RESUMO
Prodrug nanoassemblies are emerging as a novel drug delivery system for chemotherapy, comprising four fundamental modules: a drug module, a modification module, a response module, and a surface functionalization module. Among these modules, surface functionalization is an essential process to enhance the biocompatibility and stability of the nanoassemblies. Here, we selected mitoxantrone (MTO) as the drug module and DSPE-PEG2K as surface functionalization module to develop MTO prodrug nanoassemblies. We systematically evaluated the effect of surface functionalization module ratios (10%, 20%, 40%, and 60% of prodrug, WDSPE-mPEG2000/Wprodrug) on the prodrug nanoassemblies. The results indicated that 40% NPs significantly improved the self-assembly stability and cellular uptake of prodrug nanoassemblies. Compared with MTO solution, 40% NPs showed better tumor specificity and pharmacokinetics, resulting in potent antitumor activity with a good safety profile. These findings highlighted the pivotal role of the surface functionalization module in regulating the performance of mitoxantrone prodrug nanoassemblies for cancer treatment.
Assuntos
Antineoplásicos , Nanopartículas , Pró-Fármacos , Mitoxantrona , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodosRESUMO
The prodrug-based nanoassemblies offer an alternative to settle the deficiencies of traditional chemotherapy drugs. In this nanosystem, prodrugs typically comprise drug modules, modification modules, and response modules. The response modules are crucial for facilitating the accurate conversion of prodrugs at specific sites. In this work, we opted for differentiated disulfide bonds as response modules to construct docetaxel (DTX) prodrug nanoassemblies. Interestingly, a subtle change in response modules leads to a "U-shaped" conversion rate of DTX-prodrug nanoassemblies. Prodrug nanoassemblies with the least carbon numbers between the disulfide bond and ester bond (PDONα) offered the fastest conversion rate, resulting in powerful treatment outcomes with some unavoidable toxic effects. PDONß, with more carbon numbers, possessed a slow conversion rate and poor antitumor efficacy but good tolerance. With most carbon numbers in PDONγ, it demonstrated a moderate conversion rate and antitumor effect but induced a risk of lethality. Our study explored the function of response modules and highlighted their importance in prodrug development.
Assuntos
Antineoplásicos , Nanopartículas , Pró-Fármacos , Docetaxel , Pró-Fármacos/química , Linhagem Celular Tumoral , Dissulfetos/química , Carbono , Antineoplásicos/farmacologia , Nanopartículas/químicaRESUMO
Albumin has emerged as a versatile drug carrier. To harness albumin as a carrier for doxorubicin (DOX), we synthesized three acid-labile DOX prodrugs using stearic acid (SA), oleic acid (OA), and linoleic acid (LA) as the albumin-binding motif, respectively. Different from conventional albumin nanodrugs (such as Abraxane, with a drug loading of 10%), the DOX prodrugs assembled albumin nanoparticles (NPs) have an ultrahigh drug loading (>35%). Noteworthy, we demonstrated that the saturation of fatty acids exerted great influence on colloidal stability of prodrug NPs, thus affecting their in vivo pharmacokinetics, tumor accumulation and antitumor efficacy. Furthermore, the hydrazone bond-bridged DOX prodrugs could remain intact in the bloodstream but allow DOX to be released in the acidic tumor environment, resulting in improved antitumor efficacy and safety. Our work gives novel insights into the structure-to-efficacy relationship of albumin-bound fatty acid prodrugs and provides a simple strategy for advanced albumin-bound nanomedicines.
Assuntos
Nanopartículas , Neoplasias , Pró-Fármacos , Humanos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Ácidos Graxos , Doxorrubicina/uso terapêutico , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade , Concentração de Íons de Hidrogênio , Albuminas/uso terapêutico , Linhagem Celular TumoralRESUMO
Prodrug-based nanoassemblies have been developed to solve the bottlenecks of chemotherapeutic drugs. The fabricated prodrugs usually consist of active drug modules, response modules, and modification modules. Among three modules, the response modules play a vital role in controlling the intelligent drug release at tumor sites. Herein, various locations of disulfide bond linkages were selected as response modules to construct three Docetaxel (DTX) prodrugs. Interestingly, the small structural difference caused by the length of response modules endowed corresponding prodrug nanoassemblies with unique characteristic. α-DTX-OD nanoparticles (NPs) possessed the advantages of high redox-responsiveness due to their shortest linkages. However, they were too sensitive to retain the intact structure in the blood circulation, leading to severe systematic toxicity. ß-DTX-OD NPs significantly improved the pharmacokinetics of DTX but may induce damage to the liver. In comparison, γ-DTX-OD NPs with the longest linkages greatly ameliorated the delivery efficiency of DTX as well as improved DTX's tolerance dose.
