Efficacy and Safety of Low-Dose Apatinib Combined with Chemotherapy as Second-Line Treatment for Advanced Gastric Cancer: A Meta-Analysis.

INTRODUCTION: At present, there are several studies on low-dose apatinib combined with chemotherapy as a second-line treatment of advanced gastric cancer (AGC), but the conclusions are controversial. Therefore, this meta-analysis aimed to evaluate the efficacy and safety of low-dose apatinib combined with chemotherapy as a second-line treatment of AGC. METHODS: Nine databases were searched for records on apatinib combined with chemotherapy in treating AGC from inception to June 2022. The observation group received low-dose apatinib combined with chemotherapy, while the controls received chemotherapy alone or other non-placebo treatments. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. The relative risk (RR) and weighted mean difference (WMD) were used as effect sizes. RESULTS: Eight studies involving 679 patients were included in this meta-analysis. The results of the meta-analysis showed that the observation group was superior to the controls in terms of ORR (RR = 1.38, 95% confidence interval [CI]: 1.05-1.81, p = 0.02), DCR (RR = 1.35, 95% CI: 1.20-1.53, p < 0.001), OS (WMD = 4.72, 95% CI: 0.71-8.72, p < 0.001), and PFS (WMD = 2.67, 95% CI: 1.7-3.63, p < 0.001). There were no significant differences between the two groups in adverse events of any grade except hypertension (RR = 2.82, 95% CI: 2.07-3.84, p < 0.001), hand-mouth syndrome (RR = 1.84, 95% CI: 1.84-2.48, p < 0.001), and proteinuria (RR = 3.63, 95% CI: 2.31-5.7, p < 0.001). CONCLUSION: Low-dose apatinib combined with chemotherapy as a second-line therapy is more effective in improving the efficacy of AGC compared to chemotherapy alone. However, this option has the potential to increase the risk of hypertension, hand-mouth syndrome, and proteinuria.

MRI analysis of hydrogel-loaded apatinib for local therapy of hepatocellular carcinoma model in nude mice.

AIM: To investigate the effect of local treatment of gadolinium-polyethylene glycol (Gd-PEG) hydrogel containing apatinib injected into hepatocellular carcinoma model of HepG2 in nude mice, and to evaluate the MRI findings in vivo. METHODS: HepG2 cells were treated in vitro and OD 450 value were measured. The four groups (n = 6) were Apatinib-Gd-PEG hydrogel, Gd-PEG hydrogel, Apatinib, and Saline. T1WI and DWI scans were performed before and 1d, 3d, and 14d postoperatively. The samples were examined by histomorphology and immunohistochemistry for CD34 and VEGFR2. Microvessel density (MVD) was evaluated and the average optical density (AOD) of VEGFR2 was obtained by IPP6.0 image software. RESULTS: The OD450-time curves of Gd-PEG hydrogel and phosphate buffer saline (PBS) were similar and that of apatinib at all concentrations are located below; the higher the concentration, the lower the curve. On T1WI and DWI, the newly injected Gd-PEG hydrogel showed significant high signal and was immobilized in the tumor. Subsequently, the size and signal of Gd-PEG hydrogel gradually decreased with time. In Apatinib-Gd-PEG hydrogel group, compared with other three groups, MRI and histomorphology showed that the necrotic area of hepatocellular carcinoma model was larger, immunohistochemistry displayed minimal expression of CD34 and VEGFR2, the AOD of VEGFR2 and MVD differed markedly. CONCLUSION: Gd-PEG hydrogel can significantly enhance and prolong the inhibitory effect of apatinib. It can be visualized by MRI, which can be used to evaluate the local therapeutic effect.

Nano-composite hydrogels of Cu-Apa micelles for anti-vasculogenic mimicry.

