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
Redox-responsive homodimer prodrug nanoassemblies (RHPNs) have emerged as a significant technology for overcoming chemotherapeutical limitations due to their high drug-loading capacity, low excipient-associated toxicity, and straightforward preparation method. Previous studies indicated that α-position disulfide bond bridged RHPNs exhibited rapid drug release rates but unsatisfactory assembly stability. In contrast, γ-disulfide bond bridged RHPNs showed better assembly stability but low drug release rates. Therefore, designing chemical linkages that ensure both stable assembly and rapid drug release remains challenging. To address this paradox of stable assembly and rapid drug release in RHPNs, we developed carbon-spaced double-disulfide bond (CSDD)-bridged RHPNs (CSDD-RHPNs) with two carbon-spaces. Pilot studies showed that CSDD-RHPNs with two carbon-spaces exhibited enhanced assembly stability, reduction-responsive drug release, and improved selective toxicity compared to α-/γ-position single disulfide bond bridged RHPNs. Based on these findings, CSDD-RHPNs with four and six carbon-spaces were designed to further investigate the properties of CSDD-RHPNs. These CSDD-RHPNs exhibited excellent assembly ability, safety, and prolonged circulation. Particularly, CSDD-RHPNs with two carbon-spaces displayed the best antitumor efficacy on 4T1 and B16-F10 tumor-bearing mice. CSDD chemical linkages offer novel perspectives on the rational design of RHPNs, potentially overcoming the design limitations regarding contradictory assembly ability and drug release rate.
Assuntos
Carbono , Dissulfetos , Pró-Fármacos , Dissulfetos/química , Pró-Fármacos/química , Animais , Camundongos , Carbono/química , Humanos , Liberação Controlada de Fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Linhagem Celular Tumoral , Nanoestruturas/química , Dimerização , Doxorrubicina/química , Doxorrubicina/farmacologiaRESUMO
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
Despite the great progress of current bacterially based biotherapeutics, their unsatisfying efficacy and underlying safety problems have limited their clinical application. Herein, inspired by probiotic Escherichia coli strain Nissle 1917, probiotic-derived outer membrane vesicles (OMVs) are found to serve as an effective therapeutic platform for the treatment of inflammatory bowel disease (IBD). To further enhance the therapeutic effect, the probiotic-derived OMV-encapsulating manganese dioxide nanozymes are constructed, named nanoprobiotics, which can adhere to inflamed colonic epithelium and eliminate intestinal excess reactive oxygen species in the murine IBD model. Moreover, combined with the anti-inflammatory medicine metformin, nanoprobiotics could further remold the pro-inflammatory microenvironment, improve the overall richness and diversity of the gut microbiota, and exhibit better therapeutic efficacy than commercial IBD chemotherapeutics. Importantly, insignificant overt systemic toxicity in this treatment was observed. By integrating cytokine storm calm with biotherapy, we develop a safe and effective bionanoplatform for the effective treatment of inflammation-mediated intestinal diseases.
RESUMO
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 oral absorption of paclitaxel (PTX) is restricted by poor solubility in the gastrointestinal tract (GIT), low permeability, and high first-pass metabolism. Lipid carriers, such as a self-microemulsifying drug delivery system (SMEDDS), have been deemed as promising vehicles for promoting oral delivery of PTX. Herein, a lipophilic disulfide-bridged linoleic prodrug (PTX-S-S-LA) was synthesized and efficiently incorporated into SMEDDS to facilitate the oral absorption of PTX. This study mainly aims to evaluate the usefulness of the disulfide-bridged linoleic prodrug incorporated with SMEDDS and provides a new strategy for efficient oral delivery of PTX. The prodrug SMEDDS showed a markedly higher drug loading efficiency (3-fold) compared to that of parent PTX. PTX-S-S-LA SMEDDS significantly increased the drug partition (about 1.9-fold) in the intestinal micellar aqueous phase compared to PTX in the in vitro lipolysis study. Additionally, the gastrointestinal (GI) biodistribution study demonstrated that SMEDDS could enhance the GI biological adhesion and go through the lymphatic system to transport. Moreover, it was found that the reduction-sensitive prodrug (PTX-S-S-LA) has good stability in the GIT, leading to an improved antitumor efficiency without significant GI toxicity. Overall, the PTX-linoleic prodrug (PTX-S-S-LA) in combination with SMEDDS provides a promising way to enable effective oral delivery of PTX.
