Oral delivery of Sunitinib malate using carboxymethyl cellulose/poly(acrylic acid-itaconic acid)/Cloisite 30B nanocomposite hydrogel as a pH-responsive carrier.

This work aimed to fabricate a Cloisite 30B-incorporated carboxymethyl cellulose graft copolymer of acrylic acid and itaconic acid hydrogel (Hyd) via a free radical polymerization method for controlled release of Sunitinib malate anticancer drug. The synthesized samples were characterized by FTIR, XRD, TEM, and SEM-dot mapping analyses. The encapsulation efficiency of Hyd and Hyd/Cloisite 30B (6 wt%) was 81 and 93%, respectively, showing the effectiveness of Cloisite 30B in drug loading. An in vitro drug release study showed that drug release from all samples in a buffer solution with pH 7.4 was higher than in a buffer solution with pH 5.5. During 240 min, the cumulative drug release from Hyd/Cloisite 30B (94.97% at pH 7.4) is lower than Hyd (53.71% at pH 7.4). Also, drug-loaded Hyd/Cloisite 30B (6 wt%) demonstrated better antibacterial activity towards S. Aureus bacteria and E. Coli. High anticancer activity of Hyd/Cloisite 30B against MCF-7 human breast cancer cells was shown by the MTT assay, with a MCF-7 cell viability of 23.82 ± 1.23% after 72-hour incubation. Our results suggest that Hyd/Cloisite 30B could be used as a pH-controlled carrier to deliver anticancer Sunitinib malate.

Glassy carbon electrodes modified with graphitic carbon nitride nanosheets and CoNiO2 bimetallic oxide nanoparticles as electrochemical sensor for Sunitinib detection in human fluid matrices and pharmaceutical samples.

A sophisticated electrochemical sensor is presented employing a glassy carbon electrode (GCE) modified with a novel composite of synthesized graphitic carbon nitride (g-C3N4) and CoNiO2 bimetallic oxide nanoparticles (g-C3N4/CoNiO2). The sensor's electrocatalytic capabilities for Sunitinib (SUNI) oxidation were demonstrated exceptional performance with a calculated detection limit (LOD) of 52.0 nM. The successful synthesis and integrity of the composite were confirmed through meticulous characterization using various techniques. FT-IR analysis affirmed the successful synthesis of g-C3N4/CoNiO2 by providing insights into its molecular structure. XRD, FE-SEM, SEM-EDX, and BET analyses collectively validated the material's structural integrity, surface morphology, and electrocatalytic performance. Optimization of key analytical parameters, such as loading volume, concentration, electrolyte solution type, and pH, enhanced the electrocatalytic sensing capabilities of g-C3N4/CoNiO2. The synergistic interaction between g-C3N4 and CoNiO2 bimetallic oxide nanoparticles executed the sensor highly effective in the electrical oxidation of SUNI. Across a concentration range of 0.1-83.8 µM SUNI, the anodic peak current exhibited a linear increase with good precision. Application of the newly developed g-C3N4/CoNiO2 system to detect SUNI in a variety of samples, including urine, human serum, and capsule dosage forms, obtained satisfactory recoveries ranging from 97.1 to 103.0%. This methodology offers a novel approach to underscore the potential of the developed sensor for applications in biological and pharmaceutical monitoring.

Time trends for drug specific adverse events in patients on sunitinib; implications for remote monitoring.

