ABSTRACT
This paper introduces catheter-directed intravascular casting hydrogels for transarterial chemo/starvation/chemodynamic embolization (TACSCE) therapy of hepatocellular carcinoma (HCC). Comprising Mn ion-crosslinked hyaluronic acid-dopamine (HD) with glucose oxidase (for glucose decomposition to H2O2 in starvation therapy), doxorubicin (for chemotherapy), and iopamidol (for X-ray imaging), these hydrogels are fabricated for transarterial embolization therapy guided by X-ray fluoroscopy. Mn4+ (from MnO2) demonstrates strong coordination with the catechol group of HD, providing hypoxia relief through O2 generation and cellular glutathione (GSH) consumption, compared to the OH radical generation potential of Mn2+. The gelation time-controlled, catheter-injectable, and rheologically tuned multitherapeutic/embolic gel system effectively reaches distal arterioles, ensuring complete intravascular casting with fewer complications related to organic solvents. Glucose deprivation, cascade reactive oxygen species (ROS) generation, GSH depletion, and sustained release profiles of multiple drug cargos from the hydrogel system are also achieved. The combined chemo/starvation/chemodynamic efficacies of these designed hydrogel systems are confirmed in HCC cell cultures and HCC-bearing animal models. The developed radiopaque/injectable/embolic/sol-to-gel transformable systems for TACSCE therapy may offer enhanced therapeutic efficacies compared to typical transarterial embolization and transarterial chemoembolization procedures for HCC.
ABSTRACT
Background: This research main objective was to evaluate a proliposomes (PLs) formulation for the enhancement of oral bioavailability of ginsenosides, using ginsenoside Rg3 (Rg3) as a marker. Methods: A novel PLs formulation was prepared using a modified evaporation-on-matrix method. Soy phosphatidylcholine, Rg3-enriched extract, poloxamer 188 (Lutrol® F 68) and sorbitol were mixed and dissolved using a aqueous ethanolic solution, followed by the removal of ethanol and lyophilization. The characterization of Rg3-PLs formulations was performed by powder X-ray diffractometry (PXRD), transmission electron microscopy (TEM) and in vitro release. The enhancement of oral bioavailability was investigated and analyzed by non-compartmental parameters after oral administration of the formulations. Results: PXRD of Rg3-PLs indicated that Rg3 was transformed from crystalline into its amorphous form during the preparation process. The Rg3-encapsulated liposomes with vesicular-shaped morphology were generated after the reconstitution by gentle hand-shaking in water; they had a mean diameter of approximately 350 nm, a negative zeta potential (-28.6 mV) and a high entrapment efficiency (97.3%). The results of the in vitro release study exhibited that significantly more amount of Rg3 was released from the PLs formulation in comparison with that from the suspension of Rg3-enriched extract (control group). The pharmacokinetic parameters after oral administration of PLs formulation in rats showed an approximately 11.8-fold increase in the bioavailability of Rg3, compared to that of the control group. Conclusion: The developed PLs formulation could be a favorable delivery system to improve the oral bioavailability of ginsenosides, including Rg3.
ABSTRACT
Sorafenib (BAY 43-9006) was developed as a multi-kinase inhibitor to treat advanced renal cell, hepatocellular, and thyroid cancers. The cytotoxic effect of sorafenib on cancer cells results from not only inhibiting the MEK/ERK signaling pathway (the on-target effect) but also inducing oxidative damage (the off-target effect). The inhibitory effect of sorafenib on system Xc- (xCT), a cystine/glutamate antiporter, promotes ferroptosis induction and accounts for oxidative damage. While emerging studies on ferroptosis in cancers have garnered increasing attention, the lack of consideration for ferroptosis inducers (FINs) with favorable pharmacokinetics could be problematic. Herein, we remodeled the chemical structure of sorafenib, of which pharmacokinetics and safety are already assured, to customize the off-target effect (i.e., ferroptosis induction) to on-target by disrupting the adenine-binding motif. JB3, a sorafenib derivative (i.e., JB compounds), with a tenfold higher IC50 toward RAF1 because of chemical remodeling, induced strong cytotoxicity in the elastin-sensitive lung cancer cells, while it was markedly reduced by ferrostatin-1. The 24% oral bioavailability of JB3 in rats accounted for a significant anti-tumor effect of orally administrated JB3 in xenograft models. These results indicate that JB3 could be further developed as an orally bioavailable FIN in novel anti-cancer therapeutics.
