RESUMEN
Ulcerative colitis (UC) is a challenging inflammatory gastrointestinal disorder, whose therapies encounter limitations in overcoming insufficient colonic retention and rapid systemic clearance. In this study, we report an innovative polymeric prodrug nanoformulation for targeted UC treatment through sustained 5-aminosalicylic acid (5-ASA) delivery. Amphiphilic polymer-based 13.5 nm micelles were engineered to incorporate azo-linked 5-ASA prodrug motifs, enabling cleavage via colonic azoreductases. In vitro, micelles exhibited excellent stability under gastric/intestinal conditions while demonstrating controlled 5-ASA release over 24 h in colonic fluids. Orally administered micelles revealed prolonged 24-h retention and a high accumulation within inflamed murine colonic tissue. At an approximately 60% dose reduction from those most advanced recent studies, the platform halted DSS colitis progression and outperformed standard 5-ASA therapy through a 77-97% suppression of inflammatory markers. Histological analysis confirmed intact colon morphology and restored barrier protein expression. This integrated prodrug nanoformulation addresses limitations in colon-targeted UC therapy through localized bioactivation and tailored pharmacokinetics, suggesting the potential of nanotechnology-guided precision delivery to transform disease management.
Asunto(s)
Colitis , Colon , Preparaciones de Acción Retardada , Mesalamina , Micelas , Nitrorreductasas , Polímeros , Profármacos , Animales , Profármacos/química , Profármacos/farmacocinética , Mesalamina/química , Mesalamina/farmacocinética , Nitrorreductasas/metabolismo , Ratones , Colon/metabolismo , Colon/patología , Polímeros/química , Colitis/tratamiento farmacológico , Colitis/metabolismo , Preparaciones de Acción Retardada/química , NADH NADPH Oxidorreductasas/metabolismo , Ratones Endogámicos C57BL , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , MasculinoRESUMEN
Depot-type drug delivery systems are designed to deliver drugs at an effective rate over an extended period. Minimizing initial "burst" can also be important, especially with drugs causing systemic toxicity. Both goals are challenging with small hydrophilic molecules. The delivery of molecules such as the ultrapotent local anesthetic tetrodotoxin (TTX) exemplifies both challenges. Toxicity can be mitigated by conjugating TTX to polymers with ester bonds, but the slow ester hydrolysis can result in subtherapeutic TTX release. Here, we developed a prodrug strategy, based on dynamic covalent chemistry utilizing a reversible reaction between the diol TTX and phenylboronic acids. These polymeric prodrugs exhibited TTX encapsulation efficiencies exceeding 90 % and the resulting polymeric nanoparticles showed a range of TTX release rates. In vivo injection of the TTX polymeric prodrugs at the sciatic nerve reduced TTX systemic toxicity and produced nerve block lasting 9.7±2.0â h, in comparison to 1.6±0.6â h from free TTX. This approach could also be used to co-deliver the diol dexamethasone, which prolonged nerve block to 21.8±5.1â h. This work emphasized the usefulness of dynamic covalent chemistry for depot-type drug delivery systems with slow and effective drug release kinetics.
Asunto(s)
Polímeros , Profármacos , Tetrodotoxina , Profármacos/química , Profármacos/farmacología , Tetrodotoxina/química , Tetrodotoxina/toxicidad , Tetrodotoxina/administración & dosificación , Polímeros/química , Animales , Anestesia Local/métodos , Anestésicos Locales/química , Anestésicos Locales/administración & dosificación , Ácidos Borónicos/química , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Nervio Ciático/efectos de los fármacos , Liberación de Fármacos , RatonesRESUMEN
Due to their potent immunosuppressive and anti-inflammatory effects, glucocorticoids (GCs) are the most widely used medications in treating lupus nephritis (LN). Long-term use of GCs, however, is associated with numerous off-target adverse effects. To reduce GCs' adverse effects, we previously developed two polymeric dexamethasone prodrug nanomedicines: N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based dexamethasone prodrug (P-Dex), and micelle-forming polyethylene glycol (PEG)-based dexamethasone prodrug (ZSJ-0228). Both P-Dex and ZSJ-0228 provided sustained amelioration of LN in lupus-prone NZB/W F1 mice with reduced GC-associated adverse effects. Here, we have extended our investigation to the MRL/lpr mouse model of LN. Compared to dose equivalent daily dexamethasone sodium phosphate (Dex) treatment, monthly P-Dex or ZSJ-0228 treatments were more effective in reducing proteinuria and extending the lifespan of MRL/lpr mice. Unlike the daily Dex treatment, ZSJ-0228 was not associated with measurable GC-associated adverse effects. In contrast, adrenal gland atrophy was observed in P-Dex treated mice.
