RESUMEN
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.
RESUMEN
Indocyanine green (ICG), glucose oxidase (GOx), and copper(II) sulfate (Cu)-installed hybrid gel based on organic nanorod (cellulose nanocrystal [CNC]) and inorganic nanodisk (Laponite [LAP]) was developed to perform a combination of starvation therapy (ST), chemodynamic therapy (CDT), and photothermal therapy (PTT) for localized cancers. A hybrid CNC/LAP network with a nematic phase was designed to enable instant gelation, controlled viscoelasticity, syringe injectability, and longer in vivo retention. Moreover, ICG was introduced into the CNC/LAP gel system to induce hyperthermia of tumor tissue, amplifying the CDT effect; GOx was used for glucose deprivation (related to the Warburg effect); and Cu was introduced for hydroxyl radical generation (based on Fenton-like chemistry) and cellular glutathione (GSH) degradation in cancer cells. The ICG/GOx/Cu-installed CNC/LAP gel in combination with near-infrared (NIR) laser realized improved antiproliferation, cellular reactive oxygen species (ROS) generation, cellular GSH degradation, and apoptosis induction in colorectal cancer (CT-26) cells. In addition, local injection of the CNC/ICG/GOx/Cu/LAP gel into the implanted CT-26 tumor while irradiating it with NIR laser provided strong tumor growth suppression effects. In conclusion, the designed hybrid nanorod/nanodisk gel network can be efficiently applied to the local PTT/ST/CDT of cancer cells.
RESUMEN
Cascade hydroxyl radical generating hydrogel reactor structures including a chemotherapeutic agent are invented for multiple treatment of breast cancer. Glucose oxidase (GOx) and cupric sulfate (Cu) are introduced for transforming accumulated glucose (in cancer cells) to hydroxyl radicals for starvation/chemodynamic therapy. Cu may also suppress cancer cell growth via cuproptosis-mediated cell death. Berberine hydrochloride (BER) is engaged as a chemotherapeutic agent in the hydrogel reactor for combining with starvation/chemodynamic/cuproptosis therapeutic modalities. Moreover, Cu is participated as a gel crosslinker by coordinating with catechol groups in hyaluronic acid-dopamine (HD) polymer. Controlling viscoelasticity of hydrogel reactor can extend the retention time following local injection and provide sustained drug release patterns. Low biodegradation rate of designed HD/BER/GOx/Cu hydrogel can reduce dosing frequency in local cancer therapy and avoid invasiveness-related inconveniences. Especially, it is anticipated that HD/BER/GOx/Cu hydrogel system can be applied for reducing size of breast cancer prior to surgery as well as tumor growth suppression in clinical application.
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Apoptosis , Neoplasias de la Mama , Neoplasias , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Catálisis , Línea Celular Tumoral , Glucosa Oxidasa/metabolismo , Hidrogeles , Peróxido de Hidrógeno/química , Radical Hidroxilo/química , Neoplasias/terapia , CobreRESUMEN
A hyaluronic acid (HA)-based one-pot hydrogel reactor with single syringe injection and immediate gelation was developed for starvation therapy (ST), chemodynamic therapy (CDT), ferroptosis, and photothermal therapy (PTT) against breast cancer. A rheologically tuned hydrogel network, composed of HA-phenylboronic acid (HP) and HA-dopamine (HD), was designed by introducing a boronate ester linkage (phenylboronic acid-dopamine interaction) and polydopamine bond (pH control). Ferrocene (Fc)-conjugated HP (Fc-HP) was synthesized to achieve ferroptosis, Fenton reaction-involved toxic hydroxyl radical (â¢OH) generation, and photothermal ablation in cancer therapy. Glucose oxidase (GOx) was entrapped in the pH-modulated Fc-HP (Fc-HP°)/HD hydrogel network for converting intracellular glucose to H2O2 to enable its own supply. The GOx/Fc combination-installed hydrogel reactor system can provide sustained ST/CDT/PTT functions along with ferroptosis. Injection of Fc-HP°/HD/GOx hydrogel with single-syringe injectability, shear-thinning feature, and self-healing capability offered a slow biodegradation rate and high safety profiles. Peritumorally injected Fc-HP°/HD/GOx hydrogel also efficiently suppressed the growth of breast cancer based on multifunctional therapeutic approaches with reduced dosing frequency. Hyperthermia induced by near-infrared (NIR) laser absorption may amplify the therapeutic effects of free radicals. It is expected that this Fc-HP°/HD/GOx hydrogel system can be applied to local cancer therapy with high efficacy and safety profiles.