Subject(s)
Antineoplastic Agents , Ferroptosis , Lung Neoplasms , Sorafenib , Sorafenib/pharmacology , Sorafenib/administration & dosage , Ferroptosis/drug effects , Humans , Animals , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Administration, Oral , Antineoplastic Agents/pharmacology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Biological Availability , Cell Line, Tumor , Mice , Rats , Xenograft Model Antitumor Assays , Male , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Mice, NudeABSTRACT
Recent studies on osteosarcoma regimens have mainly focused on modifying the combination of antineoplastic agents rather than enhancing the therapeutic efficacy of each component. Here, an albumin nanocluster (NC)-assisted methotrexate (MTX), doxorubicin (DOX), and cisplatin (MAP) regimen with improved antitumor efficacy is presented. Human serum albumin (HSA) is decorated with thiamine pyrophosphate (TPP) to increase the affinity to the bone tumor microenvironment (TME). MTX or DOX (hydrophobic MAP components) is adsorbed to HSA-TPP via hydrophobic interactions. MTX- or DOX-adsorbed HSA-TPP NCs exhibit 20.8- and 1.64-fold higher binding affinity to hydroxyapatite, respectively, than corresponding HSA NCs, suggesting improved targeting ability to the bone TME via TPP decoration. A modified MAP regimen consisting of MTX- or DOX-adsorbed HSA-TPP NCs and free cisplatin displays a higher synergistic anticancer effect in HOS/MNNG human osteosarcoma cells than conventional MAP. TPP-decorated NCs show 1.53-fold higher tumor accumulation than unmodified NCs in an orthotopic osteosarcoma mouse model, indicating increased bone tumor distribution. As a result, the modified regimen more significantly suppresses tumor growth in vivo than solution-based conventional MAP, suggesting that HSA-TPP NC-assisted MAP may be a promising strategy for osteosarcoma treatment.
ABSTRACT
Bentonite (BT), an orally administrable natural clay, is widely used for medical and pharmaceutical purposes due to its unique properties, including swelling, adsorption and ion-exchange. However, its application as a matrix of amorphous solid dispersion (ASD) formulations is rarely reported, despite the fact that drugs can adsorb to BT in an amorphous state. The objective of this study was to explore the feasibility of BT as a water-insoluble ASD matrix for enhancing the oral bioavailability of poorly water-soluble drugs, including sorafenib (SF). We prepared a novel BT-based ASD of an SF-BT composite (SFBTC) by adsorbing SF onto BT under acidic conditions using the ionic interaction between cationic SF and negatively charged BT. Scanning electron microscopy (SEM), powder X-ray diffractometry (pXRD), and differential scanning calorimetry (DSC) analyses revealed that SF adsorbed to BT in an amorphous state at SF:BT ratios from 1:3 to 1:10. In pharmacokinetic studies in rats, SFBTC (1:3) significantly improved the oral bioavailability of SF, and the AUClast of SFBTC (1:3) was 3.3-fold higher than that of NEXAVAR®, a commercial product of SF. An in vitro release study under sink conditions revealed that SFBTC (1:3) completely released SF in a pH-dependent manner, while a nonsink condition study indicated the generation of supersaturation under intestinal pH conditions. A kinetic solubility study showed that the release of SFBTC (1:3) followed the diffusion-controlled mechanism, which is a typical characteristic of water-insoluble matrix-based ASDs. The pharmacokinetic studies of drug-BT composites of various drugs belonging to BCS class II indicated that the pKa value of the adsorbed drugs is one of the most important factors determining their dissolution and oral bioavailability. These results suggest that BT could be a promising water-insoluble ASD matrix for improving the oral bioavailability of poorly water-soluble drugs, including SF.