Asunto(s)
Nefritis Lúpica , Profármacos , Animales , Dexametasona/farmacología , Dexametasona/uso terapéutico , Glucocorticoides/uso terapéutico , Riñón , Nefritis Lúpica/tratamiento farmacológico , Ratones , Ratones Endogámicos MRL lpr , Ratones Endogámicos NZB , Polímeros/farmacología , Profármacos/farmacología , Profármacos/uso terapéuticoRESUMEN
Glucocorticoids (GCs) are widely used in the clinical management of lupus nephritis (LN). Their long-term use, however, is associated with the risk of significant systemic side effects. We have developed a poly(ethylene glycol) (PEG)-based dexamethasone (Dex) prodrug (i.e., ZSJ-0228) and in a previous study, demonstrated its potential therapeutic efficacy in mice with established LN, while avoiding systemic GC-associated toxicity. In the present study, we have employed a dose-escalation design to establish the optimal dose-response relationships for ZSJ-0228 in treating LN and further investigated the safety of ZSJ-0228 in lupus-prone NZB/W F1 mice with established nephritis. ZSJ-0228 was intravenously (i.v.) administered monthly at four levels: 0.5 (L1), 1.0 (L2), 3.0 (L3), and 8.0 (L4) mg/kg/day Dex equivalent. For controls, mice were treated with i.v. saline every 4 weeks. In addition, a group of mice received intraperitoneal injections (i.p.) of Dex every day or i.v. injections of Dex every four weeks. Treatment of mice with LN with ZSJ-0228 dosed at L1 resulted in the resolution of proteinuria in 14% of the mice. Mice treated with ZSJ-0228 dosed at L2 and L3 levels resulted in the resolution of proteinuria in â¼60% of the mice in both groups. Treatment with ZSJ-0228 dosed at L4 resulted in the resolution of proteinuria in 30% of the mice. The reduction and/or resolution of the proteinuria, improvement in renal histological scores, and survival data indicate that the most effective dose range for ZSJ-0228 in treating LN in NZB/W F1 mice is between 1.0 and 3.0 mg/kg/day Dex equivalent. Typical GC-associated side effects (e.g., osteopenia, adrenal glands atrophy, etc.) were not observed in any of the ZSJ-0228 treatment groups, confirming its excellent safety profile.
Asunto(s)
Dexametasona/administración & dosificación , Nefritis Lúpica/tratamiento farmacológico , Animales , Dexametasona/efectos adversos , Dexametasona/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Nefritis Lúpica/inmunología , Ratones , Polietilenglicoles , Profármacos/administración & dosificación , Profármacos/químicaRESUMEN
Neoantigen-based cancer vaccines are promising for boosting cytotoxic T lymphocyte (CTL) responses. However, the therapeutic effect of cancer vaccines is severely blunted by functional suppression of the dendritic cells (DCs). Herein, we demonstrated an acid-responsive polymeric nanovaccine for activating the stimulator of interferon genes (STING) pathway and improving cancer immunotherapy. The nanovaccines were fabricated by integrating an acid-activatable polymeric conjugate of the STING agonist and neoantigen into one single nanoplatform. The nanovaccines efficiently accumulated at the lymph nodes for promoting DC uptake and facilitating cytosol release of the neoantigens. Meanwhile, the STING agonist activated the STING pathway in the DCs to elicit interferon-ß secretion and to boost T-cell priming with the neoantigen. The nanovaccine dramatically inhibited tumor growth and occurrence of B16-OVA melanoma and 4T1 breast tumors in immunocompetent mouse models. Combination immunotherapy with the nanovaccines and anti-PD-L1 antibody demonstrated further improved antitumor efficacy in a 4T1 breast tumor model.