Vasculogenic mimicry (VM) describes the phenomenon whereby fluid-conducting vessels are formed by highly invasive tumour cells, which supply blood to tumours during their early growth stages. Single antiangiogenic agents have limited inhibitory effects on VM, therefore, a multi-pathway anti-VM strategy is required. In this study, Apatinib (Apa) was coordinated with Cu2+ to form a Cu-Apa copper complex. The latter was loaded into oligo-hyaluronic acid (HA) polymeric micelles (HA-Chol) and subsequently embedded in Astragalus polysaccharide-based in situ hydrogels (APsGels) to generate Cu-Apa/HA-Chol@APsGels. In this system, Cu-Apa exerts the combined effects of Cu2+ and Apa to inhibit VM; HA-Chol micelles achieve targeted drug delivery and enhance endocytosis efficiency; APsGels realise sustained release of the drugs to ensure an anti-VM effect. This system demonstrated improved VM inhibition with low cytotoxicity and high biocompatibility, wound healing, and transwell invasion in three-dimensional cell cultured VM. Moreover, this system significantly inhibited VM formation and melanoma growth in a mouse tumour transplantation model. This study provides an effective strategy for inhibiting VM.

Association of Apatinib and Breast Cancer: A systematic review and meta-analysis.

BACKGROUND: Breast cancer (BC) is a common malignant tumor. Apatinib in combination with other treatments has been used for BC; however, its safety and efficacy are not well-known. Therefore, this meta-analysis was performed to assess the efficacy and safety of apatinib in the treatment of BC. METHODS: Studies comparing the effects of apatinib-based therapy versus control among BC patients were included. On January 21, 2022, a systematic search was performed in 9 databases. The risk ratio (RR) with 95% confidence interval (CI) was used to estimate efficacy and safety. The I square value (I2) was used to assess heterogeneity. A leave-one-out sensitivity analysis was also conducted. Publication bias was assessed by funnel plots and Egger's and Begg's tests. RESULTS: A total of 31 studies including 2,258 BC patients were included. The results showed that apatinib group had a significant improvement in disease control rate (DCR, RR = 1.43, 95% CI = 1.35-1.52, I2 = 43.8%) and objective response rate (ORR, RR = 1.79, 95% CI = 1.51-2.13, I2 = 61.8%) compared to the control group. Except for hemorrhage, hypertension, and hand-foot syndrome, the adverse events were similar between apatinib group and control group. Subgroup analyses found statistically significant differences in DCR in all subgroups except for apatinib combined with radiation therapy and with paclitaxel liposome plus S1. For ORR, there were statistically significant differences in all subgroups except for the radiation therapy, and apatinib monotherapy subgroups. CONCLUSIONS: Our study shown apatinib showed good efficacy and acceptable safety in the treatment of BC patients. More high-quality randomized controlled trials from different regions and countries are needed to confirm our findings.

Apatinib plus 5-fluorouracil as a third or subsequent-line treatment option for metastatic colorectal cancer: a phase-II, single-arm, prospective study.

Background: For metastatic colorectal cancer (mCRC) patients for whom at least 2 lines of previous standard therapies have failed, the prognosis is often unfavorable due to very limited subsequent treatment options. We sought to explore the efficacy of apatinib, an oral small-molecule vascular endothelial growth factor receptor-2 inhibitor, plus 5-fluorouracil (5-FU) as a third- or subsequent-line treatment for mCRC. Methods: In this phase-II, single-arm, prospective study, the eligible patients had been histologically confirmed to have adenocarcinoma of the colon or rectum for which at least 2 previous regimens of standard therapies had failed. All the patients were treated with a daily dose of 250 mg of apatinib, in combination with capecitabine, Tegafur Gimeracil Oteracil Potassium Capsule (S-1), or 5-FU, until disease progression, unacceptable toxicity, or consent withdrawal. Results: From June 2017 to April 2018, 16 patients were enrolled in this study. Among them, 4 achieved partial response, 7 had stable disease, and 5 had progression disease, resulting in an objective response rate of 25.00% [95% confidence interval (CI): 7.27-52.38%], and a disease control rate of 68.75% (95% CI: 41.34-88.98%). The median progression-free survival (PFS) was 4.83 months (95% CI: 2.17-8.90 months), and the median overall survival (OS) was 9.10 months (95% CI: 5.59-15.18 months). The common treatment-related adverse events (AEs) were hand-foot syndrome (56.25%), hypertension (37.50%), proteinuria (37.50%), gingival bleeding (18.75%) and abdominal pain (18.75%). Grade 3 AEs, including hand-foot syndrome (18.75%), hypertension (12.50%), and proteinuria (12.50%), were observed in 7 patients. Conclusions: The combination regimen of apatinib plus 5-FU had encouraging anti-tumor efficacy, and is a feasible third- or subsequent-line treatment option for mCRC. Trial Registration: ClinicalTrials.gov Identifier: NCT03210064.

