RESUMO
In addition to the conventional chemotherapeutic drugs, potent inhibitors of key enzymes that are differentially overexpressed in cancer cells and associated with its progression are often considered as the drugs of choice for treating cancer. Aldose reductase (AR), which is primarily associated with complications of diabetes, is known to be closely related to the development of cancer and drug resistance. Epalrestat (EPA), an FDA-approved drug, is a potent inhibitor of AR and exhibits anticancer activity. However, its poor pharmacokinetic properties limit its bioavailability and therapeutic benefits. We report herein the first examples of esterase-responsive turn-on fluorogenic prodrugs for the sustained release of EPA to cancer cells with a turn-on fluorescence readout. Carboxylesterases are known to be overexpressed in several organ-specific cancer cells and help in selective uncaging of drug from the prodrugs. The prodrugs were synthesized using a multistep organic synthesis and successfully characterized. Absorption and emission spectroscopic studies indicated successful activation of the prodrugs in the presence of porcine liver esterase (PLE) under physiological condition. HPLC studies revealed a simultaneous release of both the drug and the fluorophore from the prodrugs over time with mechanistic insights. While the inhibitory potential of EPA released from the prodrugs toward the enzyme AR was validated in the aqueous medium, the anticancer activity of the prodrugs was studied in a representative cervical cancer cell line. Interestingly, our results revealed that the development of the prodrugs can significantly enhance the anticancer potential of EPA. Finally, the drug uncaging process from the prodrugs by the intracellular esterases was studied in the cellular medium by measuring the turn-on fluorescence using fluorescence microscopy. Therefore, the present study highlights the rational development of the fluorogenic prodrugs of EPA, which will help enhance its anticancer potential with better therapeutic potential.
RESUMO
Hyaluronic acid (HA)-based tumor microenvironment-responsive nanocontainers are attractive candidates for anticancer drug delivery due to HA's excellent biocompatibility, biodegradability, and CD44-targeting properties. Nevertheless, the consecutive synthesis of stabilized, stealthy, responsive HA-based multicomponent nanomedicines generally requires multi-step preparation and purification procedures, leading to batch-to-batch variation and scale-up difficulties. To develop a facile yet robust strategy for promoted translations, a silica monomer containing a cross-linkable diethoxysilyl unit was prepared to enable in situ crosslinking without any additives. Further combined with the host-guest inclusion complexation between ß-cyclodextrin-grafted HA (HA-CD) and ferrocene-functionalized polymers, ferrocene-terminated poly(oligo(ethylene glycol) methyl ether methacrylate (Fc-POEGMA) and Fc-terminated poly(ε-caprolactone)-b-poly(3-(diethoxymethylsilyl)propyl(2-(methacryloyloxy)ethyl) carbamate) (Fc-PCL-b-PDESPMA), a reactive oxygen species (ROS)-sensitive supramolecular polymer construct, Fc-POEGMA/Fc-PCL-b-PDESPMA@HA-CD was readily fabricated to integrate stealthy POEGMA, tumor active targeting HA, and an in situ cross-linkable PDESPMA sequence. Supramolecular amphiphilic copolymers with two different POEGMA contents of 25â¯wt% (P1) and 20â¯wt% (P2) were prepared via a simple physical mixing process, affording two core-crosslinked (CCL) micelles via an in situ sol-gel process of ethoxysilyl groups. The P1-based CCL micelles show not only desired colloidal stability against high dilution, but also an intracellular ROS-mimicking environment-induced particulate aggregation that is beneficial for promoted intracellular release of the loaded cargoes. Most importantly, P1-based nanomedicines exhibited greater cytotoxicity in CD44 receptor-positive HeLa cells than that in CD44 receptor-negative MCF-7 cells. Overall, this work developed HA-based nanomedicines with sufficient extracellular colloidal stability and efficient intracellular destabilization properties for enhanced anticancer drug delivery via smart integration of in situ crosslinking and supramolecular complexation.
RESUMO
Hypoxia, cancer, tissue damage, and acidic pH conditions are interrelated, as chronic hypoxic conditions enhance the malignant phenotype of cancer cells, causing more aggressive tissue destruction, and hypoxic cells rely on anaerobic glycolysis, leading to the accumulation of lactic acid. Therefore, the administration of oxygen is necessary to support the functions of healthy cells until the formation of new blood vessels and to increase the oxygen supply to cancerous tissues to improve the efficacy of antitumor drugs on tumor cells. In addition to O2 supply, pH-dependent delivery of anticancer drugs is desired to target cancer cells and reduce drug side effects on healthy cells. However, the simultaneous delivery of O2 and pH-dependent anticancer drugs via nanomaterials and their effects on the viability of normal and cancer cells under hypoxic conditions have not been studied in sufficient numbers. This study describes the synthesis of a pH-responsive nanomaterial containing oxygen and anticancer drugs that exhibits sustained O2 release over a 14 d period under hypoxic conditions and pH-dependent sustained release of anticancer drugs over 30 d. The simultaneous administration of O2 and anticancer drugs results in higher cell survival of normal cells than that of cancer cells under hypoxic and normoxic conditions.