Subject(s)
Bentonite , Water , Rats , Animals , Biological Availability , Water/chemistry , Solubility , Drug CompoundingABSTRACT
Camostat mesylate is expected to be promising as a treatment option for COVID-19, in addition to other indications for which it is currently used. Furthermore, in vitro experiments have confirmed the potential of camostat and its metabolites to be effective against COVID-19. Therefore, clinical trials were conducted to evaluate the safety and pharmacokinetic characteristics of camostat after single-dose administration. Additionally, we aim to predict the pharmacokinetics of repeated dosing through modeling and simulation based on clinical trials. Clinical trials were conducted on healthy Korean adults, and an analysis was carried out of the metabolites of camostat, GBPA, and GBA. Pharmacokinetic modeling and simulation were performed using Monolix. There were no safety issues (AEs, physical examinations, clinical laboratory tests, vital sign measurements, and ECG) during the clinical trial. The pharmacokinetic characteristics at various doses were identified. It was confirmed that AUC last and Cmax increased in proportion to dose in both GBPA and GBA, and linearity was also confirmed in log-transformed power model regression. Additionally, the accumulation index was predicted (1.12 and 1.08 for GBPA and GBA). The pharmacokinetics of camostat for various dose administrations and indications can be predicted prior to clinical trials using the developed camostat model. Furthermore, it can be used for various indications by connecting it with pharmacodynamic information.
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Although cyclodextrin-based renal-clearable nanocarriers have a high potential for clinical translation in targeted cancer therapy, their designs remain to be optimized for tumour retention. Here we report on the design of a tailored structure for renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery. Twenty cyclodextrin derivatives with different charged moieties and spacers are synthesized and screened for colloidal stability. The resulting five candidates are evaluated for biodistribution and an optimized structure is identified. The optimized cyclodextrin shows a high tumour accumulation and is used for delivery of doxorubicin and ulixertinib. Higher tumour accumulation and tumour penetration facilitates tumour elimination. The improved antitumour efficacy is demonstrated in heterotopic and orthotopic colorectal cancer models.
Subject(s)
Colorectal Neoplasms , Cyclodextrins , Humans , Tissue Distribution , Drug Delivery Systems/methods , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Colorectal Neoplasms/drug therapy , Drug Carriers/chemistryABSTRACT
Bone malignancy features a mineralized extracellular matrix primarily composed of hydroxyapatite, which interferes with the distribution and activity of antineoplastic agents. Herein, we report bone tumor-homing polymeric nanotherapeutics consisting of alendronate-decorated chondroitin sulfate A-graft-poly(lactide-co-glycolide) and doxorubicin (DOX), named PLCSA-AD, which displayed a prolonged retention profile in the tumor microenvironment and augmented therapeutic efficacy via inhibition of the mevalonate pathway. PLCSA-AD exhibited a 1.72-fold lower IC50 value than free DOX and a higher affinity for hydroxyapatite than PLCSA in HOS/MNNG cell-based 2D bone tumor-mimicking models. The inhibition of the mevalonate pathway by PLCSA-AD in tumor cells was verified by investigating the cytosolic fraction of unprenylated proteins, where blank PLCSA-AD significantly increased the expression of cytosolic Ras and RhoA without changing their total cellular amounts. In a bone tumor-mimicking xenografted mouse model, AD-decorated nanotherapeutics significantly increased tumor accumulation (1.73-fold) compared with PLCSA, and higher adsorption to hydroxyapatites was observed in the histological analysis of the tumor. As a result, inhibition of the mevalonate pathway and improvement in tumor accumulation led to markedly enhanced therapeutic efficacy in vivo, suggesting that PLCSA-AD could be promising nanotherapeutics for bone tumor treatment.
