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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The programmed site-specific delivery of the angiostatin sunitinib and chemotherapeutic paclitaxel for highly efficient tumor treatment.

Malignant solid tumors are composed of tumor cells, stromal cells and the complex networks of the tumor microenvironment (TME), which is the underlying cause of the unsatisfactory outcome of conventional chemotherapy approaches only aimed at cancer cell killing. In this study, a novel TME-responsive polymeric micelle has been developed for the programmed site-specific delivery of the angiostatin sunitinib and chemotherapeutic paclitaxel (PTX). The pH-sensitive micelle core encapsulates PTX, while ß-cyclodextrin molecules being conjugated to the micelle shell via matrix metalloproteinase 2 (MMP-2) sensitive peptides include sunitinib. Following the pH and MMP-2 dual sensitive structure design, the micelle may sequentially release sunitinib inside the tumor extracellular matrix and PTX into cancer cells through responding to enriched MMP-2 levels and decreased pH, respectively. Consequently, the anti-angiogenesis effect of sunitinib and tumor cell-killing effect of PTX synergize, resulting in highly efficient tumor treatment.

HP-1 inhibits the progression of ccRCC and enhances sunitinib therapeutic effects by suppressing EMT.

Trametes robiniophila Murr (Huaier) has been used for many years as an adjuvant treatment for tumors. Sunitinib is the first-line therapy for end-stage renal cancer, but its side effects and drug resistance limit its clinical application. Cell counting kit- 8 (CCK-8), colony formation, scratch, and Transwell assays showed that Huaier polysaccharide (HP-1) reduced tumor progression. Its combination with sunitinib elicited stronger antitumor effects, including induction of apoptosis and cycle arrest. HP-1-induced effects depended on CIP2A downregulation and suppression of the EMT process. Moreover, qPCR and western blotting experiments showed that CIP2A downregulation was particularly pronounced after treatment with the combination therapy and was associated with EMT suppression. In addition, the HP-1/sunitinib combination inhibited the PI3K/Akt/VEGFR pathway, reducing the expression of pathway-related proteins. The HP-1-induced enhancement of sunitinib effects on tumor growth were also observed in vivo in a xenograft mouse model. Overall, these results indicated that HP-1 exerted antitumor effects against clear cell renal cell carcinoma (ccRCC) and enhanced the therapeutic efficacy of sunitinib.

Carrier-Enhanced Anticancer Efficacy of Sunitinib-Loaded Green Tea-Based Micellar Nanocomplex beyond Tumor-Targeted Delivery.

Although a few nanomedicines have been approved for clinical use in cancer treatment, that recognizes improved patient safety through targeted delivery, their improved efficacy over conventional drugs has remained marginal. One of the typical drawbacks of nanocarriers for cancer therapy is a low drug-loading capacity that leads to insufficient efficacy and requires an increase in dosage and/or frequency of administration, which in turn increases carrier toxicity. In contrast, elevating drug-loading would cause the risk of nanocarrier instability, resulting in low efficacy and off-target toxicity. This intractable drug-to-carrier ratio has imposed constraints on the design and development of nanocarriers. However, if the nanocarrier has intrinsic therapeutic effects, the efficacy would be synergistically augmented with less concern for the drug-to-carrier ratio. Sunitinib-loaded micellar nanocomplex (SU-MNC) was formed using poly(ethylene glycol)-conjugated epigallocatechin-3-O-gallate (PEG-EGCG) as such a carrier. SU-MNC specifically inhibited the vascular endothelial growth factor-induced proliferation of endothelial cells, exhibiting minimal cytotoxicity to normal renal cells. SU-MNC showed enhanced anticancer effects and less toxicity than SU administered orally/intravenously on human renal cell carcinoma-xenografted mice, demonstrating more efficient effects on anti-angiogenesis, apoptosis induction, and proliferation inhibition against tumors. In comparison, a conventional nanocarrier, SU-loaded polymeric micelle (SU-PM) comprised of PEG-b-poly(lactic acid) (PEG-PLA) copolymer, only reduced toxicity with no elevated efficacy, despite comparable drug-loading and tumor-targeting efficiency to SU-MNC. Improved efficacy of SU-MNC was ascribed to the carrier-drug synergies with the high-performance carrier of PEG-EGCG besides tumor-targeted delivery.

Using molecular dynamics simulation to explore the binding of the three potent anticancer drugs sorafenib, streptozotocin, and sunitinib to functionalized carbon nanotubes.

The adsorption of the anticancer drugs sorafenib (SF), streptozotocin (STZ), and sunitinib (STB) on pristine and functionalized carbon nanotubes (FCNTs, functionalized with valine or phenylalanine moieties) was investigated using molecular dynamics simulation. Descriptors such as the van der Waals (vdW) energy, the number of hydrogen bonds, and the radial distribution function were considered. It was found that the type of functional group on the nanotube is a key influence on the vdW interaction energy between a drug molecule and a nanotube. In addition, the positions of the functional groups on a nanotube are a key influence on the adsorption of drug molecules on its surface. Our study indicated that the adsorption of STZ on CNT/FCNTs involves a partial π-π interaction and hydrogen bonding, whereas SF and STB are adsorbed on CNT/FCNTs through π-π stacking and hydrogen bonding. Our results suggest that altering the functionalization of the nanotube surface can affect the drug-nanotube interaction. The results reported here should aid attempts to optimize the design of novel CNT-based drug carriers.