INTRODUCTION: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor used to treat metastatic renal cell carcinoma (mRCC). Patients on sunitinib do require regular in-person appointments to monitor for adverse events (AEs). Given the Covid-19 pandemic, regular in-person visits expose patients to an increased risk of infection in addition to potentially preventable travel costs. This study investigated the feasibility of implementing a remote monitoring strategy for patients being treated with sunitinib for mRCC by examining the time trends of AEs. MATERIALS AND METHODS: In this retrospective chart review of patients with a diagnosis of mRCC, 167 patients received sunitinib during their treatment. The time between initiation of treatment and the first AE was recorded. The AEs were categorized according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5. Survival analysis was used to calculate the time-to-AE. RESULTS: Of the 167 patients identified, 145 experienced an AE (86.8%). Hypertension was the most common AE with 80% of AEs were ≤ Grade 2. Incidence of AE dropped by 91% after 3 months follow up and a further 36% after 6 months. The cumulative incidence of AEs were 87.8%, 94.6% and 98.0%, at 3, 6 and 9 months respectively. The severity of AEs observed were 39.3%, 38.6%, 20.7%, 1.4%,0% of Grade 1-5 events respectively. A trend of grade migration to less severe grades was also shown over time, with percentage of Grade ≥ 3 toxicity dropping from 22% between 0-3 months to 14% beyond 6 months follow up. CONCLUSIONS: The role of remote monitoring for mRCC patients on sunitinib remains relevant now with new waves of the Covid-19 pandemic, triggered by novel variants. The majority of AEs observed were of low severity ≤ Grade 2, with a trend of reduced AE frequency and severity most prevalent beyond 3 months of follow up. This data appears to support the implementation of a remote monitoring strategy 3 months after initiation of treatment.

Microwave-assisted solid-phase synthesis of nitrogen-doping carbon dot with good solvent compatibility and its sensing of sunitinib.

Microwave-assisted solid-phase synthesis method was simple, convenient, and fast, and herein adopted to produce nitrogen-doping carbon dots (N-CDs) in only 3 min. The N-CDs possessed high fluorescence quantum yield up to 15.9% with satisfactory stability to the environmental pH, ionic strength, and ultraviolet radiation. Particularly, the N-CDs had excellent dispersibility in both water and water-compatible organic solvents with similar fluorescence properties. Sunitinib, a small-molecule tyrosine inhibitor effective for some solid tumors, was found to quench the fluorescence of N-CDs in these media via the inner-filter effect. Hence, it was convenient to combine the proper sample pretreatment with the N-CD probe for sensing sunitinib avoiding the medium incompatibility problem. For rat plasma sample, salting-out liquid-liquid extraction was employed to minimize the sample matrix and concentrate the target sunitinib from aqueous to acetonitrile. The fluorescence detection of sunitinib was then achieved in acetonitrile by the addition of the proper amount of N-CDs. The method provided a good linearity of 0.1 µg/mL to 7 µg/mL with a limit of detection of 30 ng/mL, which met the requirement of the therapeutic drug monitoring of sunitinib. The developed method was potential for on-site detection of sunitinib.

Development of a Competitive Enzyme-Linked Immunosorbent Assay for the Determination of Sunitinib Unaffected by Light-Induced Isomerization.

Sunitinib is an oral multi-targeted tyrosine kinase inhibitor approved for treating metastatic renal cell carcinoma. This study reports a specific and sensitive competitive enzyme-linked immunosorbent assay (ELISA) for the pharmacokinetic evaluation of sunitinib. Anti-sunitinib serum was obtained from mice by using N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (DFPC) as a hapten, which has the same substructure as sunitinib, in order to avoid the effects of structural changes in the geometrical isomers of sunitinib. Enzyme labeling of sunitinib with horseradish peroxidase was similarly performed using DFPC. Serum sunitinib concentrations below the limit of quantification of 0.52 ng/mL were reproducibly measurable. This ELISA was specific for sunitinib (Z- and E-isomers) and showed very low cross-reactivity (0.094%) with its major metabolite, N-desethyl sunitinib. Its analytical applicability was demonstrated by a kinetic study with human liver microsomes. In addition, the levels of sunitinib measured by ELISA in a kinetic study with human liver microsomes were comparable with those measured by HPLC, and there was a strong correlation between the values determined by both methods (y = 1.065x - 51.2, R2 = 0.9804). The developed ELISA provides for the specific and sensitive quantification of sunitinib without the influence of its major metabolite or light-induced geometric isomers. This ELISA will be a valuable tool in pharmacokinetic studies of sunitinib.

Sunitinib inhibits RNase L by destabilizing its active dimer conformation.