Effect of different doses of apatinib mesylate combined with chemotherapy on advanced oral cancer.

OBJECTIVE: To investigate the therapeutic effect and safety of different doses of apatinib mesylate combined with chemotherapy in the treatment of advanced oral cancer. METHODS: Totally 100 patients with advanced oral cancer admitted to our hospital from January 2019 to July 2020 were retrospectively analyzed and divided into a control group (500 mg apatinib mesylate combined with chemotherapy) and an experimental group (250 mg apatinib mesylate combined with chemotherapy). The two groups were compared in terms of the incidence of adverse reactions, treatment effective rate, disease control rate, objective response rate, Karnofsky performance status (KPS) score (quality of life), score of the mental status scale in non-psychiatric settings (MSSNS), survival rates and vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR-2) after treatment. In addition, logistic regression was used to analyze the influencing factors for KPS<85 after oral cancer treatment. RESULTS: The treatment effective rate, disease control rate, objective response rate, KPS score (quality of life), survival rates in the experimental group were all significantly improved compared to those in the control group (all P<0.05), and the incidence of adverse reactions, MSSNS score, and the levels of VEGF and VEGFR-2 after treatment in the experimental group were significantly lower than those in the control group (all P<0.05). Furthermore, a history of smoking, a history of drinking, a tooth brushing index <3, the frequency of teeth cleansing ≤1 time per year, a history of oral diseases >3 times, and poor nutritional status were independent risk factors for KPS<85 after oral cancer treatment. CONCLUSION: Apatinib mesylate (250 mg) combined with chemotherapy can reach optimal efficacy with highest safety but least adverse effects for patients with advanced oral cancer.

Hyaluronic acid reduction-sensitive polymeric micelles achieving co-delivery of tumor-targeting paclitaxel/apatinib effectively reverse cancer multidrug resistance.

Multidrug resistance (MDR) of cancer cells is a significant challenge in chemotherapy, highlighting the urgent medical need for simple and reproducible strategies to reverse this process. Here, we report the development of an active tumor-targeting and redox-responsive nanoplatform (PA-ss-NP) using hyaluronic acid-g-cystamine dihydrochloride-poly-ε-(benzyloxycarbonyl)-L-lysine (HA-ss-PLLZ) to co-deliver paclitaxel (PTX) and apatinib (APA) for effective reversal of MDR. This smart nanoplatform specifically bound to CD44 receptors, leading to selective accumulation at the tumor site and uptake by MCF-7/ADR cells. Under high concentrations of cellular glutathione (GSH), the nanocarrier was degraded rapidly with complete release of its encapsulated drugs. Released APA effectively inhibited the function of the P-glycoprotein (P-gp) drug pump and improved the sensitivity of MDR cells to chemotherapeutic agents, leading to the recovery of PTX chemosensitivity in MDR cells. As expected, this newly developed intelligent drug delivery system could effectively control MDR, both in vitro and in vivo.

Evaluating supersaturation in vitro and predicting its performance in vivo with Biphasic gastrointestinal Simulator: A case study of a BCS IIB drug.

This study aimed to develop an evaluation approach for supersaturation by employing an in vitro bio-mimicking apparatus designed to predict in vivo performance. The Biphasic Gastrointestinal Simulator (BGIS) is composed of three chambers with absorption phases that represent the stomach, duodenum, and jejunum, respectively. The concentration of apatinib in each chamber was detected by fiber optical probes in situ. The dissolution data and the pharmacokinetic data were correlated by GastroplusTM. The precipitates were characterized by polarizing microscope, Scanning Electron Microscopy, Powder X-ray diffraction and Differential scanning calorimetry. According to the results, Vinylpyrrolidone-vinyl acetate copolymer (CoPVP) prolonged supersaturation by improving solubility and inhibiting crystallization, while Hydroxypropyl methylcellulose (HPMC) prolonged supersaturation by inhibiting crystallization alone. Furthermore, a predictive in vitro-in vivo correlation was established, which confirmed the anti-precipitation effect of CoPVP and HPMC on in vitro performance and in vivo behavior. In conclusion, CoPVP and HPMC increased and prolonged the supersaturation of apatinib, and then improved its bioavailability. Moreover, BGIS was demonstrated to be a significant approach for simulating in vivo conditions for in vitro-in vivo correlation in a supersaturation study. This study presents a promising approach for evaluating supersaturation, screening precipitation inhibitors in vitro, and predicting their performances in vivo.