ABSTRACT
Purpose: Orobol is an isoflavone that has a potent skin protection effect. The objective of this study was to prepare a novel bentonite-based composite formulation of orobol to enhance topical skin delivery. Methods: The composition was optimized based on the orobol content in the composite and the in vitro release studies, followed by the in vitro and in vivo hairless mouse skin deposition studies. Physicochemical characterizations of the composite formulation were performed by powder X-ray refractometry (XRD) and scanning electron microscopy (SEM). The in vitro cytotoxicity and in vivo toxicity studies were conducted in human keratinocytes and in hairless mouse, respectively. Results and Discussions: The in vitro release of orobol from the bentonite composites was higher than that from the suspension, which was further increased with the addition of phosphatidylcholine. The composite formulation significantly enhanced the in vitro and in vivo skin deposition of orobol in hairless mouse skin compared to the orobol suspension. Moreover, the addition of phosphatidyl choline not only improved the dissolution and incomplete release of orobol from the bentonite composite but also enhanced the deposition of orobol in the skin. XRD histograms and SEM images confirmed that the enhanced dissolution of orobol from the composite was attributed to its amorphous state on bentonite. The in vitro and in vivo toxicity studies support the safety and biocompatibility of the orobol-loaded bentonite composite formulation. Conclusion: These findings suggest that the orobol-loaded bentonite composite formulation could be a potential topical skin delivery system for orobol.
Subject(s)
Bentonite , Skin , Mice , Animals , Humans , Bentonite/chemistry , Mice, Hairless , FlavonoidsABSTRACT
Bentonite (BT) is a biocompatible clay mineral that has advantageous properties as a pharmaceutical excipient. However, the application of BT in controlled-release oral formulations has been challenging due to incomplete drug release from BT-drug complexes. The objective of this study was to investigate the effect of modifying BT with zwitterionic phosphatidylcholine (PC) to enhance the dissolution of drugs, thereby increasing their oral bioavailability. Quetiapine (QTP) was chosen as a model drug, and the composition of the complex (BT-PC-QTP) was optimized to have the maximum QTP content and increase the total amount of QTP released. The in vitro release study showed that the incorporation of an appropriate amount of PC into BT improved the low release rate of the BT-QTP complex at pH 7.4, while the pH-dependent release property of BT was maintained. In an in vivo pharmacokinetic study in rats, the oral administration of the BT-PC-QTP complex showed significantly higher Cmax and AUC values than the BT-QTP complex. Moreover, BT-PC-QTP showed a 2.4-fold enhancement of oral bioavailability compared to the QTP powder group. The scanning electron microscopy (SEM), powder X-ray diffraction (pXRD), and differential scanning calorimetry (DSC) studies confirmed that the intercalation of PC and QTP into BT resulted in the adsorption of QTP in an amorphous state. The characterization of the nanoparticles generated from the BT-PC-QTP complex supported that PC enhanced the dissolution of QTP by forming nanosized PC particles. Taken together, the modification of BT with PC can be applied in pharmaceutical industry as a platform strategy to control the release of the BT-drug complex and enhance the oral bioavailability of poorly water-soluble drugs.
Subject(s)
Bentonite , Lecithins , Rats , Animals , Biological Availability , Drug Liberation , Quetiapine Fumarate , Solubility , Powders , Spectroscopy, Fourier Transform Infrared/methods , Calorimetry, Differential Scanning , Administration, Oral , X-Ray Diffraction , Delayed-Action PreparationsABSTRACT
A donepezil hydrochloride (DPZ)-reinforced cellulose nanocrystal (CNC) hydrogel structure with pH control was developed for sustained drug delivery through subcutaneous injection. In the present study, an aggregated CNC gel was fabricated by reducing the electrostatic repulsion between CNC particles by incorporating DPZ and adjusting the pH value to 7.7. The crosslinked CNC/DPZ (cCNC/DPZ) gel exhibited immediate gelation, injection capability through a single syringe, improved viscoelasticity, and shear-thinning properties. Interactions between the CNCs and DPZ and pH regulation were assessed using several solid-state studies, and a sustained release profile of the DPZ from the cCNC/DPZ gel was also observed. In the pharmacokinetic study, a higher half-life and mean residence time and lower maximum drug concentration values were obtained in the cCNC/DPZ group than in the DPZ solution and CNC/DPZ groups after subcutaneous injection. Drug salt form-incorporated and pH-controlled CNC hydrogel systems can be safely applied to the subcutaneous delivery of DPZ.