Assuntos
Antineoplásicos , Nanopartículas , Pró-Fármacos , Docetaxel , Pró-Fármacos/química , Nanopartículas/química , Liberação Controlada de Fármacos , Antineoplásicos/química , Linhagem Celular Tumoral , Portadores de Fármacos/químicaRESUMO
The current state of antitumor nanomedicines is severely restricted by poor penetration in solid tumors. It is indicated that extracellular vesicles (EVs) secreted by tumor cells can mediate the intercellular transport of antitumor drug molecules in the tumor microenvironment. However, the inefficient generation of EVs inhibits the application of this approach. Herein, we construct an EV-mediated self-propelled liposome containing monensin as the EV secretion stimulant and photosensitizer pyropheophorbide-a (PPa) as a therapeutic agent. Monensin and PPa are first transferred to the tumor plasma membrane with the help of membrane fusogenic liposomes. By hitchhiking EVs secreted by the outer tumor cells, both drugs are layer-by-layer transferred into the deep region of a solid tumor. Particularly, monensin, serving as a sustainable booster, significantly amplifies the EV-mediated PPa penetration by stimulating EV production. Our results show that this endogenous EV-driven nanoplatform leads to deep tumor penetration and enhanced phototherapeutic efficacy.
Assuntos
Vesículas Extracelulares , Neoplasias , Humanos , Lipossomos/metabolismo , Monensin/metabolismo , Monensin/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Microambiente TumoralRESUMO
The antitumor efficiency and clinical translation of traditional nanomedicines is mainly restricted by low drug loading, complex preparation technology, and potential toxicity caused by the overused carrier materials. In recent decades, small-molecule prodrug nanoassemblies (SMP-NAs), which are formed by the self-assembly of prodrugs themselves, have been widely investigated with distinct advantages of ultrahigh drug-loading and negligible excipients-trigged adverse reaction. Benefited from the simple preparation process, SMP-NAs are widely used for chemotherapy, phototherapy, immunotherapy, and tumor diagnosis. In addition, combination therapy based on the accurate co-delivery behavior of SMP-NAs can effectively address the challenges of tumor heterogeneity and multidrug resistance. Recent trends in SMP-NAs are outlined, and the corresponding self-assembly mechanisms are discussed in detail. Besides, the smart stimuli-responsive SMP-NAs and the combination therapy based on SMP-NAs are summarized, with special emphasis on the structure-function relationships. Finally, the outlooks and potential challenges of SMP-NAs in cancer therapy are highlighted.
Assuntos
Antineoplásicos , Nanopartículas , Pró-Fármacos , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , NanomedicinaRESUMO
BACKGROUND: Photothermal therapy (PTT) has been extensively investigated as a tumor-localizing therapeutic modality for neoplastic disorders. However, the hyperthermia effect of PTT is greatly restricted by the thermoresistance of tumor cells. Particularly, the compensatory expression of heat shock protein 90 (HSP90) has been found to significantly accelerate the thermal tolerance of tumor cells. Thus, a combination of HSP90 inhibitor and photothermal photosensitizer is expected to significantly enhance antitumor efficacy of PTT through hyperthermia sensitization. However, it remains challenging to precisely co-deliver two or more drugs into tumors. METHODS: A carrier-free co-delivery nanoassembly of gambogic acid (GA, a HSP90 inhibitor) and DiR is ingeniously fabricated based on a facile and precise molecular co-assembly technique. The assembly mechanisms, photothermal conversion efficiency, laser-triggered drug release, cellular uptake, synergistic cytotoxicity of the nanoassembly are investigated in vitro. Furthermore, the pharmacokinetics, biodistribution and self-enhanced PTT efficacy were explored in vivo. RESULTS: The nanoassembly presents multiple advantages throughout the whole drug delivery process, including carrier-free fabrication with good reproducibility, high drug co-loading efficiency with convenient dose adjustment, synchronous co-delivery of DiR and GA with long systemic circulation, as well as self-tracing tumor accumulation with efficient photothermal conversion. As expected, HSP90 inhibition-augmented PTT is observed in a 4T1 tumor BALB/c mice xenograft model. CONCLUSION: Our study provides a novel and facile dual-drug co-assembly strategy for self-sensitized cancer therapy.