Initial Therapy of Advanced Anaplastic Thyroid Cancer via Targeting VEGFR-2: A Case Report.

Preclinical studies have demonstrated that Apatinib, major targeting vascular endothelial growth factor receptor-2 (VEGFR-2), could inhibit the proliferation of anaplastic thyroid carcinoma (ATC) cells in vitro and in vivo. The efficacy and safety in ATC patients, however, remains unknown. Here, we report the case of a 93-year-old female with advanced ATC who initially treated with Apatinib. The tumor shrank notably 4 weeks after the initiation of therapy, which sustained for more than 30 weeks. The cervical CT illuminated a stable disease with a best response of 19.7% of the primary lesion and shrinkage of the metastatic lymph node. Adverse events, including hypertension, dental ulcer, hand-foot syndrome, fatigue, and anorexia, were observed and lightened with supportive treatment and dose reductions. The overall survival of the patient was 41 weeks. This is the first report describing the effectiveness of the VEGFR-2 inhibitor for the treatment of advanced ATC, warranting clinical trials to further ascertain its utility in this challenging setting.

Enhanced uptake and improved anti-tumor efficacy of doxorubicin loaded fibrin gel with liposomal apatinib in colorectal cancer.

Colorectal cancer (CRC) exhibited high incidence rate worldwide and the advanced CRC had a poor prognosis. Thereupon, seeking efficient treatment for CRC is critical. Apatinib is a novel vascular epithelial growth factor receptor (VEGFR) inhibitor with inspiring therapeutic effect in some malignant cancers. In our study, doxorubicin was mixed in fibrin gel and apatinib was encapsulated with self-synthesized liposome. The results showed liposomal apatinib (Lipo-Apatinib) could enhance the intracellular uptake of doxorubicin in vitro. Moreover, compared with doxorubicin loaded fibrin gel (DOX-FG) alone, the combination of DOX-FG and Lipo-Apatinib significantly improved the anti-tumor effect in mice CRC subcutaneous model and abdominal metastasis model Drug combination successfully inhibited tumor angiogenesis and tumor proliferation, and also promoted tumor apoptosis. Our data suggested that combined therapy of DOX-FG and Lipo-Apatinib would be a promising treatment approach for CRC.

Good local tumor control but lethal hemorrhage after apatinib treatment for intractable squamous carcinoma of the floor of the mouth: a case report.

The treatment of repeatedly recurrent carcinoma of the floor of the mouth (FOM) is challenging. There is no standard strategy for such patients with poor physical condition after multiple lines of treatment. Angiogenesis is a key in tumor initiation, growth, and dissemination. Apatinib, a potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), has been approved for the treatment of late-stage gastric or gastroesophageal junction adenocarcinoma that is resistant to at least two lines of chemotherapy. Its application in intractable FOM squamous carcinoma has never been described before. Herein, we present the case of a heavily treated patient with FOM squamous carcinoma undergoing a third local relapse in the right region of the neck and anterior cervical region. Oral apatinib was administered daily at a dose of 250 mg. There was clear and rapid efficacy that led to complete remission. However, giant, deep ulcers formed due to tumor necrosis. The patient eventually died of massive bleeding resulting from the major cervical vascular rupture caused by tumor necrosis and erosion. This case is novel and instructional, highlighting that apatinib might be effective, with manageable toxicity, for certain patients with refractory head and neck squamous cell carcinoma (HNSCC). The advantages and disadvantages of apatinib should be carefully evaluated, and close surveillance and quick intervention as required are critical to reduce fatal cancer-associated complications. The role of apatinib in recurrent or metastatic HNSCC needs to be clarified by multicenter trials in the near future.