Asunto(s)
Vacunas contra el Cáncer , Inmunoterapia , Neoplasias , Profármacos , Animales , Células Dendríticas/inmunología , Ratones , Ratones Endogámicos C57BL , Neoplasias/prevención & control , Polímeros , Profármacos/uso terapéutico , VacunaciónRESUMEN
Polycrystalline methacryloyl monomers of the antibacterial drug nalidixic acid with an anhydride bond to the drug carboxyl group were prepared. The physicochemical properties of the synthesized vinyl monomer were characterized using X-ray powder diffraction, thermal analysis, and polarized light microscopy measurements. Mechanochemical solid-state polymerization of the resulting monomers was carried out to yield a novel polymeric prodrug. The in vitro hydrolysis behavior of the polymeric prodrug indicated that the release rate of drug from the polymeric prodrug was clearly dependent on the pH value of the hydrolysis solution. Moreover, sustained release of the drug at an almost constant rate for more than 10 hr was shown in both neutral and alkaline solutions. The results suggest that anhydride-based polymeric prodrugs could be potentially useful in colon targeted drug delivery systems.
Asunto(s)
Anhídridos/química , Antibacterianos/química , Metacrilatos/química , Ácido Nalidíxico/química , Polímeros/química , Profármacos/química , Liberación de Fármacos , Humanos , Hidrólisis , Polimerizacion , PolvosRESUMEN
PURPOSE: The discovery of nano drug delivery system has rendered a great hope for improving cancer therapy. However, there are some inevitable obstacles that constrain its development, such as the physical and biological barriers, the toxicity of carrier materials and the physiological toxicity of drugs. Here, we report a polymeric prodrug micelle (PPM) with pH/redox dual-sensitivity, which was prepared using methoxy poly (ethylene glycol) (mPEG) with favorable biosafety to improve cancer therapy. METHOD: The tumor microenvironment stimuli-responsive PPMs were prepared and characterized in vitro and in vivo. RESULTS: Our data displayed that the PPMs with excellent biocompatibility exhibited the stimuli-responsive drug release behavior under the microenvironment of cancer cells, superior cellular internalization and lower cytotoxicity. A new method to control drug release behavior was proposed by comparing the release behavior of PPMs formed by PEG of different molecular weight. Furthermore, the fabricated PPMs exhibited the "oral-like" blood concentration curve, improved biodistribution, reduced tissue toxicity and excellent antitumor efficiency in vivo. Consistently, these results indicated that PPMs improved chemotherapeutic efficiency and reduced side effects of the model drug doxorubicin (DOX). CONCLUSION: The prepared pH/redox dual-sensitive PPM enhanced the chemotherapy effect on the tumor site while reducing the physiological toxicity of DOX. Graphical Abstract.
Asunto(s)
Portadores de Fármacos/química , Micelas , Polietilenglicoles/química , Profármacos/química , Microambiente Tumoral , Células A549 , Animales , Antineoplásicos/administración & dosificación , Preparaciones de Acción Retardada , Doxorrubicina/administración & dosificación , Humanos , Masculino , Ratones Endogámicos BALB C , Profármacos/administración & dosificación , Ratas Sprague-DawleyRESUMEN
Stimuli-responsive nanomedicine with theranostic functionalities with reduced side-effects has attracted growing attention, although there are some major obstacles to overcome before clinical applications. Herein, we present an acid-activatable theranostic unimolecular micelles based on amphiphilic star-like polymeric prodrug to systematically address typical existing issues. This smart polymeric prodrug has a preferable size of about 35 nm and strong micellar stability in aqueous solution, which is beneficial to long-term blood circulation and efficient extravasation from tumoral vessels. Remarkably, the polymeric prodrug has a high drug loading rate up to 53.1 wt%, which induces considerably higher cytotoxicity against tumor cells (HeLa cells and MCF-7 cells) than normal cells (HUVEC cells) suggesting a spontaneous tumor-specific targeting capability. Moreover, the polymeric prodrug can serve as a fluorescent nanoprobe activated by the acidic microenvironment in tumor cells, which can be used as a promising platform for tumor diagnosis. The superior antitumor effect in this in vitro study demonstrates the potential of this prodrug as a promising platform for drug delivery and cancer therapy.