Assuntos
Nanoestruturas/química , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Xantonas/química , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Lasers , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/metabolismo , Terapia Fototérmica , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Transplante Heterólogo , Xantonas/metabolismo , Xantonas/uso terapêuticoRESUMO
The potential toxicity of nanocarrier excipients and complicated preparation technologies have impeded the clinical application of nanomedicine. Recently, pure drug-assembled nanosystems (PDANS) have been widely investigated, due to the unique self-assembly characteristics of pure drug molecules. PDANS provides a facile nanoplatform for developing carrier-free nanomedicine. Herein, the recent trends in PDANS for cancer therapy are outlined. First, the emerging strategies to develop single pure drug-based nanoassemblies are discussed. Second, co-assembly of two or more pure drugs for efficient combination therapy is overviewed. Then, the functional self-assembly of non-cytotoxic agents in tumor sites is presented. Finally, the rational design and self-assembly mechanisms of these unique nanoplatforms are highlighted.
Assuntos
Sistemas de Liberação de Medicamentos , Neoplasias , Excipientes , Humanos , Nanomedicina , Neoplasias/tratamento farmacológicoRESUMO
The current state of chemotherapy is far from satisfaction, restricted by the inefficient drug delivery and the off-target toxicity. Prodrug nanoassemblies are emerging as efficient platforms for chemotherapy. Herein, three docetaxel dimeric prodrugs are designed using diselenide bond, disulfide bond, or dicarbide bond as linkages. Interestingly, diselenide bond-bridged dimeric prodrug can self-assemble into stable nanoparticles with impressive high drug loading (≈70%, w/w). Compared with disulfide bond and dicarbide bond, diselenide bond greatly facilitates the self-assembly of dimeric prodrug, and then improves the colloidal stability, blood circulation time, and antitumor efficacy of prodrug nanoassemblies. Furthermore, the redox-sensitive diselenide bond can specifically respond to the overexpressed reactive oxygen species and glutathione in tumor cells, leading to tumor-specific drug release. Therefore, diselenide bond bridged prodrug nanoassemblies exhibit discriminating cytotoxicity between tumor cells and normal cells, significantly alleviating the systemic toxicity of docetaxel. The present work gains in-depth insight into the impact of diselenide bond on the dimeric prodrug nanoassemblies, and provides promising strategies for the rational design of the high efficiency-low toxicity chemotherapeutical nanomedicines.
Assuntos
Antineoplásicos , Nanopartículas , Pró-Fármacos , Linhagem Celular Tumoral , Docetaxel , Liberação Controlada de Fármacos , NanomedicinaRESUMO
A single nanodrug delivery system for combined delivery of paclitaxel and doxorubicin that integrates high co-loading efficiency, synchronous co-delivery of combined drugs, controllable drug release, and maintains the drug combination at fixed synergistic ratios has been proven to be challenging. Here, we report a redox dual-responsive prodrug nanosystem consisting of a paclitaxel-doxorubicin heterodimeric prodrug with a thioether bond linkage to effectively co-deliver two therapeutic drugs. The heterodimeric prodrug could self-assemble into uniform nanoaggregates containing DSPE-PEG2K with a precise drug co-loading ratio in water, and possessed a high co-loading content. We demonstrated that this nanosystem provided strong synergistic effects in MCF-7 and 4 T1 cells. In vivo, this nanosystem results in a long blood circulation, high accumulation in the tumor, and significant inhibition of tumor growth in BALB/c mice bearing 4 T1 tumors. Such a simple, safe, and efficient heterodimeric prodrug nanosystem exhibits great potential for clinical translation in future combination chemotherapy treatments.