The pseudokinase (PK) RNase L is a functional ribonuclease and plays important roles in human innate immunity. The ribonuclease activity of RNase L can be regulated by the kinase inhibitor sunitinib. The combined use of oncolytic virus and sunitinib has been shown to exert synergistic effects in anticancer therapy. In this study, we aimed to uncover the mechanism of action through which sunitinib inhibits RNase L. We solved the crystal structures of RNase L in complex with sunitinib and its analogs toceranib and SU11652. Our results showed that sunitinib bound to the ATP-binding pocket of RNase L. Unexpectedly, the αA helix linking the ankyrin repeat-domain and the PK domain affected the binding mode of sunitinib and resulted in an unusual flipped orientation relative to other structures in PDB. Molecular dynamics simulations and dynamic light scattering results support that the binding of sunitinib in the PK domain destabilized the dimer conformation of RNase L and allosterically inhibited its ribonuclease activity. Our study suggested that dimer destabilization could be an effective strategy for the discovery of RNase L inhibitors and that targeting the ATP-binding pocket in the PK domain of RNase L was an efficient approach for modulating its ribonuclease activity.

Multiple conformational states of the HPK1 kinase domain in complex with sunitinib reveal the structural changes accompanying HPK1 trans-regulation.

Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) is a Ser/Thr kinase that operates via the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways to dampen the T-cell response and antitumor immunity. Accordingly, selective HPK1 inhibition is considered a means to enhance antitumor immunity. Sunitinib, a multi-receptor tyrosine kinase (RTK) inhibitor approved for the management of gastrointestinal stromal tumors (GISTs), renal cell carcinoma (RCC), and pancreatic cancer, has been reported to inhibit HPK1 in vitro In this report, we describe the crystal structures of the native HPK1 kinase domain in both nonphosphorylated and doubly phosphorylated states, in addition to a double phosphomimetic mutant (T165E,S171E), each complexed with sunitinib at 2.17-3.00-Å resolutions. The native nonphosphorylated cocrystal structure revealed an inactive dimer in which the activation loop of each monomer partially occupies the ATP- and substrate-binding sites of the partner monomer. In contrast, the structure of the protein with a doubly phosphorylated activation loop exhibited an active kinase conformation with a greatly reduced monomer-monomer interface. Conversely, the phosphomimetic mutant cocrystal structure disclosed an alternative arrangement in which the activation loops are in an extended domain-swapped configuration. These structural results indicate that HPK1 is a highly dynamic kinase that undergoes trans-regulation via dimer formation and extensive intramolecular and intermolecular remodeling of the activation segment.

Paclitaxel/sunitinib-loaded micelles promote an antitumor response in vitro through synergistic immunogenic cell death for triple-negative breast cancer.

Chemotherapy-induced immunogenic cell death (ICD) may offer a strategy to improve the effect of the therapeutic treatment of triple-negative breast cancer (TNBC) by eliciting broad antitumor immunity. However, chemotherapy shows a limited therapeutic effect because of multi-drug resistance and the immunosuppressive tumor microenvironment (TME) of TNBC. The unique pharmacological actions of sunitinib (SUN) indicate its possible synergies with paclitaxel (PTX) to enhance chemo-immunotherapy for TNBC. Here, we prepared a co-delivery platform composed of poly(styrene-co-maleic anhydride) (SMA) via a self-assembly process for a combination of PTX and SUN, which was able to induce a higher synergistic ICD. The nanomicellar delivery of PTX and SUN loaded at an optimal ratio of 1:5 (PTX:SUN) presented the characteristics of an appropriate particle size, long-term stability, and time sequence release which synergistically promoted the apoptosis of MDA-MB-231 tumor cells. Moreover, we demonstrated that the combination of PTX and SUN could significantly induce a synergistic effect because it promoted an ICD response, improved tumor immunogenicity, and regulated immunosuppressive factors in the TME. Overall, PTX and SUN with synergistic effects entrapped in a self-assembly nano-delivery system could offer the potential for clinical applicationof a combination chemo-immunotherapy strategy to improve the effect of the therapeutic treatment of TNBC.