Asunto(s)
Antineoplásicos/química , Polímeros/química , Profármacos/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Células HeLa , Células Endoteliales de la Vena Umbilical Humana , Humanos , Células MCF-7 , MicelasRESUMEN
Polymeric prodrug nanoparticles have gained increasing attention in the field of anticancer drug delivery because of their dual functions as a drug carrier and a therapeutic agent. Doxorubicin (DOX) is a highly effective chemotherapeutic agent for various cancers but causes cardiotoxicity. In this work, we developed polymeric prodrug (pHU) nanoparticles that serve as both a drug carrier of DOX and a therapeutic agent. The composition of pHU includes antiangiogenic hydroxybenzyl alcohol (HBA) and ursodeoxycholic acid (UDCA), covalently incorporated through hydrogen peroxide (H2O2)-responsive peroxalate. To enhance cancer cell specificity, pHU nanoparticles were surface decorated with taurodeoxycholic acid (TUDCA) to facilitate p-selectin-mediated cancer targeting. TUDCA-coated and DOX-loaded pHU nanoparticles (t-pHUDs) exhibited controlled release of DOX triggered by H2O2, characteristic of the tumor microenvironment. t-pHUDs also effectively suppressed cancer cell migration and vascular endothelial growth factor (VEGF) expression in response to H2O2. In animal studies, t-pHUDs exhibited highly potent anticancer activity. Notably, t-pHUDs, with their ability to accumulate preferentially in tumors due to the p-selectin targeting, surpassed the therapeutic efficacy of equivalent DOX and pHU nanoparticles alone. What is more, t-pHUDs significantly suppressed VEGF expression in tumors and mitigated hepato- and cardiotoxicity of DOX. Given their cancer targeting ability, enhanced therapeutic efficacy and minimized off-target toxicity, t-pHUDs present an innovative and targeted approach with great translational potential as an anticancer therapeutic agent.
Asunto(s)
Doxorrubicina , Nanopartículas , Profármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Profármacos/administración & dosificación , Profármacos/química , Nanopartículas/química , Animales , Humanos , Línea Celular Tumoral , Ratones Endogámicos BALB C , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Peróxido de Hidrógeno , Portadores de Fármacos/química , Ácido Ursodesoxicólico/administración & dosificación , Ácido Ursodesoxicólico/química , Liberación de Fármacos , Ratones Desnudos , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/química , Polímeros/química , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratones , Femenino , Sistemas de Liberación de Medicamentos , Movimiento Celular/efectos de los fármacos , Alcoholes Bencílicos/administración & dosificación , Alcoholes Bencílicos/químicaRESUMEN
Tumor-associated macrophages (TAMs) usually adopt a tumor-promoting M2-like phenotype, which largely impedes the immune response and therapeutic efficacy of solid tumors. Repolarizing TAMs from M2 to the antitumor M1 phenotype is crucial for reshaping the tumor immunosuppressive microenvironment (TIME). Herein, we developed self-assembled nanoparticles from the polymeric prodrug of resiquimod (R848) to reprogram the TIME for robust cancer immunotherapy. The polymeric prodrug was constructed by conjugating the R848 derivative to terminal amino groups of the linear dendritic polymer composed of linear poly(ethylene glycol) and lysine dendrimer. The amphiphilic prodrug self-assembled into nanoparticles (PLRS) of around 35 nm with a spherical morphology. PLRS nanoparticles could be internalized by antigen-presenting cells (APCs) in vitro and thus efficiently repolarized macrophages from M2 to M1 and facilitated the maturation of APCs. In addition, PLRS significantly inhibited tumor growth in the 4T1 orthotopic breast cancer model with much lower systemic side effects. Mechanistic studies suggested that PLRS significantly stimulated the TIME by repolarizing TAMs into the M1 phenotype and increased the infiltration of cytotoxic T cells into the tumor. This study provides an effective polymeric prodrug-based strategy to improve the therapeutic efficacy of R848 in cancer immunotherapy.