Subject(s)
Nanoparticles , Cellulose/chemistry , Donepezil , Hydrogels/chemistry , Nanoparticles/chemistry , Static ElectricityABSTRACT
PURPOSE: Teriparatide is an effective drug for the treatment of osteoporosis. This study examines the relationship between the drug delivery properties of the solid formulation with teriparatide and the pharmacokinetic properties of teriparatide in vivo. METHODS: Teriparatide microneedles with different dissolution rates were prepared using sucrose and carboxymethylcellulose (CMC). There were three aspects of this study: (1) The dissolution rate of teriparatide from both formulations (sucrose and CMC) was measured in vitro. (2) After administration into porcine skin ex vivo, the diffusion rate of FITC-dextran was observed using a confocal microscope. (3) Pharmacokinetic studies were performed in rats and pharmacokinetic data compared with the release rate and the diffusion pattern. RESULTS: In the in vitro dissolution experiment, 80% of teriparatide was released within 30 min from the CMC MNs, whereas 80% of teriparatide was released within 10 min from the sucrose MNs. After 30 min, the fluorescence intensity on the surface of the MNs was 40% of the initial intensity for sucrose MNs and 90% for CMC MNs. In the pharmacokinetic study, the Cmax values of the CMC and sucrose MNs were 868 pg/mL and 6809 pg/mL, respectively, and the AUClast values were 6771 pg*hr/mL for the CMC MNs and 17,171 pg*hr/mL for the sucrose MNs. CONCLUSIONS: When teriparatide is delivered into the skin using microneedles, the release rate from the solid formulation determines the drug's pharmacokinetic properties. The diffusion pattern of fluorescence into the skin can be used to anticipate the pharmacokinetic properties of the drug.
Subject(s)
Needles , Teriparatide , Administration, Cutaneous , Animals , Carboxymethylcellulose Sodium , Drug Delivery Systems , Microinjections , Pharmaceutical Preparations , Rats , Skin , Sucrose , SwineABSTRACT
Hydroxyapatite-binding albumin nanoclusters (NCs) were developed for improving the anticancer agent accumulation in bone tumors. Human serum albumin (HSA) was decorated with alendronate (AD), and doxorubicin (DOX)-loaded NCs (HSA-AD/DOX) were fabricated via the ball-milling technology, an innovative nano-fabrication method by which more than 90% of the secondary structures of albumin can be preserved. The targeting ability of NCs was confirmed using a novel in vitro bone cancer model, wherein hydroxyapatite and collagen, the major components of the bone matrix representing the highly mineralized bone tumor microenvironment, were co-cultured with HOS/MNNG, a human osteosarcoma cell line. The binding affinity of HSA-AD/DOX to hydroxyapatite was evaluated based on the DOX binding efficiency. HSA-AD/DOX showed a 5.04-fold higher affinity than HSA/DOX. The enhanced distribution of HSA-AD/DOX to bone tumors was verified using a newly developed mouse model bearing HOS/MNNG tumors with hydroxyapatite beads. HSA-AD/DOX led to a 52.0% increase in tumor accumulation compared to that of the unmodified HSA/DOX. This is mainly due to the hydroxyapatite-binding affinity of the AD moiety, which is supported by histological analyses performed on the dissected tumors. Furthermore, HSA-AD/DOX changed the protein expression patterns of the tumors, implying the enhanced apoptotic process. Overall, the targeting ability of HSA-AD/DOX are effectively translated into improved therapeutic efficacy in bone tumor-xenografted mice, suggesting that the developed NCs are a promising delivery system for bone tumor treatment.