Integrin-targeted AmpRGD sunitinib liposomes as integrated antiangiogenic tools.

We report here the preparation, physico-chemical characterization, and biological evaluation of a new liposome formulation as a tool for tumor angiogenesis inhibition. Liposomes are loaded with sunitinib, a tyrosine kinase inhibitor, and decorated with cyclo-aminoprolineRGD units (cAmpRGD), efficient and selective ligands for integrin αVß3. The RGD units play multiple roles since they target the nanovehicles at the integrin αVß3-overexpressing cells (e.g. activated endothelial cells), favor their active cell internalization, providing drug accumulation in the cytoplasm, and likely take part in the angiogenesis inhibition by interfering in the αVß3-VEGFR2 cross-talk. Both in vitro and in vivo studies show a better efficacy of this integrated antiangiogenic tool with respect to the free sunitinib and untargeted sunitinib-loaded liposomes. This system could allow a lower administration of the drug and, by increasing the vector specificity, reduce side-effects in a prolonged antiangiogenic therapy.

The influence of light sources on sunitinib measurements with photoisomerization.

Sunitinib is an orally administered tyrosine kinase inhibitor. Therapeutic drug monitoring is an important component of the follow-up of patients because of high interpatient variability in the pharmacokinetics of sunitinib and large variabilities in its efficacy and toxicity. The aim of the present study was to examine the light stability of sunitinib and confirm the effects of light exposure on sunitinib measurements by LC-MS/MS. Sunitinib and its active metabolite, SU12662, convert Z isomers to E isomers with exposure to light. The Z-E photoisomerization ratio reached a plateau at 35% for both E isomers in methanol within 15 min of normal light exposure (700 lx). However, the Z isomer of the sunitinib and SU12662 peak area ratios in plasma decreased by 10% within 15 min. These results suggest that sunitinib samples need to be handled without light exposure in all sample preparation steps. Alternatively, it should be measured sunitinib and SU12662 after the sample has reached photoisomerical equilibrium. These results suggest that the sunitinib therapeutic range changes depending on light conditions during sample handling in sunitinib and SU12662 measurements.

Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML.

Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Sunitinib, a multikinase inhibitor, was the first Fms-like tyrosine kinase 3 (FLT3) inhibitor clinically used against AML. Off-target effects are a major concern for multikinase inhibitors. As targeted delivery may reduce such undesired side effects, our goal was to develop novel amino acid substituted derivatives of sunitinib which are potent candidates to be used conjugated with antibodies and peptides. In the current paper we present the synthesis, physicochemical and in vitro characterization of sixty two Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutant kinase inhibitors, bearing amino acid moieties, fit to be conjugated with peptide-based delivery systems via their carboxyl group. We determined the solubility, pKa, CHI and LogP values of the compounds along with their inhibition potential against FLT3-ITD mutant kinase and on MV4-11 cell line. The ester derivatives of the compounds inhibit the growth of the MV4-11 leukemia cell line at submicromolar concentration.

Multi-parameter MRI to investigate vasculature modulation and photo-thermal ablation combination therapy against cancer.

Nanotransducer-mediated photothermal therapy (PTT) has emerged as an attractive therapy modality against cancer, but its efficacy is often limited by the amount of nanoparticles delivered to tumors. Previous studies showed a vasculature modulation treatment, which dilates or prunes tumor blood vessels, may enhance tumor uptake of nanoparticles. However, exploiting these approaches for improved PTT has seldom been studied. In this study, we investigated the impact of mild hyperthermia or anti-angiogenesis therapy on PTT. Briefly, we gave tumor-bearing balb/c mice low doses of sunitinib or submerged tumors in a 42 °C water bath. Next, we injected PEGylated reduced graphene oxide (RGO-PEG) and irradiated the tumors to induce PTT. We then followed up the treatment with multi-parameter MRI. Contrary to expectation, both vessel modulation strategies led to diminished PTT efficacy. Our results show that vessel modulation does not warrant improved PTT, and should be carefully gauged when used in combination with PTT.