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Neoplasias de la Mama , Hipertermia Inducida , Neoplasias , Ácidos Borónicos , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Dopamina/uso terapéutico , Ésteres/uso terapéutico , Femenino , Compuestos Ferrosos , Glucosa/metabolismo , Glucosa Oxidasa/química , Glucosa Oxidasa/uso terapéutico , Humanos , Ácido Hialurónico/química , Hidrogeles/química , Peróxido de Hidrógeno/metabolismo , Radical Hidroxilo/uso terapéutico , Metalocenos/uso terapéutico , Neoplasias/tratamiento farmacológicoRESUMEN
Fast disintegrating and dissolving nanofiber (NF) mat was devised to deliver roxithromycin for the treatment of the respiratory tract infection. NF membrane was made by an electrospinning process with poly(vinyl alcohol) (PVA), hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and d-α-tocopheryl polyethylene glycol succinate (TPGS) for local application of roxithromycin. Roxithromycin has a poor water solubility thus HP-ß-CD is introduced for enhancing drug solubility by forming an inclusion complex in this study. The addition of TPGS provided multiple roles such as accelerating wetting, disintegration, and dissolution speed and overcoming bacterial resistance. Roxithromycin was successfully entrapped in NF structure and drug amorphization occurred during the electrospinning process. PVA/HP-ß-CD/TPGS/roxithromycin (PHTR) NF exhibited faster wetting, disintegration, and dissolution speed rather than the other NF mats. PHTR NF displayed higher antibacterial potentials in Gram-negative bacteria (E. coli) and Gram-positive bacteria (S. aureus) compared to other NF mat formulations. The administration of PHTR NF to oral cavity in pneumococcal disease mouse model provided the most efficient therapeutic potentials in lung tissue. Designed multiple phase-based NF mat may be one of powerful local drug delivery systems for the therapy of respiratory tract infection.
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Nanofibras , Roxitromicina , 2-Hidroxipropil-beta-Ciclodextrina , Animales , Antibacterianos/farmacología , Portadores de Fármacos , Escherichia coli , Ratones , Boca , Roxitromicina/farmacología , Solubilidad , Staphylococcus aureusRESUMEN
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.