Assuntos
Pró-Fármacos , Paclitaxel , Dissulfetos , Distribuição Tecidual , Emulsões , Sistemas de Liberação de Medicamentos , Solubilidade , Disponibilidade Biológica , Administração OralRESUMO
Liposomes (lipos), one of the most successful nanotherapeutics in the clinic, have made a rapid advance over the past few years. However, still, several challenges exist for lipos for clinical practice, such as low drug loading and premature drug leakage during in vivo circulation. Paclitaxel (PTX), a commonly used first-line drug for cancer chemotherapy, was chosen as the model drug. Due to its non-ionizable and water-insoluble characteristics, the drug-loading efficiency of the marketable PTX lipos, Lipusu, is only 6.76%. Herein, we designed an ionizable PTX prodrug (PTXP) by modifying phenylboronic acid on the C2' hydroxyl group of PTX for the remote loading of liposomal formulations through the pH gradient method. Compared with Lipusu, PTXP lipos displayed a 34% higher loading efficiency and an encapsulation efficiency of approximately 95%. A series of in vitro/vivo experiments indicated that PTXP lipos possess colloidal stability, prolonged blood circulation, high tumor site accumulation, potent anti-tumor effects, and safety. A combination of ionizable prodrugs and remote loading has proved to be an effective and simple strategy to achieve high liposomal encapsulation efficiency of poorly soluble non-ionizable drugs for clinical application.
Assuntos
Neoplasias da Mama , Pró-Fármacos , Humanos , Feminino , Lipossomos , Linhagem Celular Tumoral , Paclitaxel/uso terapêutico , Neoplasias da Mama/tratamento farmacológicoRESUMO
Oncolytic viruses (OVs) have been widely used as anticancer therapeutics because of their systemic immune responses during viral replication. However, the low enrichment of OVs within tumors and limited immune activation have hindered their clinical application. Herein, we proposed the concept of bacteria-assisted targeting of OVs to tumors, with liposome-cloaked oncolytic adenoviruses (OAs) conjugated onto tumor-homing Escherichia coli BL21 (designated as E. coli-lipo-OAs) for enhanced cancer immunotherapy. Notably, the enrichment of OAs transported by self-propelled bacterial microbe vehicles in E. coli-lipo-OAs in a nonsmall cell lung tumor can be potentiated by more than 170-fold compared with that of intravenously injected bare OAs. In vivo studies further revealed that E. coli-lipo-OAs administered intravenously significantly enhanced antitumor immunity through bacterial-viral-augmented immune responses. Our findings suggest that the self-driving microbe vehicle as a systemic delivery system for OVs can be a potent platform for developing future anticancer biotherapeutics at the clinical level.
Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Escherichia coli , Humanos , Imunoterapia , Neoplasias/terapia , Vírus Oncolíticos/genéticaRESUMO
The pivotal factors affecting the survival rate of patients include metastasis and tumor recurrence after the resection of the primary tumor. Anti-PD-L1 antibody (aPD-L1) has promising efficacy but with some side effects for the off-target binding between aPD-L1 and normal tissues. Here, inspired by the excellent targeting capability of platelets with respect to tumor cells, we propose bioengineered platelets (PDNGs) with inner-loaded doxorubicin (DOX) and outer-anchored aPD-L1-cross-linked nanogels to reduce tumor relapse and metastatic spread postoperation. The cargo does not impair the normal physiological functions of platelets. Free aPD-L1 is cross-linked to form nanogels with a higher drug-loading efficiency and is sustainably released to trigger the T-cell-mediated destruction of tumor cells, reversing the tumor immunosuppressive microenvironment. PDNGs can reduce the postoperative tumor recurrence and metastasis rate, prolonging the survival time of mice. Our findings indicate that bioengineered platelets are promising in postsurgical cancer treatment by the tumor-capturing and in situ microvesicle-secreting capabilities of platelets.