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Nanopartículas , Pró-Fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Disulfide bonds have been widely used to develop reduction-responsive drug-delivery systems (DDS) for cancer therapy. We propose that disulfide bonds might be also used as an oxidation-responsive linkage just like thioether bonds, which can be oxidized to hydrophilic sulfoxide or sulphone in the presence of oxidation stimuli. To test our hypothesis, we design three novel paclitaxel-citronellol conjugates linked via different lengths of disulfide-bond-containing carbon chain. The prodrugs can self-assemble into uniform-size nanoparticles with impressively high drug loading (>55%). As expected, the disulfide-bond-bridged prodrug nanoparticles show redox dual-responsive drug release. More interestingly, the position of disulfide bonds in the carbon chain linkage has profound impacts on the redox dual responsiveness, thereby affecting the drug release, cytotoxicity, pharmacokinetics, biodistribution, and in vivo antitumor efficacy of prodrug nanoassemblies. The redox dual-responsive mechanism is elucidated, and how the position of disulfide bonds in the carbon chain affects the redox dual responsiveness and antitumor efficiency of prodrug nanoassemblies is also clarified. Our findings give new insight into the stimuli responsiveness of disulfide bonds and provide a good foundation for the development of novel redox dual-responsive DDS for cancer therapy.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Preparações de Ação Retardada/química , Dissulfetos/química , Nanopartículas/química , Paclitaxel/administração & dosagem , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Liberação Controlada de Fármacos , Humanos , Camundongos Nus , Neoplasias/tratamento farmacológico , Oxirredução , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêuticoRESUMO
A redox-responsive docetaxel (DTX) prodrug consisting of a disulfide linkage between DTX and vitamin E (DTX-SS-VE) was synthesized in our laboratory and was successfully formulated into liposomes. The aim of this study was to optimize the formulation and investigate the cellular uptake of DTX prodrug-loaded liposomes (DPLs). The content of DTX-SS-VE was determined by ultrahigh-performance liquid chromatography (UPLC). The formulation and process were optimized using entrapment efficiency (EE), drug-loading (DL), particle size and polydispersity index (PDI) as the evaluation indices. The optimal formulation was as follows: drug/lipid ratio of 1:12, cholesterol/lipid ratio of 1:10, hydration temperature of 40 °C, sonication power and time of 400 W and 5 min. The EE, DL and particle size of the optimized DPLs were 97.60 ± 0.03%, 7.09 ± 0.22% and 93.06 ± 0.72 nm, respectively. DPLs had good dilution stability under the physiological conditions over 24 h. In addition, DPLs were found to enter tumor cells via different pathways and released DTX from the prodrug to induce apoptosis. Taken together, the optimized formulation and process were found to be a simple, stable and applicable method for the preparation of DPLs that could successfully escape from lysosomes.
Assuntos
Lipossomos/química , Oxirredução/efeitos dos fármacos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Taxoides/administração & dosagem , Taxoides/química , Células A549 , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Transporte Biológico , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Docetaxel , Portadores de Fármacos/química , Humanos , Lipídeos/administração & dosagem , Lipídeos/química , Tamanho da Partícula , Vitamina E/administração & dosagem , Vitamina E/químicaRESUMO
Codelivery of multiple drugs with complementary anticancer mechanisms by nanocarriers offers an effective strategy to treat cancers. Herein, conjugation (PTX-SS-VE) of paclitaxel (PTX) to vitamin E succinate (VE) self-assembled nanoparticles were used to load tetrandrine (TET) for combinational treatment against breast carcinoma. The ratio of PTX-SS-VE and TET was optimized. Compared with PTX, the TET/PTX-SS-VE coloaded nanoparticles (TPNPs) demonstrated superior cytotoxicity against both MCF-7 cells and MCF-7/Adr cells. TPNPs were facilitated to release PTX and TET under a highly reductive environment in tumor cells through the in vitro simulative release study. Cell apoptosis study and Western blotting analysis exhibited TPNPs could significantly increase cell apoptosis via modulating the levels of Bcl-2 protein and Caspase-3, which might be triggered by excess cellular reactive oxygen species (ROS) production through an intracellular ROS detection test. Cellular uptake study showed that TET could increase PTX accumulation in MCF-7/Adr cells but not in MCF-7 cells, which explained stronger synergetic efficacy of TPNPs on MCF-7/Adr cells. Overall, encapsulation of hydrophobic drugs, such as TET, in reduction-sensitive PTX-SS-VE nanoparticles provides a prospective strategy to effectively overcome the multidrug resistance of tumor cells in a synergistic manner. Such a uniquely small molecular weight prodrug-nanocarrier opens up new perspectives for the development of nanomedicines.