Subject(s)
Bone Neoplasms , Doxorubicin , Albumins/chemistry , Animals , Bone Neoplasms/drug therapy , Cell Line, Tumor , Doxorubicin/chemistry , Doxorubicin/therapeutic use , Hydroxyapatites , Mice , Tumor MicroenvironmentABSTRACT
Lipids, which along with carbohydrates and proteins are among the most important nutrients for the living organism, have a variety of biological functions that can be applied widely in biomedicine. A fatty acid, the most fundamental biological lipid, may be classified by length of its aliphatic chain, and the short-, medium-, and long-chain fatty acids and each have distinct biological activities with therapeutic relevance. For example, short-chain fatty acids have immune regulatory activities and could be useful against autoimmune disease; medium-chain fatty acids generate ketogenic metabolites and may be used to control seizure; and some metabolites oxidized from long-chain fatty acids could be used to treat metabolic disorders. Glycerolipids play important roles in pathological environments, such as those of cancers or metabolic disorders, and thus are regarded as a potential therapeutic target. Phospholipids represent the main building unit of the plasma membrane of cells, and play key roles in cellular signaling. Due to their physical properties, glycerophospholipids are frequently used as pharmaceutical ingredients, in addition to being potential novel drug targets for treating disease. Sphingolipids, which comprise another component of the plasma membrane, have their own distinct biological functions and have been investigated in nanotechnological applications such as drug delivery systems. Saccharolipids, which are derived from bacteria, have endotoxin effects that stimulate the immune system. Chemically modified saccharolipids might be useful for cancer immunotherapy or as vaccine adjuvants. This review will address the important biological function of several key lipids and offer critical insights into their potential therapeutic applications.
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CO2 gas generating poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) was designed for rapid release of tanespimycin (17-AAG) in transarterial chemoembolization (TACE) treatment of hepatocellular carcinoma (HCC). As poorly water-soluble drug is generally released from PLGA MS in a sustained manner, the drug release profile should be controlled according to its clinical indications. In current study, responding to immediate increase in hypoxia inducible factor-1α (HIF-1α) level under hypoxia state followed by embolization of tumor feeding arteries, sodium bicarbonate (NaHCO3) was added to PLGA/17-AAG MS for fast drug release by CO2 gas generation in slightly acidic tumor microenvironment. With the aid of NaHCO3, initial burst release of 17-AAG was available without losing the micron-size and spherical shape of designed MS for embolization of artery. Acid-responsive CO2 gas generation and subsequent immediate release of 17-AAG from MS were successfully verified. PLGA/17-AAG/NaHCO3 MS-treated group exhibited higher antiproliferation and apoptosis induction efficacies in McA-RH7777 and SNU-761 cells. McA-RH7777 tumor-implanted rats treated by TACE using PLGA/17-AAG/NaHCO3 MS presented a complete therapeutic response. All these findings suggest that developed tumor microenvironment-responsive gas-generating MS can be efficiently applied to TACE therapy of HCC.
Subject(s)
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Animals , Carcinoma, Hepatocellular/drug therapy , Hypoxia , Liver Neoplasms/drug therapy , Microspheres , Rats , Tumor MicroenvironmentABSTRACT
The daily oral administration of acetylcholinesterase (AChE) inhibitors for Alzheimer's disease features low patient compliance and can lead to low efficacy or high toxicity owing to irregular intake. Herein, we developed a subcutaneously injectable hyaluronic acid hydrogel (MLC/HSA hydrogel) hybridized with microstructured lipid carriers (MLCs) and human serum albumin (HSA) for the sustained release of donepezil (DNP) with reduced initial burst release. The lipid carrier was designed to have a microsized mean diameter (32.6 ± 12.8 µm) to be well-localized in the hydrogel. The hybridization of MLCs and HSA enhanced the structural integrity of the HA hydrogel, as demonstrated by the measurements of storage modulus (G'), loss modulus (Gâ³), and viscosity. In the pharmacokinetic study, subcutaneous administration of MLC/HSA hydrogel in rats prolonged the release of DNP for up to seven days and reduced the initial plasma concentration, where the Cmax value was 0.3-fold lower than that of the control hydrogel without a significant change in the AUClast value. Histological analyses of the hydrogels supported their biocompatibility for subcutaneous injection. These results suggest that a new hybrid MLC/HSA hydrogel could be promising as a subcutaneously injectable controlled drug delivery system for the treatment of Alzheimer's disease.