Assuntos
Plaquetas , Melanoma , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Melanoma/tratamento farmacológico , Camundongos , Nanogéis , Recidiva Local de Neoplasia , Microambiente TumoralRESUMO
Inspired by the natural phenomenon of phenolic-protein interactions, we translate this "naturally evolved interaction" to a "phenolic acid derivative based albumin bound" technology, through the synthesis of phenolic acid derivatives comprising a therapeutic cargo linked to a phenolic motif. Phenolic acid derivatives can bind to albumin and form nanocomplexes after microfluidic mixing. This strategy has been successfully applied to different types of anticancer drugs, including taxanes, anthraquinones, etoposides, and terpenoids. Paclitaxel was selected as a model drug for an in-depth study. Three novel paclitaxel-phenolic acid conjugates have been synthesized. Molecular dynamics simulations provide insights into the self-assembled mechanisms of phenolic-protein nanocomplexes. The nanocomplexes show improved pharmacokinetics, elevated tolerability, decreased neurotoxicity, and enhanced anticancer efficacies in multiple murine xenograft models of breast cancer, in comparison with two clinically approved formulations, Taxol (polyoxyethylated castor oil-formulated paclitaxel) and Abraxane (nab-paclitaxel). Such a robust system provides a broadly applicable platform for the development of albumin-based nanomedicines and has great potential for clinical translation.
Assuntos
Neoplasias da Mama , Nanopartículas , Humanos , Animais , Camundongos , Feminino , Albumina Sérica Humana , Paclitaxel/uso terapêutico , Paclitaxel/farmacocinética , Albuminas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Nanopartículas/uso terapêuticoRESUMO
Latuda® is an oral tablet approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia. However, the clinical efficacy of Latuda® is compromised by patient noncompliance due to frequent daily administration, especially for patients experiencing severe schizophrenia, whose medication is often needed for several months to years. Hence, developing a long-acting injectable formulation of lurasidone is urgently needed. Herein, a poorly water-soluble lurasidone pamoate (LP) salt was synthesized via the facile ion pair-based salt formation technology. The solubility of LP was decreased by 233 folds compared with that of lurasidone hydrochloride (LH). Furthermore, suspensions of LH and LP with three different particle sizes, including 400 nm small-sized nanocrystals (SNCs), 4 µm medium-sized microcrystals (MMCs), and 15 µm large-sized microcrystals (LMCs) were prepared and characterized by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The in vitro release results showed that particle sizes had great effects on the sustained release of LH, where large-sized particles exhibited superior sustained release than the smaller ones. Besides, LP suspensions exhibited better sustained release than LH suspensions at the same size scale. Moreover, the pharmacokinetics showed that LP LMCs produced an extended in vivo intramuscularly injectable profile for up to 45 days, which was 10 days longer than that of the LH LMCs. Our findings demonstrated that particle size had appreciable impacts on drug sustained release and provided valuable knowledge for the rational design of optimized micronized suspensions for long-acting injectables.