Assuntos
Benzilisoquinolinas/química , Neoplasias da Mama/metabolismo , Nanopartículas/química , Pró-Fármacos/química , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Caspase 3/metabolismo , Humanos , Células MCF-7 , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Chemotherapeutic efficacy can be greatly improved by developing nanoparticulate drug delivery systems (nano-DDS) with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, we report a novel redox dual-responsive prodrug-nanosystem self-assembled by hydrophobic small-molecule conjugates of paclitaxel (PTX) and oleic acid (OA). Thioether linked conjugates (PTX-S-OA) and dithioether inserted conjugates (PTX-2S-OA) are designed to respond to the redox-heterogeneity in tumor. Dithioether has been reported to show redox dual-responsiveness, but we find that PTX-S-OA exhibits superior redox sensitivity over PTX-2S-OA, achieving more rapid and selective release of free PTX from the prodrug nanoassemblies triggered by redox stimuli. PEGylated PTX-S-OA nanoassemblies, with impressively high drug loading (57.4%), exhibit potent antitumor activity in a human epidermoid carcinoma xenograft. This novel prodrug-nanosystem addresses concerns related to the low drug loading and inefficient drug release from hydrophobic prodrugs of PTX, and provides possibilities for the development of redox dual-sensitive conjugates or polymers for efficient anticancer drug delivery.
Assuntos
Portadores de Fármacos , Ácidos Graxos/química , Nanoconjugados , Paclitaxel/administração & dosagem , Pró-Fármacos/administração & dosagem , Animais , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Oxirredução , Ratos Sprague-Dawley , SulfetosRESUMO
The conjugate of paclitaxel (PTX) and docosahexaenoic acid has entered into clinical trials. However, the most recent clinical outcomes fell short of expectations, due to the extremely slow drug release from the hydrophobic conjugates. Herein, a novel prodrug-based nanoplatform self-assembled by the disulfide bond linked conjugates of PTX and oleic acid for rapid and differential release of PTX in tumor cells is reported. This redox-responsive prodrug-nanosystem demonstrates multiple therapeutic advantages, including one-step facile fabrication, high drug-loading efficiency (56%, w/w), on-demand drug release responding to redox stimuli, as well as favorable cellular uptake and biodistribution. These advantages result in significantly enhanced antitumor efficacy in vivo, with the tumor almost completely disappearing in mice. Such a uniquely engineered prodrug-nanosystem has great potential to be used as potent chemotherapeutic nanomedicine in clinical cancer therapy.
Assuntos
Nanomedicina/métodos , Ácido Oleico/química , Pró-Fármacos/química , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos Nus , Oxirredução , Paclitaxel/administração & dosagem , Paclitaxel/química , Paclitaxel/uso terapêutico , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
Homodimeric prodrug nanoassemblies (HDPNs) hold promise for improving the delivery efficiency of chemo-drugs. However, the key challenge lies in designing rational chemical linkers that can simultaneously ensure the chemical stability, self-assembly stability, and site-specific activation of prodrugs. The "in series" increase in sulfur atoms, such as trisulfide bond, can improve the assembly stability of HDPNs to a certain extent, but limits the chemical stability of prodrugs. Herein, trithiocarbonate bond (âSC(S)Sâ), with a stable "satellite-type" distribution of sulfur atoms, is developed via the insertion of a central carbon atom in trisulfide bonds. âSC(S)Sâ bond effectively addresses the existing predicament of HDPNs by improving the chemical and self-assembly stability of homodimeric prodrugs while maintaining the on-demand bioactivation. Furthermore, âSC(S)Sâ bond inhibits antioxidant defense system, leading to up-regulation of the cellular ROS and apoptosis of tumor cells. These improvements of âSC(S)Sâ bond endow the HDPNs with in vivo longevity and tumor specificity, ultimately enhancing the therapeutic outcomes. âSC(S)Sâ bond is, therefore, promising for overcoming the bottleneck of HDPNs for efficient oncological therapy.
