RESUMO
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.
Assuntos
Colite , Colo , Preparações de Ação Retardada , Mesalamina , Micelas , Nitrorredutases , Polímeros , Pró-Fármacos , Animais , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Mesalamina/química , Mesalamina/farmacocinética , Nitrorredutases/metabolismo , Camundongos , Colo/metabolismo , Colo/patologia , Polímeros/química , Colite/tratamento farmacológico , Colite/metabolismo , Preparações de Ação Retardada/química , NADH NADPH Oxirredutases/metabolismo , Camundongos Endogâmicos C57BL , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , MasculinoRESUMO
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.
Assuntos
Polímeros , Pró-Fármacos , Tetrodotoxina , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Tetrodotoxina/química , Tetrodotoxina/toxicidade , Tetrodotoxina/administração & dosagem , Polímeros/química , Animais , Anestesia Local/métodos , Anestésicos Locais/química , Anestésicos Locais/administração & dosagem , Ácidos Borônicos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Nervo Isquiático/efeitos dos fármacos , Liberação Controlada de Fármacos , CamundongosRESUMO
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.
Assuntos
Doxorrubicina , Nanopartículas , Pró-Fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Nanopartículas/química , Animais , Humanos , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Peróxido de Hidrogênio , Portadores de Fármacos/química , Ácido Ursodesoxicólico/administração & dosagem , Ácido Ursodesoxicólico/química , Liberação Controlada de Fármacos , Camundongos Nus , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/química , Polímeros/química , Fator A de Crescimento do Endotélio Vascular/metabolismo , Camundongos , Feminino , Sistemas de Liberação de Medicamentos , Movimento Celular/efeitos dos fármacos , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/químicaRESUMO
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.
Assuntos
Imidazóis , Imunoterapia , Nanopartículas , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Animais , Camundongos , Imidazóis/química , Imidazóis/farmacologia , Nanopartículas/química , Feminino , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Humanos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Células RAW 264.7 , Polietilenoglicóis/química , Microambiente Tumoral/efeitos dos fármacos , Dendrímeros/química , Dendrímeros/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismoRESUMO
Disulfiram (DSF), an FDA-approved drug for treating alcoholism, has been verified with Cu2+-dependent anticancer activity by forming Cu(DTC)2, the complex of one of its metabolites diethyldithiocarbamate (DTC) and Cu2+. Nevertheless, the antitumor effect is limited by insufficient Cu(DTC)2 formation in suit and off-target system toxicity. Herein, we developed a fibroblast activation protein α (FAPα) activatable nanoagent (HfD-HID-Cu) for co-delivery of DTC polymeric prodrug and exogenous Cu2+ to achieve enhanced cancer-specific therapy and activatable in situ fluorescence imaging meanwhile. HfD-HID-Cu was simply constructed through the co-assembly of the DTC polymeric prodrug (HA-fap-DTC) and the copper-loaded IR808-conjugated polymer (HA-IR-DPA-Cu), which could serve as the "OFF-to-ON" switch for chemotherapy and fluorescence. With the high expression of FAPα in tumor tissues, HA-fap-DTC could be activated specifically to release DTC, while maintaining inactive in normal tissues. The liberated DTC within tumor tissues could contend for Cu2+ from HA-IR-DPA-Cu, resulting in the formation of highly cytotoxic Cu(DTC)2in situ for chemotherapy, concomitant with the fluorescence recovery of cyanine dye for tumor imaging. This work provides an effective strategy for co-delivery of DTC prodrug and Cu2+ for tumor theranostic with improved selectivity and minimal side effects. STATEMENT OF SIGNIFICANCE: DSF-based antitumor therapy is highly dependent on Cu2+. However, the non-synchronous distribution of DSF/DTC and Cu2+ in tumor tissues attenuates the antitumor efficacy. The insufficient Cu(DTC)2 formation in suit and off-target distribution greatly limit the anti-tumor application. This study provides a nanoagent for co-delivery of DTC polymeric prodrug and Cu2+ by simple co-assembly to achieve their synchronous tumor distribution. It can be selectively activated by FAPα, forming cytotoxic Cu(DTC)2in suit for tumor-specific chemotherapy and reducing the systemic toxicity. In addition to chemotherapy, the nanoagent can emit fluorescence under the sequential triggering of FAPα and released DTC for tumor imaging. Overall, this study renders a promising strategy for improved Cu(DTC)2-based antitumor therapy and imaging.
RESUMO
Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug (molecular weight, MW: 93.5 kDa) was produced by reversible addition-fragmentation chain transfer (RAFT) polymerization. The amphiphilic block polymer-doxorubicin (DOX) prodrug was employed to deliver a hydrophobic photosensitizer (PS), chlorin e6 (Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione (GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 kDa in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition (TGI, 58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.