Near-infrared light-activated IR780-loaded liposomes for anti-tumor angiogenesis and Photothermal therapy.

Tumor angiogenesis is a key step in the process of tumor development, and antitumor angiogenesis has a profound influence on tumor growth. Herein we report a dual-function drug delivery system comprising a Near-infrared (NIR) dye and an anti-angiogenic drug within liposomes (Lip-IR780-Sunitinib) for enhanced antitumor therapy. The hydrophobic NIR dye IR780 was loaded into the liposome phospholipid bilayer, and the bilayer would be disrupted by laser irradiation so that anti-angiogenic drug sunitinib release would be activated remotely at the tumor site. The released hydrophilic sunitinib could potentially target multiple VEGF receptors on the tumor endothelial cell surface to inhibit angiogenesis. Meanwhile, IR780-loaded liposomes kill the cancer cells by photothermal therapy. Lip-IR780-Sunitinib exhibited enhanced anti-tumor and anti-angiogenic effects in vitro and in vivo. This system facilitates easy and controlled release of cargos to achieve anti-tumor angiogenesis and photothermal therapy.

Characterization and optimization of magnetic molecularly imprinted nanofibers for determination of sunitinib in human serum and capsule samples.

This article reports a spectrofluorometric method for the determination of sunitinib (STB) drug based on molecularly imprinted nanofibers fabricated by the electrospinning method and modified by magnetic nanoparticles as sorbent. The characterization of magnetic molecularly imprinted nanofibers (MMINs) was carried out using X-ray diffraction (XRD), scanning electron microscope (SEM), and transmission electron microscopy (TEM), which confirmed the successful synthesis of MMINs with well-distributed magnetite nanoparticles. Drug adsorption and desorption were optimized and important parameters such as sample pH, nanofiber mass, adsorption and desorption time, eluent solvent and sample volume were analyzed. The results demonstrated that the MMINs act as a selective sorbent for STB and can be readily collected through an external magnetic field. Methanol was used as the best eluent solvent for STB desorption from MNIN. A linear correlation was observed between the STB concentrations and fluorescence intensities in the range of 0.01-15.0 mg L-1. The detection limit for this method was 0.002 mg L-1. The relative standard deviation (RSD) of 2.6 % for 1.0 mg L-1 and 1.1 % for 10 mg L-1 of STB (n = 3) were obtained, which indicates that the developed method is precise in determining STB. Human serum and capsule analysis show the applicability of the proposed sensor for real samples.

Development of dispersive solid phase extraction based on magnetic metal organic framework for the extraction of sunitinib in biological samples and its determination by high performance liquid chromatography-tandem mass spectrometry.

Herein, a simple, sensitive, and reliable dispersive solid phase extraction was reported for the efficient extraction of sunitinib from biological samples. To facilitate the extraction of the desired analyte from urine and plasma samples, magnetic MIL-101Cr (NH2) @SiO2 @ NiFe2O4 was synthesized by a hydrothermal method and applied as an effective sorbent during the extraction process. After adsorption of the drug using 10 mg of MIL-101Cr (NH2) @ SiO2 @ NiFe2O4 nanoparticles through vortexing (1 min), the sorbent was separatedfrom the sample solution using a magnet. To eluate the drug, the sorbent containing the sunitinib was contacted with 100 µL dimethylformamide. The eluent was analyzed by high performance liquid chromatography-tandem mass spectrometry. Reasonable validation data consisting of low limits of detection (0.14, 0.35, and 0.70 ng mL-1 in deionized water, plasma, and urine) and quantification (0.48, 1.2, and 2.4 ng mL-1 in deionized water, plasma, and urine, respectively), a wide linear range of the calibration curve (0.48-200, 1.2-200, and 2.4-100 ng mL-1 in deionized water, plasma, and urine, respectively) good extraction recovery (76 %), and low relative standard deviations for inter- and intra-day precisions (6.9 %) were obtained by the method. Eventually, the proposed procedure was effectively implemented on both plasma and urine samples, yielding successful outcomes.