Asunto(s)
Imidazoles , Inmunoterapia , Nanopartículas , Profármacos , Profármacos/química , Profármacos/farmacología , Profármacos/uso terapéutico , Animales , Ratones , Imidazoles/química , Imidazoles/farmacología , Nanopartículas/química , Femenino , Ratones Endogámicos BALB C , Línea Celular Tumoral , Humanos , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/inmunología , Antineoplásicos/química , Antineoplásicos/farmacología , Células RAW 264.7 , Polietilenglicoles/química , Microambiente Tumoral/efectos de los fármacos , Dendrímeros/química , Dendrímeros/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismoRESUMEN
Docetaxel (DTX) has become one of the most important cytotoxic drugs to treat cancer; nevertheless, its poor hydrophilicity and non-specific distribution of DTX lead to detrimental side effects. In this article, we devised carboxymethylcellulose (CMC)-conjugated polymeric prodrug micelles (mPEG-CMC-DTX PMs) for DTX delivery. The ester-bonded polymeric prodrug, mPEG-CMC-DTX, was synthesized and exhibited the capacity for self-assembling into polymeric micelles. The CMC is profusely substituted and acetylated to promote the coupling rate of DTX. Covalent binding of DTX and CMC through an ester bond can be hydrolyzed to dissociate the bond under the action of esterase in the tumor. The mPEG-CMC-DTX PMs displayed promoted drug loading (>50 %, wt), commendable stability, and sustained release behavior in vitro. The gradual release of the prodrug amplified the selectivity of cytotoxicity between normal cells and tumor cells, mitigating the systemic toxicity of mPEG-CMC-DTX PMs and enabling dose intensification. Notably, mPEG-CMC-DTX PMs demonstrated a superior antitumor efficacy and low systemic toxicity due to the elevated tolerance dosage (even at 40 mg/kg DTX). In summation, mPEG-CMC-DTX PMs harmonized the antitumor efficacy and toxicity of DTX. In essence, innovative perspectives for the rational design of CMC-conjugated polymeric prodrug micelles for the delivery of potently toxic drugs were proffered.
Asunto(s)
Antineoplásicos , Profármacos , Docetaxel/farmacología , Micelas , Profármacos/farmacología , Carboximetilcelulosa de Sodio , Taxoides/química , Polietilenglicoles/química , Antineoplásicos/química , Polímeros/química , Ésteres , Línea Celular TumoralRESUMEN
Ischemia/reperfusion (IR) injury is an inevitable pathological event occurring when blood is resupplied to the tissues after a period of ischemia. One of major causes of IR injury is the overproduction of reactive oxygen species (ROS) including hydrogen peroxide (H2O2), which mediates the expression of various inflammatory cytokines to exacerbate tissue damages. The overproduced H2O2 could therefore serve as a diagnostic and therapeutic biomarker of IR injury. In this study, poly(boronated methacrylate) (pBMA) nanoparticles were developed as nanotheranostic agents for renal IR injury, which not only generate CO2 bubbles to enhance the ultrasound contrast but also provide potent preventive effects in a H2O2-triggered manner. The surface of pBMA nanoparticles was decorated with taurodeoxycholic acid (TUDCA) that binds P-selectin overexpressed in inflamed tissues. In the mouse model of renal IR injury, TUDCA-coated pBMA (T-pBMA) nanoparticles preferentially accumulated in the injured kidney and markedly enhanced the ultrasound contrast. T-pBMA nanoparticles also effectively prevented renal IR injury by scavenging H2O2 and suppressing the expression of inflammatory cytokines. Treatment progress of IR injury could be also monitored by echogenic T-pBMA nanoparticles. Given their targeting ability, excellent H2O2-responsiveness, anti-inflammatory activity and H2O2-triggered echogenicity, T-pBMA nanoparticles have excellent translational potential for the management of various H2O2-related diseases including IR injury.