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Portadores de Fármacos/química , Ácido Hialurónico/análogos & derivados , Hidrogeles/química , Indoles/química , Polímeros/química , Animales , Plásticos Biodegradables/síntesis química , Plásticos Biodegradables/química , Plásticos Biodegradables/toxicidad , Ciclodextrinas/síntesis química , Ciclodextrinas/química , Ciclodextrinas/toxicidad , Donepezilo/química , Portadores de Fármacos/síntesis química , Portadores de Fármacos/toxicidad , Liberación de Fármacos , Ácido Hialurónico/toxicidad , Hidrogeles/síntesis química , Hidrogeles/toxicidad , Indoles/síntesis química , Indoles/toxicidad , Masculino , Ratones Endogámicos ICR , Microesferas , Poloxámero/síntesis química , Poloxámero/química , Poloxámero/toxicidad , Polímeros/síntesis química , Polímeros/toxicidad , Rotaxanos/síntesis química , Rotaxanos/química , Rotaxanos/toxicidad , Sustancias Viscoelásticas/síntesis química , Sustancias Viscoelásticas/química , Sustancias Viscoelásticas/toxicidadRESUMEN
Elaborately and serially pH-modulated hydrogels possessing optimized viscoelastic natures for short gelation time and single syringe injection were designed for peritumoral injection of an anticancer agent. Boronate ester bonds between phenylboronic acid (PBA) (installed in HA-PBA (HP)) and dopamine (included in HA-dopamine (HD)) along with self-polymerization of dopamine (via interactions between HD conjugates) were introduced as the main cross-linking strategies of a hyaluronic acid (HA) hydrogel. Considering pKa values (8.0-9.5) of PBA and dopamine, the pH of each polymer dispersion was controlled elaborately for injection through a single syringe, and the final pH was tuned nearby the physiological pH (pH 7.8). The shear-thinning behavior, self-healing property, and single syringe injectability of a designed hydrogel cross-linked nearby physiological pH may provide its convenient application to peritumoral injection and prolonged retention in local cancer therapy. Erlotinib (ERT) was encapsulated in a microsphere (MS), and it was further embedded in an HP/HD-based hydrogel for sustained and locoregional delivery. A rheologically tuned hydrogel containing an ERT MS exhibited superior tumor-suppressive efficiencies compared to the other groups in A549 tumor-bearing mice. A designed injectable hydrogel through a single syringe system may be efficiently applied to local cancer therapy with lower toxicities to healthy organs.
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Antineoplásicos/administración & dosificación , Boratos/química , Preparaciones de Acción Retardada/química , Clorhidrato de Erlotinib/administración & dosificación , Hidrogeles/química , Células A549 , Animales , Antineoplásicos/uso terapéutico , Clorhidrato de Erlotinib/uso terapéutico , Esterificación , Humanos , Concentración de Iones de Hidrógeno , Inyecciones , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos ICRRESUMEN
Doxorubicin (DOX)-engineered poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) including phloretin (PHL) were designed and the feasible contribution of sialic acid (SA) to the improved tumor targeting and penetration capabilities was elucidated in lung adenocarcinoma models. DOX has been clinically used as liposomal formulations after its introduction to the inner side of vehicles, however DOX is anchored in the outer surface of PLGA NPs for improved tumor penetration by interactions with SA in this study. DOX (positively charged at physiological pH) was adsorbed onto the negatively charged PLGA NPs via electrostatic interactions and consequent binding of SA (negatively charged at physiological pH) to DOX located in NPs was also elucidated. DOX layer in DOX@PLGA NPs rendered improved endocytosis and partial contribution of SA (expressed in cancer cells) to that endocytosis was demonstrated. DOX@PLGA/PHL NPs provided enhanced antiproliferation potentials in A549 cells rather than single agent (DOX or PHL)-installed NPs. In addition, DOX-SA interactions seemed to play critical roles in tumor infiltration and accumulation of DOX@PLGA NPs in A549 tumor-xenografted mouse model. All these findings support the novel use of DOX which is used for the surface engineering of NPs for improved tumor targeting and penetration.
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Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Ácido N-Acetilneuramínico/metabolismo , Nanopartículas/administración & dosificación , Animales , Apoptosis , Proliferación Celular , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Nanopartículas/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Monopotassium phosphate and pH modulation-reinforced hydrogel based on hyaluronic acid (HA) grafted with dopamine (dopa) was fabricated as one of subcutaneous injection formulations of donepezil (DPZ). Both incorporation of KH2PO4 and pH adjustment finally attributed to tuning viscoelastic and biodegradable properties of hydrogel system. Appropriate gelation time for in situ gel formation, single syringe injectability, self-healing capability, and viscoelastic features were accomplished with the optimization of KH2PO4 concentration in hydrogel systems. DPZ base (as a poorly water soluble drug) was encapsulated in poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) and it was further embedded in the hydrogel structure for sustained drug release. Biodegradability of designed KH2PO4-incorporated HA-dopa/DPZ MS hydrogel system was assessed by optical imaging and the remained gel weight of crosslinked HA-dopa hydrogel group was 3.4-fold higher than that of unmodified HA-dopa mixture group on day 14 (p < 0.05). Subcutaneous injection of KH2PO4-incorporated HA-dopa/DPZ MS hydrogel did not induce any severe systemic toxicities. All these data suggest that designed HA-dopa/DPZ MS hydrogel structure crosslinked by KH2PO4 incorporation and pH adjustment can be one of promising subcutaneous injection formulations for sustained drug delivery.