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.

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.

Exploring binding mechanisms of VEGFR2 with three drugs lenvatinib, sorafenib, and sunitinib by molecular dynamics simulation and free energy calculation.

Lenvatinib (LEN), sorafenib (SOR), and sunitinib (SUN) are drugs targeting vascular endothelial growth factor receptor 2 (VEGFR2). Despite sharing similar chemical structures and bioactivities, LEN and SOR bind to different functional states of VEGFR2, viz. DFG-in and DFG-out state, respectively. SUN binds to the DFG-out state of VEGFR2 just like SOR but with less potency. Thus, detail binding mechanisms between VEGFR2 and these drugs, especially dynamic interaction, are valuable for future drug design. In the present work, molecular dynamics simulation, essential dynamic analysis, and molecular mechanics/generalized born surface area were performed to these VEGFR2-drugs systems. Rank of calculated binding affinities is in accordance with the experimental data. The binding free energy calculation suggests that van der Waals interaction plays a vital role in the binding. Per-residue free energy decomposition indicates that residues L840, V848, A866, E885, L889, V899, V916, F918, C919, L1035, C1045, D1046, and F1047 play an important role in the binding between VEGFR2 and LEN/SOR. While residues L840, V848, E917, F918, C919, G922, L1035, and F1047 contribute the major hydrophobic interaction for SUN binding to the receptor. Our results also reveal that residue E885/D1046 plays a vital role in binding via forming hydrogen bonds with drugs.

A CD44-Targeting Programmable Drug Delivery System for Enhancing and Sensitizing Chemotherapy to Drug-Resistant Cancer.

Programmable drug delivery systems hold great promise to enhance cancer treatment. Herein, a programmable drug delivery system using a chondroitin sulfate (CS)-based composite nanoparticle was developed for enhancing and sensitizing chemotherapy to drug-resistant cancer. The nanoparticle was composed of a cross-linked CS hydrogel shell and hydrophobic cores containing both free drugs and CS-linked prodrugs. Interestingly, the nanoparticle could mediate tumor-specific CD44 targeting. After specific cellular uptake, the payloads were suddenly released because of the decomposition of the CS shell, and the free drug molecules with synergistic effects induced tumor-specific cytotoxicity rapidly. Subsequently, the inner cores of the nanoparticles sustainedly release their cargos in drug-resistant tumor cells to keep the effective drug concentration against the drug efflux mediated by P-glycoprotein. CS dissociated from the outer shell and sensitized cancer cells to the antitumor drugs through downregulation of Bcl-XL, an antiapoptosis protein. Such a programmable drug delivery system with specific tumor-targeting and sensitized therapy is promising for rational drug delivery and provides more versatility for controlled release in biomedical applications.

Controlling methacryloyl substitution of chondroitin sulfate: injectable hydrogels with tunable long-term drug release profiles.

Drug delivery systems capable of local sustained release of small molecule therapeutics remain a critical need in many fields, including oncology. Here, a system to create tunable hydrogels capable of modulating the loading and release of cationic small molecule therapeutics was developed. Chondroitin sulfate (CS) is a sulfated glycosaminoglycan that has many promising properties, including biocompatibility, biodegradation and chemically modifiable groups for both covalent and non-covalent bonding. CS was covalently modified with photocrosslinkable methacryloyl groups (CSMA) to develop an injectable hydrogel fabrication. Utilizing anionic groups, cationic drugs can be adsorbed and released from the hydrogels. This study demonstrates the synthesis of CSMA with a varying degree of substitution (DS) to generate hydrogels with varying swelling properties, maximum injection force, and drug release kinetics. The DS of the synthesized CSMA ranged from 0.05 ± 0.02 (2 h reaction) to 0.28 ± 0.02 (24 h reaction) with a DS of 1 representing 100% modification. The altered DS resulted in changes in hydrogel properties with the swelling of 20% CSMA hydrogels ranging from 42 (2 h reaction) to 13 (24 h reaction) and injection forces ranging from 18 N (2 h reaction) to 94 N (24 h reaction). The release of sunitinib, an oncology therapeutic that inhibits intracellular signaling by targeting multiple receptor tyrosine kinases, ranged from 18 µg per day (2 h reaction) to 9 µg per day (24 h reaction). While decreasing the DS increased the hydrogel swelling and rate of therapeutic release, it also limited the hydrogel fabrication range to only those containing 10% or higher CSMA. Blended polymer systems with poly(vinyl alcohol)-methacrylate (PVAMA) were fabricated to stabilize the resulting hydrogels via attenuating the swelling properties. Release profiles previously unattainable with the pure CSMA hydrogels were achieved with the blended hydrogel formulations. Overall, these studies identify a method to formulate tunable CSMA and blended CSMA/PVAMA hydrogels capable of sustained release of cationic therapeutics over six weeks with applications in oncology therapeutics.