Engineered Biomimetic Nanovesicles Synergistically Remodel Folate-Nucleotide and γ-Aminobutyric Acid Metabolism to Overcome Sunitinib-Resistant Renal Cell Carcinoma.

Reprogramming of cellular metabolism in tumors promoted the epithelial-mesenchymal transition (EMT) process and established immune-suppressive tumor microenvironments (iTME), leading to drug resistance and tumor progression. Therefore, remodeling the cellular metabolism of tumor cells was a promising strategy to overcome drug-resistant tumors. Herein, CD276 and MTHFD2 were identified as a specific marker and a therapeutic target, respectively, for targeting sunitinib-resistant clear cell renal cell carcinoma (ccRCC) and its cancer stem cell (CSC) population. The blockade of MTHFD2 was confirmed to overcome drug resistance via remodeling of folate-nucleotide metabolism. Moreover, the manganese dioxide nanoparticle was proven here by a high-throughput metabolome to be capable of remodeling γ-aminobutyric acid (GABA) metabolism in tumor cells to reconstruct the iTME. Based on these findings, engineered CD276-CD133 dual-targeting biomimetic nanovesicle EMφ-siMTHFD2-MnO2@Suni was designed to overcome drug resistance and terminate tumor progression of ccRCC. Using ccRCC-bearing immune-humanized NPG model mice, EMφ-siMTHFD2-MnO2@Suni was observed to remodel folate-nucleotide and GABA metabolism to deactivate the EMT process and reconstruct the iTME thereby overcoming the drug resistance. In the incomplete-tumor-resection recurrence model and metastasis model, EMφ-siMTHFD2-MnO2@Suni reduced recurrence and metastasis in vivo. This work thus provided an innovative approach that held great potential in the treatment of drug-resistant ccRCC by remodeling cellular metabolism.

A new high-performance liquid chromatography-tandem mass spectrometry method for the determination of sunitinib and N-desethyl sunitinib in human plasma: Light-induced isomerism overtaking towards therapeutic drug monitoring in clinical routine.

Sunitinib is approved for advanced renal cell cancer, imatinib-resistant or -intolerant gastrointestinal stromal tumors and pancreatic neuroendocrine cancers. It is prescribed at a fixed dose but its plasma exposure shows large inter-individual variations. Taking into account the narrow therapeutic window and the positive exposure-efficacy relationship, there is a robust rationale for its therapeutic drug monitoring. In fact, a target plasma concentration of sunitinib plus its active metabolite, N-desethyl sunitinib, ≥50 ng/mL was suggested. In order to quantify sunitinib and N-desethyl sunitinib in patients' plasma, we developed and validated a new LC-MS/MS method applicable to clinical routine. In solution, sunitinib and N-desethyl sunitinib undergo to photo-isomerization and many published methods overcome this problem by conducting the entire procedures of samples collection and handling under strictly light-protection. Our method is based on a simple and fast procedure that quantitatively reconverts the E-isomer of both analytes, obtained during sample draw and processing without light-protection, into their Z-forms. Moreover, our method uses a small plasma volume (30 µL) and the analytes are extracted by a rapid protein precipitation. It was validated according to EMA-FDA guidelines. The calibration curves resulted linear (R2 always >0.993) over the concentration ranges (0.1-500 ng/mL for sunitinib, 0.1-250 ng/mL for N-desethyl sunitinib) with a good precision (within 7.7 % for sunitinib and 10.8% for N- desethyl sunitinib) and accuracy (range 95.8-102.9% for sunitinib and 92.3-106.2% for N-desethyl sunitinib). This method was applied to a pharmacokinetic study in one patient treated with sunitinib. Moreover, as incurred samples reanalysis is an established part of the bioanalytical process to support clinical studies, its assessment was performed early in order to assure that any reproducibility issues was detected as soon as possible. The percentage difference between the two runs resulted within ±20% in all the re-analysed samples for both sunitinib and N- desethyl sunitinib.

Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles.