Apatinib-loaded nanoparticles suppress vascular endothelial growth factor-induced angiogenesis and experimental corneal neovascularization.

Pathological angiogenesis is one of the major symptoms of severe ocular diseases, including corneal neovascularization. The blockade of vascular endothelial growth factor (VEGF) action has been recognized as an efficient strategy for treating corneal neovascularization. In this study, we aimed to investigate whether nanoparticle-based delivery of apatinib, a novel and selective inhibitor of VEGF receptor 2, inhibits VEGF-mediated angiogenesis and suppresses experimental corneal neovascularization. Water-insoluble apatinib was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro angiogenesis assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles potently inhibited VEGF-induced tube formation, scratch wounding migration, and proliferation of human endothelial cells. In a rat model of alkali burn injury-induced corneal neovascularization, a subconjunctival injection of Apa-HSA-PEG nanoparticles induced a significant decrease in neovascularization compared to that observed with an injection of free apatinib solution or phosphate-buffered saline. An in vivo distribution study using HSA-PEG nanoparticles loaded with fluorescent hydrophobic model drugs revealed the presence of a substantial number of nanoparticles in the corneal stroma within 24 h after injection. These in vitro and in vivo results demonstrate that apatinib-loaded nanoparticles may be promising for the prevention and treatment of corneal neovascularization-related ocular disorders.

Cyclic RGD peptide-modified liposomal drug delivery system for targeted oral apatinib administration: enhanced cellular uptake and improved therapeutic effects.

Apatinib is an oral tyrosine kinase inhibitor, which selectively targets vascular endothelial growth factor receptor 2 and has the potential to treat many tumors therapeutically. Cyclic arginylglycylaspartic acid (cRGD)- and polyethylene glycol (PEG)-modified liposomes (cRGD-Lipo-PEG) were constructed to act as a targeted delivery system for the delivery of apatinib to the human colonic cancer cell line, HCT116. These cRGD-modified liposomes specifically recognized integrin αvß3 and exhibited greater uptake efficiency with respect to delivering liposomes into HCT116 cells when compared to nontargeted liposomes (Lipo-PEG), as well as greater death of tumor cells and apoptosis. The mechanism by which cRGD-Lipo-PEG targets cells was elucidated further with competition assays. To determine the anticancer efficacy in vivo, nude mice were implanted with HCT116 xenografts and treated with apatinib-loaded liposomes or free apatinib intravenously or via intragastric administration. The active and passive targeting of cRGD-Lipo-PEG led to significant tumor treatment targeting ability, better inhibition of tumor growth, and less toxicity when compared with treatments using uncombined apatinib. The results presented strongly support the case for cRGD-Lipo-PEG representing a targeted delivery system for apatinib in the treatment of colonic cancer.

pH-responsive carboxymethyl chitosan-derived micelles as apatinib carriers for effective anti-angiogenesis activity: Preparation and in vitro evaluation.

In this study, carboxymethyl chitosan-graft-poly-(ε-caprolactone) copolymers (CMCS-g-PCL) were synthesized and used to encapsulate apatinib to prepare apatinib-loaded CMCS-g-PCL (CPA) micelles. CPA micelles' sizes were 100-150nm at pH 7.4 while aggregated to 300-350nm at pH 6.4, and the release rate at pH 6.4 was faster than pH 7.4, indicating CPA micelles have a pH-responsive activity. Furthermore, the release rate decreased with an increased grafting ratio of CMCS-g-PCL, which was shown by the results of release experiments from CPA-2 to CPA-10 micelles. A series of cell experiments demonstrated that blank micelles were non-toxic for human umbilical endothelial cells (HUVECs) below 0.125mg/ml, CPA micelles had significant inhibiting effect on HUVECs as IC50 was near 3.125µg/ml, and the drug effect could be adjusted by altering grafting ratio of CMCS-g-PCL. These results suggest that CPA micelles may be used as an effective drug delivery system for anti-angiogenesis cancer therapy.