increased γ-H2AX levels in tumor cells. Overall, compared with AL and AL-HA-Tyr, RT+AL-HA-Tyr improved tumor hypoxia, enhanced anti-tumor effects, and prolonged the survival of mice bearing LLC.

Anlotinib suppressed tumor cell proliferation and migration in hypopharyngeal carcinoma

“…Meanwhile, it can reduce tumor interstitial fluid pressure, increase drug penetration in tumors, and avoid hypoxia-induced immune escape. 16 , 17 Gao et al 20 found that anlotinib-treated lung cancer mouse models showed reduced HIF-1α expression. So, we assume that anlotinib may inhibit the tumor by regulating HIF-1α expression.…”

Self-Supplying of Hydrogen Peroxide/Oxygen Based on CaO2-Co3O4 Cascade Nanoreactors for Cellular Microenvironment Regulation

“…Although H 2 O 2 is overexpressed in cancer cells, its concentration is far from enough for chemodynamic therapy (CDT) . In addition, hypoxia can adversely affect the effectiveness of photodynamic therapy (PDT), sonodynamic therapy (SDT), and radiation therapy, thus increasing the degree of intracellular hypoxia. − Moreover, hypoxia can activate a sequence of targets such as glucose transporters and vascular endothelial growth factors, which can influence the occurrence, proliferation, and metastasis of tumor cells . Therefore, it is crucial to regulate hydrogen peroxide and oxygen in cancer cells to mitigate these challenges.…”

Gemcitabine Plus Anlotinib Is Effective and Safe Compared to Gemcitabine Plus Docetaxel in Advanced Soft Tissue Sarcoma

“…Increasing studies (17)(18)(19)(20) have shown that anti-angiogenesis in combination with chemotherapy yielded synergetic effects in several malignancies including breast cancer, lung cancer, and sarcomas. Preclinical studies (21,22) showed that anti-angiogenesis therapy not only induced tumor cell apoptosis but also induced tumor vascular normalization, improved hypoxia, and increased the delivery of chemotherapy drugs. In the ALTER0203 trial (12), anlotinib demonstrated superior ORR (10.13% vs. 1.33%) and median PFS (6.27 months vs. 1.47 months) over placebo in advanced STS after the failure of standard chemotherapy.…”