Asunto(s)
Nanopartículas , Profármacos , Daño por Reperfusión , Ratones , Animales , Profármacos/uso terapéutico , Antioxidantes/uso terapéutico , Peróxido de Hidrógeno/metabolismo , Daño por Reperfusión/diagnóstico por imagen , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Antiinflamatorios/uso terapéutico , Polímeros/uso terapéutico , Isquemia/tratamiento farmacológico , Medios de Contraste , CitocinasRESUMEN
In the treatment of tumor-targeted small-molecule anti-cancer drugs, antibody-mediated therapies, especially for antibody-drug conjugates (ADCs), have revealed great latent force. However, the therapeutic drugs provided by ADCs possess limitation. Considering that the combination of antibodies and nano-drugs can broaden their applicability in the field of tumor treatment, herein, we developed an antibody conjugated polymeric prodrug nanoparticles SAE-PEG-b-PBYP-ss-CPT for targeted camptothecin (CPT) delivery to liver tumor cells. The diblock copolymer was composed of PEG and biodegradable polyphosphoester (PBYP) containing alkynyl groups in the side chain. A derivative of CPT (CPT-ss-N3) was bonded to the PBYP via "click" reaction. The diethyl squarate (SAE) in the terminal of PEG chain was used as a functional group to bond with CD147 monoclonal antibody (CD147 mAb). The particle size and size distribution of the both nanoparticles, with antibody binding (namely CD147-CPT NPs) and without antibody (abbreviated as CPT-loaded NPs), were measured by dynamic light scattering (DLS). The morphologies of both two kinds of nanoparticles were observed by transmission electron microscope (TEM). The results of X-ray photoelectron spectroscopy (XPS) showed that CD147 mAb had been coupled to the surface of CPT-loaded NPs. Endocytosis test indicated that CD147-CPT NPs had higher uptake rate and accumulation in HepG2 cells than those of CPT-loaded NPs without antibodies, due to CD147 mAb can specifically bind to CD147 protein overexpressed in HepG2 cells. We establish a method to bond monoclonal antibodies to anti-cancer polymeric prodrugs, and endow biodegradable polymeric prodrugs with precise targeting functions to liver cancer cells.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Basigina/química , Materiales Biocompatibles/farmacología , Camptotecina/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Inmunoconjugados/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Antineoplásicos Fitogénicos/química , Basigina/genética , Basigina/metabolismo , Materiales Biocompatibles/química , Camptotecina/química , Carcinoma Hepatocelular/patología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Inmunoconjugados/química , Neoplasias Hepáticas/patología , Ensayo de Materiales , Estructura Molecular , Nanomedicina , Tamaño de la Partícula , Profármacos/química , Profármacos/farmacologíaRESUMEN
A novel multiple environment-sensitive polymeric prodrug of gambogic acid (GA) based on chitosan graftomer was fabricated for cancer treatment. Folic acid-chitosan conjugates was complexed with thermosensitive amine terminated poly-N-isopropylacrylamide (NH2-PNIPAM) to develop FA-CSPN. Gambogic acid was conjugated with the graftomer via esterification to achieve high drug-loading capacity and controlled drug release. The resulting amphiphilic prodrug, O-(gambogic acid)-N-(folic acid)-N'-(NH2-PNIPAM) chitosan graftomer (GFCP), could self-assemble into micelles. As expected, the micelles were stable and biocompatible, featuring pH-, esterase- and temperature-dependent manner of drug release. Moreover, the anticancer effect studies of GFCP micelles were performed using a tumor-bearing mouse model and cellular assays (tumor cell uptake assay, cytotoxicity and tumor-sphere penetration). Collectively, GFCP micelles show both potential in vivo and in vitro in improving the anticancer effectiveness of GA owing to high loading capacity, targeted tumor accumulation, and multiple tumor microenvironmental responsiveness.
Asunto(s)
Antineoplásicos/uso terapéutico , Quitosano/análogos & derivados , Quitosano/uso terapéutico , Neoplasias/tratamiento farmacológico , Profármacos/uso terapéutico , Xantonas/uso terapéutico , Resinas Acrílicas/síntesis química , Resinas Acrílicas/química , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quitosano/síntesis química , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Liberación de Fármacos , Ácido Fólico/análogos & derivados , Ácido Fólico/síntesis química , Humanos , Concentración de Iones de Hidrógeno , Masculino , Ratones , Micelas , Neoplasias/patología , Profármacos/síntesis química , Temperatura , Xantonas/síntesis químicaRESUMEN
Multidrug resistance (MDR) is one of the main reasons for tumor chemotherapy failure. Podophyllotoxin (PPT) has been reported that can suppress MDR cancer cell growth; however, effective delivery of PPT to MDR cancer cells is challenged by cascaded bio-barriers. To effectively deliver PPT to MDR cancer cells, a PPT polymeric prodrug micelle (PCDMA) with the charge-conversion capability and self-acceleration drug release function are fabricated, which is composed of a pH and reactive oxygen species (ROS) sequentially responsive PPT-polymeric prodrug and an ROS generation agent, cucurbitacin B (CuB). After reach to tumor tissue, the surface charge of PCDMA could rapidly reverse to positive in the tumor extracellular environment to promote cellular uptake. Subsequently, the PCDMA could be degraded to release PPT and CuB in response to an intracellular high ROS condition. The released CuB is competent for generating ROS, which in turn accelerates the release of PPT and CuB. Eventually, the released PPT could kill MDR cancer cells. The in vitro and in vivo studies demonstrated that PCDMA was effectively internalized by cancer cells and produces massive ROS intracellular, rapid release drug, and effectively overcame MDR compared with the control cells, due to the tumor-specific weakly acidic and ROS-rich environment. Our results suggest that the pH/ROS dual-responsive PCDMA micelles with surface charge-reversal and self-amplifying ROS-response drug release provide an excellent platform for potential MDR cancer treatment.
Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Micelas , Podofilotoxina/farmacología , Profármacos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Células A549 , Animales , Supervivencia Celular , Química Farmacéutica , Portadores de Fármacos , Liberación de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Ratones , Podofilotoxina/administración & dosificación , Polímeros/química , Profármacos/administración & dosificación , Propiedades de Superficie , Triterpenos/metabolismoRESUMEN
Ursolic acid (UA), found widely in nature, exerts effective anti-tumoral activity against various malignant tumors. However, the low water solubility and poor bioavailability of UA have greatly hindered its translation to the clinic. To overcome these drawbacks, a simple redox-sensitive UA polymeric prodrug was synthesized by conjugating UA to polyethylene glycol using a disulfide bond. This formulation can self-assemble into micelles (U-SS-M) in aqueous solutions to produce small size micelles (â¼62.5 nm in diameter) with high drug loading efficiency (â¼16.7%) that exhibit pH and reduction dual-sensitivity. The cell and animal studies performed using the osteosarcoma MG-63 cell line and MG-63 cancer xenograft mice as the model systems consistently confirmed that the U-SS-M formulation could significantly prolong the circulation in blood and favor accumulation in tumor tissue. Targeted accumulation allows the U-SS-M to be effectively internalized by cancer cells, where the rapid release of UA is favored by a glutathione-rich and acidic intracellular environment, and ultimately achieves potent antitumor efficacy.
Asunto(s)
Antineoplásicos Fitogénicos/química , Osteosarcoma/tratamiento farmacológico , Polietilenglicoles/química , Polímeros/química , Profármacos , Triterpenos/química , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias Óseas , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Humanos , Ratones , Micelas , Oxidación-Reducción , Polímeros/administración & dosificación , Polímeros de Estímulo Receptivo , Triterpenos/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto , Ácido UrsólicoRESUMEN
A facile synthetic methodology has been developed to prepare multifaceted polymeric prodrugs that are targeted, biodegradable, and nontoxic, and used for the delivery of combination therapy. This is the first instance of the delivery of the WHO recommended antimalarial combination of lumefantrine (LUM, drug 1) and artemether (AM, drug 2) via a polymeric prodrug. To achieve this, reversible addition-fragmentation chain transfer (RAFT)-mediated polymerization of N-vinylpyrrolidone (NVP) was conducted using a hydroxy-functional RAFT agent, and the resulting polymer was used as the macroinitiator in the ring-opening polymerization (ROP) of α-allylvalerolactone (AVL) to synthesize the biodegradable block copolymer of poly(N-vinylpyrrolidone) and poly(α-allylvalerolactone) (PVP-b-PAVL). The ω-end thiol group of PVP was protected using 2,2'-pyridyldisulfide prior to the ROP, and was conveniently used to bioconjugate a peptidic targeting ligand. To attach LUM, the allyl groups of PVP-b-PAVL underwent oxidation to introduce carboxylic acid groups, which were then esterified with ethylene glycol vinyl ether. Finally, LUM was conjugated to the block copolymer via an acid-labile acetal linkage in a "click"-type reaction, and AM was entrapped within the hydrophobic core of the self-assembled aggregates to render biodegradable multidrug-loaded micelles with targeting ability for combination therapy.