Neovascular age-related macular degeneration and diabetic retinopathy are prevalent causes of vision loss requiring frequent intravitreous injections of VEGF-neutralizing proteins, and under-treatment is common and problematic. Here we report incorporation of sunitinib, a tyrosine kinase inhibitor that blocks VEGF receptors, into a non-inflammatory biodegradable polymer to generate sunitinib microparticles specially formulated to self-aggregate into a depot. A single intravitreous injection of sunitinib microparticles potently suppresses choroidal neovascularization in mice for six months and in another model, blocks VEGF-induced leukostasis and retinal nonperfusion, which are associated with diabetic retinopathy progression. After intravitreous injection in rabbits, sunitinib microparticles self-aggregate into a depot that remains localized and maintains therapeutic levels of sunitinib in retinal pigmented epithelium/choroid and retina for more than six months. There is no intraocular inflammation or retinal toxicity. Intravitreous injection of sunitinib microparticles provides a promising approach to achieve sustained suppression of VEGF signaling and improve outcomes in patients with retinal vascular diseases.

Novel 2-indolinone thiazole hybrids as sunitinib analogues: Design, synthesis, and potent VEGFR-2 inhibition with potential anti-renal cancer activity.

Novel 2-indolinone thiazole hybrids were designed and synthesized as VEGFR-2 inhibitors based on sunitinib, an FDA-approved anticancer drug. The proposed structures of the prepared 2-indolinone thiazole hybrids were confirmed based on their spectral data and CHN analyses. The target compounds were screened in vitro for their anti-VEGFR-2 activity. All tested compounds exhibited a potent submicromolar inhibition of VEGFR-2 kinase with IC50 values ranging from 0.067 to 0.422 µM, relative to sunitinib reference drug (IC50 = 0.075 ± 0.002 µM). Compounds 5, 15a, 15b, 17, 19c displayed excellent VEGFR-2 inhibitory activity, comparable or nearly equipotent to sunitinib. Compound 13b stood out as the most potent against VEGFR-2 showing IC50 value of 0.067 ± 0.002 µM, lower than that of sunitinib. In addition, the most potent derivatives were assessed for their anticancer activity against two renal cancer cell lines. Compound 13b (IC50 = 3.9 ± 0.13 µM) was more potent than sunitinib (IC50 = 4.93 ± 0.16 µM) against CAKI-1 cell line. Moreover, thiazole 15b displayed excellent anticancer activity against CAKI-1 cell line (IC50 = 3.31 ± 0.11 µM), superior to that of sunitinib (IC50 = 4.93 ± 0.16 µM). Thiazole 15b was also equipotent to sunitinib (IC50 = 1.23 ± 0.04 µM) against A498 cell line. Besides, compound 15b revealed a safety profile much better than that of sunitinib against normal human renal cells. Furthermore, a docking study revealed a proper fitting of the most active compounds into the ATP binding site of VEGFR-2, rationalizing their potent anti-VEGFR-2 activity.

Local delivery of sunitinib and Ce6 via redox-responsive zwitterionic hydrogels effectively prevents osteosarcoma recurrence.

Surgery combined with adjuvant or neoadjuvant chemotherapy is still the standard treatment for osteosarcoma. However, the high risk of tumor recurrence and side effects of chemotherapy usually lead to high mortality for cancer patients. Herein, the multi-targeted receptor tyrosine kinase (RTK) inhibitor sunitinib (Sun) and photodynamic therapy (PDT) drug chlorin e6 (Ce6) were locally delivered to the postoperative tumor site via a zwitterionic hydrogel. This hydrogel exhibited excellent biocompatibility and redox responsiveness. In vitro study demonstrated that Sun/Ce6@Gel induced 143B human osteosarcoma cell apoptosis via downregulating the expression of Bcl-2 and upregulating the expression levels of Bax and caspase-3. Similarly, the in vivo study showed that Sun/Ce6@Gel provided sustained drug release under redox conditions, and then synergistically induced tumor apoptosis to prevent tumor recurrence without systemic toxicity. Therefore, local implantation of Sun/Ce6@Gel may be a promising topical therapeutic method for prevention of the recurrence of osteosarcoma after surgery.