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Polypseudorotaxane structure and polydopamine bond-based crosslinked hyaluronic acid (HA) hydrogels including donepezil-loaded microspheres were developed for subcutaneous injection. Both dopamine and polyethylene glycol (PEG) were covalently bonded to the HA polymer for catechol polymerization and inclusion complexation with alpha-cyclodextrin (α-CD), respectively. A PEG chain of HA-dopamine-PEG (HD-PEG) conjugate was threaded with α-CD to make a polypseudorotaxane structure and its pH was adjusted to 8.5 for dopamine polymerization. Poly(lactic-co-glycolic acid) (PLGA)/donepezil microsphere (PDM) was embedded into the HD-PEG network for its sustained release. The HD-PEG/α-CD/PDM 8.5 hydrogel system exhibited an immediate gelation pattern, injectability through single syringe, self-healing ability, and shear-thinning behavior. Donepezil was released from the HD-PEG/α-CD/PDM 8.5 hydrogel in a sustained pattern. Following subcutaneous injection, the weight of excised HD-PEG/α-CD/PDM 8.5 hydrogel was higher than the other groups on day 14. These findings support the clinical feasibility of the HD-PEG/α-CD/PDM 8.5 hydrogel for subcutaneous injection.
Subject(s)
Drug Carriers/chemistry , Hyaluronic Acid/analogs & derivatives , Hydrogels/chemistry , Indoles/chemistry , Polymers/chemistry , Animals , Biodegradable Plastics/chemical synthesis , Biodegradable Plastics/chemistry , Biodegradable Plastics/toxicity , Cyclodextrins/chemical synthesis , Cyclodextrins/chemistry , Cyclodextrins/toxicity , Donepezil/chemistry , Drug Carriers/chemical synthesis , Drug Carriers/toxicity , Drug Liberation , Hyaluronic Acid/toxicity , Hydrogels/chemical synthesis , Hydrogels/toxicity , Indoles/chemical synthesis , Indoles/toxicity , Male , Mice, Inbred ICR , Microspheres , Poloxamer/chemical synthesis , Poloxamer/chemistry , Poloxamer/toxicity , Polymers/chemical synthesis , Polymers/toxicity , Rotaxanes/chemical synthesis , Rotaxanes/chemistry , Rotaxanes/toxicity , Viscoelastic Substances/chemical synthesis , Viscoelastic Substances/chemistry , Viscoelastic Substances/toxicityABSTRACT
The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on a global scale urges prompt and effective countermeasures. Recently, a study has reported that coronavirus disease-19 (COVID-19), the disease caused by SARS-CoV-2 infection, is associated with a decrease in albumin level, an increase in NETosis, blood coagulation, and cytokine level. Here, we present drug-loaded albumin nanoparticles as a therapeutic agent to resolve the clinical outcomes observed in severe SARS-CoV-2 patients. PEGylated nanoparticle albumin-bound (PNAB) was used to promote prolonged bioactivity of steroidal ginsenoside saponins, PNAB-Rg6 and PNAB-Rgx365. Our data indicate that the application of PNAB-steroidal ginsenoside can effectively reduce histone H4 and NETosis-related factors in the plasma, and alleviate SREBP2-mediated systemic inflammation in the PBMCs of SARS-CoV-2 ICU patients. The engineered blood vessel model confirmed that these drugs are effective in suppressing blood clot formation and vascular inflammation. Moreover, the animal model experiment showed that these drugs are effective in promoting the survival rate by alleviating tissue damage and cytokine storm. Altogether, our findings suggest that these PNAB-steroidal ginsenoside drugs have potential applications in the treatment of symptoms associated with severe SARS-CoV-2 patients, such as coagulation and cytokine storm.