Asunto(s)
Malaria , Profármacos , Portadores de Fármacos , Humanos , Malaria/tratamiento farmacológico , Micelas , PolímerosRESUMEN
We developed dual biologically responsive nanogapped gold nanoparticle vesicles loaded with immune inhibitor and carrying an anticancer polymeric prodrug for synergistic concurrent chemo-immunotherapy against primary and metastatic tumors, along with guided cargo release by photoacoustic (PA) imaging in the second near-infrared (NIR-II) window. The responsive vesicle was prepared by self-assembly of nanogapped gold nanoparticles (AuNNPs) grafted with poly(ethylene glycol) (PEG) and dual pH/GSH-responsive polyprodug poly(SN38-co-4-vinylpyridine) (termed AuNNP@PEG/PSN38VP), showing intense PA signal in the NIR-II window. The effect of the rigidity of hydrophobic polymer PSN38VP on the assembled structures and the formation mechanism of AuNNP@SN38 Ve were elucidated by computational simulations. The immune inhibitor BLZ-945 was encapsulated into the vesicles, resulting in pH-responsive release of BLZ-945 for targeted immunotherapy, followed by the dissociation of the vesicles into single AuNNP@PEG/PSN38VP. The hydrophilic AuNNP@PEG/PSN38VP nanoparticles could penetrate deep into the tumor tissues and release the anticancer drug SN38 under the reductive environment. A PA signal in the NIR-II window in the deep tumor region was obtained. The BLZ-945-loaded vesicle enabled enhanced PA imaging-guided concurrent chemo-immunotherapy efficacy, inhibiting the growth of both primary tumors and metastatic tumors.
Asunto(s)
Nanopartículas del Metal , Nanopartículas , Técnicas Fotoacústicas , Oro , Inmunoterapia , PolímerosRESUMEN
The development of small molecule anticancer drugs, with low water solubility and high toxicity, into polymeric prodrugs has developed into a promising strategy in clinical application. In this study, we synthesized a novel G3-C12-mediated esterase-sensitive tumor-targeting polymeric prodrug of camptothecin (CPT), P(OEGMA-co-CPT-co-G3-C12), and explored its anticancer activity against androgen-independent prostate cancer in vitro and in vivo. Compared to free CPT, the multifunctional polymeric prodrug demonstrated improved water solubility and stability, higher intracellular uptake, and enhanced cytotoxicity in DU145 cells in vitro. Furthermore, it displayed an improved accumulation in the tumor and an enhanced anticancer activity in vivo. Hence, P(OEGMA-co-CPT-co-G3-C12) could be a promising drug in the treatment of androgen-independent prostate cancer.
Asunto(s)
Proteínas Sanguíneas/metabolismo , Camptotecina/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Desarrollo de Medicamentos/métodos , Galectinas/metabolismo , Profármacos/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Animales , Camptotecina/administración & dosificación , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Polímeros/administración & dosificación , Polímeros/metabolismo , Profármacos/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Immunochemotherapy is viewed as a promising approach for cancer therapy via combination treatment with immune-modulating drugs and chemotherapeutic drugs. A novel dual-functional immunostimulatory polymeric prodrug carrier PEG2k-Fmoc-1-MT was developed for simultaneously delivering 1-methyl tryptophan (1-MT) of an indoleamine 2,3-dioxygenase (IDO) inhibitor and chemotherapeutic doxorubicin (DOX) for breast cancer immunochemotherapy. DOX/PEG2k-Fmoc-1-MT micelles were more effective in cell proliferation inhibition and apoptosis induction in 4T1 cells. PEG2k-Fmoc-1-MT prodrug micelles presented enhanced inhibition ability of IDO with decreased kynurenine production and increased the proliferation in dose-dependent manners of effector CD4+ and CD8+ T cells. DOX/PEG2k-Fmoc-1-MT micelles exhibited prolonged blood circulation time and superior accumulation of DOX and 1-MT in tumors compared to that of DOX and 1-MT solutions. A significantly enhanced immune response of the DOX/PEG2k-Fmoc-1-MT micelles was observed with the decreasing tryptophan/kynurenine ratio in blood and tumor tissue, promoting effector CD4+ and CD8+ T cells while reducing regulatory T cell (Tregs) expression. Meanwhile, the coreleased DOX-triggered immunogenic cell death action combined with the cleaved 1-MT promoted the related cytokine secretion of tumor necrosis factor-α, interleukin-2, and interferon-γ, further facilitating the T cell-mediated immune responses. More importantly, the DOX-loaded micelles led to a significantly improved inhibition on tumor growth and prolonged animal survival rate in a 4T1 murine breast cancer model. In conclusion, DOX codelivered by a PEG2k-Fmoc-1-MT immunostimulatory polymeric prodrug showed a maximum immunochemotherapy efficacy against breast cancer.