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Donepezilo/farmacología , Sistemas de Liberación de Medicamentos , Hidrogeles/farmacología , Sustancias Viscoelásticas/química , Animales , Donepezilo/química , Dopamina/química , Dopamina/farmacología , Humanos , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Hidrogeles/química , Concentración de Iones de Hidrógeno , Inyecciones Subcutáneas , Ratones , Microesferas , Imagen Óptica , Fosfatos/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/farmacología , Compuestos de Potasio/química , Reología , Solubilidad , Sustancias Viscoelásticas/farmacología , Agua/químicaRESUMEN
Layer-by-layer approach based on the electrostatic interactions has been introduced to make multi-layered targeting ligand-chemotherapeutics-cellulose nanocrystal (CNC) structure for tumor-targeted drug delivery. Negatively charged CNC was covered with cationic doxorubicin (DOX) molecule (as a chemotherapeutic agent) to fabricate DOX@CNC and sequentially wrapped with anionic hyaluronic acid (HA) polymer (as a CD44 receptor targeting ligand). Rod-shaped HA-coated DOX@CNC (HA@DOX@CNC) has been successfully fabricated and it exhibited 327 nm length, 12 nm width, -38 mV zeta potential, and 3% DOX content. HA@DOX@CNC displayed higher cellular accumulation efficiency and antiproliferation potentials in CD44 receptor-positive lung adenocarcinoma (A549) cells compared to DOX and DOX-wrapped CNC (DOX@CNC). In A549 spheroid model, HA@DOX@CNC group exhibited superior tumor penetration capability, reactive oxygen species (ROS) production level, and cancer cell killing capacity rather than DOX and DOX@CNC group. In A549 tumor implanted mouse model, Cy5.5-labeled HA@DOX@CNC group exhibited higher tumor accumulation efficiency rather than free Cy5.5 after intravenous injection. All these findings suggest that designed HA@DOX@CNC can be one of promising biocompatible tumor-targeted nano-size drug delivery systems.
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Antineoplásicos/administración & dosificación , Celulosa/química , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Ácido Hialurónico/química , Nanopartículas/química , Células A549 , Animales , Supervivencia Celular/efectos de los fármacos , Humanos , Receptores de Hialuranos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones DesnudosRESUMEN
Sodium selenite (Se)-directed crosslinked hydrogels based on hyaluronic acid (HA)-dopamine (HD), including indocyanine green (ICG), were developed for local therapy of breast cancer. Se can induce polymerization of dopamine (in HD conjugate) by making alkaline pH value, coordinate with the functional groups of HD, and kill cancer cells by pro-oxidant effects. ICG can be entrapped in the crosslinked HD/Se hydrogel network and long lasting photothermal efficacies can be maintained for cancer therapy. HD conjugate was synthesized via an amide linkage between carboxylic acid group of HA and amine group of dopamine. HD/Se gel was fabricated by covalent bonding of dopamine group (in HD conjugate) and the coordination between selenium and functional groups of HD. Controlled rheological properties of HD/Se/ICG gel may provide easy injectability and slow biodegradability. Sufficient photothermal efficiencies were acquired after near-infrared (NIR) laser irradiation. HD/Se/ICG gel structure was remained in the mouse for 2 weeks and severe systemic toxicities were not observed in blood and histological assays. Intratumoral injection of HD/Se/ICG gel with NIR laser irradiation provided the most efficient tumor growth inhibition capability without severe systemic toxicities. HD/Se/ICG hydrogel structure can be introduced as a promising multifunctional platform for local therapy of breast cancers.