Subject(s)
COVID-19 , Ginsenosides , Nanoparticles , Albumins , Animals , Ginsenosides/pharmacology , Humans , Polyethylene Glycols , SARS-CoV-2ABSTRACT
Rationale: The type I insulin-like growth factor receptor (IGF-1R) signaling pathway plays key roles in the development and progression of numerous types of human cancers, and Src and AXL have been found to confer resistance to anti-IGF-1R therapies. Hence, co-targeting Src and AXL may be an effective strategy to overcome resistance to anti-IGF-1R therapies. However, pharmacologic targeting of these three kinases may result in enhanced toxicity. Therefore, the development of novel multitarget anticancer drugs that block IGF-1R, Src, and AXL is urgently needed. Methods: We synthesized a series of phenylpyrazolo[3,4-d]pyrimidine (PP)-based compounds, wherein the PP module was conjugated with 2,4-bis-arylamino-1,3-pyrimidines (I2) via a copper(I)-catalyzed alkyne-azide cycloaddition reaction. To develop IGF-1R/Src/AXL-targeting small molecule kinase inhibitors, we selected LL6 as an active compound and evaluated its antitumor and antimetastatic effects in vitro and in vivo using the MTT assay, colony formation assays, migration assay, flow cytometric analysis, a tumor xenograft model, the KrasG12D/+ -driven spontaneous lung tumorigenesis model, and a spontaneous metastasis model using Lewis lung carcinoma (LLC) allografts. We also determined the toxicity of LL6 in vitro and in vivo. Results: LL6 induced apoptosis and suppressed viability and colony-forming capacities of various non-small cell lung cancer (NSCLC) cell lines and their sublines with drug resistance. LL6 also suppressed the migration of NSCLC cells at nontoxic doses. Administration of LL6 in mice significantly suppressed the growth of NSCLC xenograft tumors and metastasis of LLC allograft tumors with outstanding toxicity profiles. Furthermore, the multiplicity, volume, and load of lung tumors in KrasG12D/+ transgenic mice were substantially reduced by the LL6 treatment. Conclusions: Our results show the potential of LL6 as a novel IGF-1R/Src/AXL-targeting small molecule kinase inhibitor, providing a new avenue for anticancer therapies.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor, IGF Type 1/antagonists & inhibitors , Small Molecule Libraries/pharmacology , src-Family Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Apoptosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Inbred NOD , Mice, SCID , Phosphorylation , Pyrimidines/chemistry , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Axl Receptor Tyrosine KinaseABSTRACT
Hyaluronidase (HAase) inhibitor-incorporated hyaluronic acid (HA) hydrogel cross-linked with 1,4-butanediol diglycidyl ether (BDDE) was designed to reduce the toxicity risk induced by BDDE and its biodegradation rate in subcutaneous tissue. The formulation composition of hydrogel and its preparation method were optimized to have a high swelling ratio and drug content. Quercetin (QCT) and quetiapine (QTP), as an HAase inhibitor and model drug, respectively, were incorporated into the cross-linked hydrogel using the antisolvent precipitation method for extending their release after subcutaneous injection. The cross-linked HA (cHA)-based hydrogels displayed appropriate viscoelasticity and injectability for subcutaneous injection. The incorporation of QCT (as an HAase inhibitor) in the cHA hydrogel formulation resulted in slower in vitro and in vivo degradation profiles compared to the hydrogel without QCT. Single dosing of optimized hydrogel injected via a subcutaneous route in rats did not induce any acute toxicities in the blood chemistry and histological staining studies. In the pharmacokinetic study of rats following subcutaneous injection, the cHA hydrogel with QCT exhibited a lower maximum QTP concentration and longer half-life and mean residence time values compared to the hydrogel without QCT. All of these results support the designed HAase inhibitor-incorporated cHA hydrogel being a biocompatible subcutaneous injection formulation for sustained drug delivery.