Assuntos
Antineoplásicos , Nanopartículas , Pró-Fármacos , Tionas , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Polímeros , Enxofre , Nanopartículas/química , Liberação Controlada de FármacosRESUMO
HYPOTHESIS: Hydrophilic cationic drugs such as mitoxantrone hydrochloride (MTO) pose a significant delivery challenge to the development of nanodrug systems. Herein, we report the use of a hydrophobic ion-pairing strategy to enhance the nano-assembly of MTO. EXPERIMENTS: We employed biocompatible sodium cholesteryl sulfate (SCS) as a modification module to form stable ion pairs with MTO, which balanced the intermolecular forces and facilitated nano-assembly. PEGylated MTO-SCS nanoassemblies (pMS NAs) were prepared via nanoprecipitation. We systematically evaluated the effect of the ratio of the drug module (MTO) to the modification module (SCS) on the nanoassemblies. FINDINGS: The increased lipophilicity of MTO-SCS ion pair could significantly improve the encapsulation efficiency (â¼97 %) and cellular uptake efficiency of MTO. The pMS NAs showed prolonged blood circulation, maintained the same level of tumor antiproliferative activity, and exhibited reduced toxicity compared with the free MTO solution. It is noteworthy that the stability, cellular uptake, cytotoxicity, and in vivo pharmacokinetic behavior of the pMS NAs increased in proportion to the molar ratio of SCS to MTO. This study presents a self-assembly strategy mediated by ion pairing to overcome the challenges commonly associated with the poor assembly ability of hydrophilic cationic drugs.
Assuntos
Antineoplásicos , Ésteres do Colesterol , Interações Hidrofóbicas e Hidrofílicas , Mitoxantrona , Mitoxantrona/química , Mitoxantrona/farmacologia , Mitoxantrona/farmacocinética , Humanos , Animais , Ésteres do Colesterol/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Camundongos , Proliferação de Células/efeitos dos fármacos , Cátions/química , Sobrevivência Celular/efeitos dos fármacos , Tamanho da Partícula , Nanopartículas/química , Propriedades de Superfície , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Polietilenoglicóis/químicaRESUMO
The self-assembly prodrugs are usually consisted of drug modules, activation modules, and assembly modules. Keeping the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug nanoassemblies. This study designed four docetaxel (DTX) prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules (C16, C18, C20, and C24). The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules' sensitivity. The extension of the carbon chains improved the prodrugs' self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative toxicity. The use of C20 can balance efficacy and safety. These results provide a great reference for the rational design of prodrug nanoassemblies.
RESUMO
Dimeric prodrug nanoassemblies (DPNAs) stand out as promising strategies for improving the efficiency and safety of chemotherapeutic drugs. The success of trisulfide bonds (-SSS-) in DPNAs makes polysulfide bonds a worthwhile focus. Here, we explore the comprehensive role of tetrasulfide bonds (-SSSS-) in constructing superior DPNAs. Compared to trisulfide and disulfide bonds, tetrasulfide bonds endow DPNAs with superlative self-assembly stability, prolonged blood circulation, and high tumor accumulation. Notably, the ultra-high reduction responsivity of tetrasulfide bonds make DPNAs a highly selective "tumor bomb" that can be ignited by endogenous reducing agents in tumor cells. Furthermore, we present an "add fuel to the flames" strategy to intensify the reductive stress at tumor sites by replenishing exogenous reducing agents, making considerable progress in selective tumor inhibition. This work elucidates the crucial role of tetrasulfide bonds in establishing intelligent DPNAs, alongside the combination methodology, propelling DPNAs to new heights in potent cancer therapy.
Assuntos
Pró-Fármacos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Pró-Fármacos/química , Substâncias Redutoras , Linhagem Celular TumoralRESUMO
Prodrug nanoassemblies combine the advantages of prodrug strategies and nanotechnology have been widely utilized for delivering antitumor drugs. These prodrugs typically comprise active drug modules, response modules, and modification modules. Among them, the modification modules play a critical factor in improving the self-assembly ability of the parent drug. However, the impact of the specific structure of the modification modules on prodrug self-assembly remains elusive. In this study, two gemcitabine (GEM) prodrugs are developed using 2-octyl-1-dodecanol (OD) as flexible modification modules and cholesterol (CLS) as rigid modification modules. Interestingly, the differences in the chemical structure of modification modules significantly affect the assembly performance, drug release, cytotoxicity, tumor accumulation, and antitumor efficacy of prodrug nanoassemblies. It is noteworthy that the prodrug nanoassemblies constructed with flexible modifying chains (OD) exhibit improved stability, faster drug release, and enhanced antitumor effects. Our findings elucidate the significant impact of modification modules on the construction of prodrug nanoassemblies.