RESUMO
Nanocarrier surface functionalization has been widely regarded as a promising approach for achieving precise and targeted drug delivery systems. In this work, the fabrication of functionalized-Ag-decorated Fe3O4@SiO2 (Fe3O4@SiO2-Ag) nanocarriers with folic acid (FA) and ß-cyclodextrin (BCD) exhibit a remarkable capacity for delivering two types of anticancer drugs, i.e., doxorubicin (DOX) and epirubicin (EPI), into cancer cells. The effective functionalization of Fe3O4@SiO2-Ag nanoparticles has been achieved through the use of cysteine (Cys) as an anchor for attaching FA and BCD via EDC-NHS coupling and Steglich esterification methods, respectively. The findings indicate that surface functionalization had no significant impact on the physicochemical characteristics of the nanoparticles. However, it notably affected DOX and EPI loading and release efficiency. The electrostatic conjugation of DOX/EPI onto the surface of Fe3O4@SiO2-Ag/Cys/FA and Fe3O4@SiO2-Ag/Cys/BCD exhibited maximum loading efficiency of 50-60% at concentration ratio of DOX/EPI to nanoparticles of 1:14. These nanocarriers also achieved an 40-47% DOX/EPI release over 36 days. Furthermore, the drug-loaded functionalized-nanocarrier showed cytotoxic effects on SK-MEL-2 cells, as demonstrated by an in vitro MTT assay. This suggests that the as-prepared functionalized-nanoparticles have promise as a carrier for the efficient anticancer drugs.
Assuntos
Antineoplásicos , Doxorrubicina , Portadores de Fármacos , Ácido Fólico , Dióxido de Silício , beta-Ciclodextrinas , Ácido Fólico/química , beta-Ciclodextrinas/química , Humanos , Doxorrubicina/farmacologia , Doxorrubicina/química , Doxorrubicina/administração & dosagem , Dióxido de Silício/química , Portadores de Fármacos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Epirubicina/farmacologia , Epirubicina/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacosRESUMO
Over the past few decades, there has been significant interest in smart drug delivery systems capable of carrying multiple drugs efficiently, particularly for treating genetic diseases such as cancer. Despite the development of various drug delivery systems, a safe and effective method for delivering both anticancer drugs and therapeutic genes for cancer therapy remains elusive. In this study, we describe the synthesis of a photoswitchable smart polymeric vehicle comprising a photoswitchable spiropyran moiety and an amino-acid-based cationic monomer-based block copolymer using reversible addition-fragmentation chain transfer (RAFT) polymerization. This system aims at diagnosing triple-negative breast cancer and subsequently delivering genes and anticancer agents. Triple-negative breast cancer patients have elevated concentrations of Cu2+ ions, making them excellent targets for diagnosis. The polymer can detect Cu2+ ions with a low limit of detection value of 9.06 nM. In vitro studies on doxorubicin drug release demonstrated sustained delivery at acidic pH level similar to the tumor environment. Furthermore, the polymer exhibited excellent blood compatibility even at the concentration as high as 500 µg/mL. Additionally, it displayed a high transfection efficiency of approximately 82 ± 5% in MDA-MB-231 triple-negative breast cancer cells at an N/P ratio of 50:1. It is observed that mitochondrial membrane depolarization and intracellular reactive oxygen species generation are responsible for apoptosis and the higher number of apoptotic cells, which occurred through the arrest of the G2/M phase of the cell cycle were observed. Therefore, the synthesized light-responsive cationic polymer may be an effective system for diagnosis, with an efficient anticancer drug and gene carrier for the treatment of triple-negative breast cancer in the future.
Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Sistemas de Liberação de Medicamentos , Antineoplásicos/farmacologia , Polímeros , ÍonsRESUMO
A remarkable challenge in the anticancer drug delivery system is developing an implantable system that can improve the chemotherapeutic effect. Polyurethane is an excellent implantable substrate, with flaws in hydrophobicity. We modified polyurethane via the chemical aminolysis technique to enhance the wettability and protein interaction. The created pores can release the rutin complex incorporated in the polyurethane matrix. In this work, the hybrid polymer matrix consists of Mxene synthesized via a sustainable and simple method by introducing a toxic-free MAX phase and etchants. The incorporation of Mxene and PCL can enhance physicochemical and biological compatibility. Sustainable Mxene increases oxidative stress, cell death, and antibacterial activity, which also resulted in the Mxene@APU/PCL film. Meanwhile, the drug release with respect to pH sensitivity was demonstrated in which Mxene and Mxene@APU/PCL films showed the highest release at pH 5.2; this indicates that the prepared Mxene and aminolyzed polyurethane can function according to the biological system and release the drug from the polymer matrix on slow degradation and swellability. The Mxene and Mxene@APU/PCL films showed 93.2% drug release with oxidative stress on THP-1 cells, which causes rupturing and apoptosis of cancerous cells. The Mxene@APU/PCL film can show great potential in future implantable anticancer drug delivery systems.