Assuntos
Nanopartículas , Esquizofrenia , Humanos , Cloridrato de Lurasidona/química , Solubilidade , Preparações de Ação Retardada , Suspensões , Tamanho da Partícula , Nanopartículas/químicaRESUMO
To address the limitations of norcantharidin (NCTD) in clinical applications, including restricted tumor accumulation and intense irritation, we have developed a new derivative of NCTD with (S)-1-benzyl-3-pyrrolidinol, which can be actively loaded into liposomes to achieve drug encapsulation and sustained release properties by using pH gradient loading technique. Cytotoxicity tests against cancer cell lines (Hepa 1-6 and 4 T1 cells) have demonstrated that this derivative exhibits comparable activity to NCTD in vitro. The NCTD derivative can be efficiently loaded into liposomes with high encapsulation efficiency (98.7%) and high drug loading (32.86%). Tolerability and antitumor efficacy studies showed that the liposomal NCTD derivative was well tolerated at intravenous injection doses of 3 folds higher than the parent drug solution, while significantly improved anticancer activity in vivo was achieved. This liposomal nanodrug could become a potent and safe NCTD formulation alternative for cancer therapy.
Assuntos
Antineoplásicos , Nanopartículas , Lipossomos/química , Portadores de Fármacos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Nanopartículas/uso terapêutico , Nanopartículas/química , Linhagem Celular TumoralRESUMO
BACKGROUND: Melanoma is the most serious type of skin cancer, and surgery is an effective method to treat melanoma. Unfortunately, local residual micro-infiltrated tumour cells and systemic circulating tumour cells (CTCs) are significant causes of treatment failure, leading to tumour recurrence and metastasis. METHODS: Small EVs were isolated from platelets by differential centrifugation, and doxorubicin-loaded small EVs (PexD) was prepared by mixing small EVs with doxorubicin (DOX). PexD and an anti-PD-L1 monoclonal antibody (aPD-L1) were co-encapsulated in fibrin gel. The synergistic antitumour efficacy of the gel containing PexD and aPD-L1 was assessed both in vitro and in vivo. RESULTS: Herein, we developed an in situ-formed bioresponsive gel combined with chemoimmunotherapeutic agents as a drug reservoir that could effectively inhibit both local tumour recurrence and tumour metastasis. In comparison with a DOX solution, PexD could better bind to tumour cells, induce more tumour immunogenic cell death (ICD) and promote a stronger antitumour immune response. PexD could enter the blood circulation through damaged blood vessels to track and eliminate CTCs. The concurrent release of aPD-L1 at the tumour site could impair the PD-1/PD-L1 pathway and restore the tumour-killing effect of cytotoxic T cells. This chemoimmunotherapeutic strategy triggered relatively strong T cell immune responses, significantly improving the tumour immune microenvironment. CONCLUSION: Our findings indicated that the immunotherapeutic fibrin gel could "awaken" the host innate immune system to inhibit both local tumour recurrence post-surgery and metastatic potential, thus, it could serve as a promising approach to prevent tumour recurrence.
Assuntos
Antígeno B7-H1 , Melanoma , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Humanos , Imunoterapia/métodos , Melanoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Microambiente TumoralRESUMO
Diabetic nephropathy is a microvascular complication of diabetes. Its etiology involves metabolic disorder-induced endothelial dysfunction. Endothelium-derived nitric oxide (NO) plays an important role in a number of physiological processes, including glomerular filtration and endothelial protection. NO dysregulation is an important pathogenic basis of diabetic nephropathy. Hyperglycemia and dyslipidemia can lead to oxidative stress, chronic inflammation and insulin resistance, thus affecting NO homeostasis regulated by endothelial nitric oxide synthase (eNOS) and a conglomerate of related proteins and factors. The reaction of NO and superoxide (O2.-) to form peroxynitrite (ONOO-) is the most important pathological NO pathway in diabetic nephropathy. ONOO- is a hyper-reactive oxidant and nitrating agent in vivo which can cause the uncoupling of eNOS. The uncoupled eNOS does not produce NO but produces superoxide. Thus, eNOS uncoupling is a critical contributor of NO dysregulation. Understanding the regulatory mechanism of NO and the effects of various pathological conditions on it could reveal the pathophysiology of diabetic nephropathy, potential drug targets and mechanisms of action. We believe that increasing the stability and activity of eNOS dimers, promoting NO synthesis and increasing NO/ONOO- ratio could guide the development of drugs to treat diabetic nephropathy. We will illustrate these actions with some clinically used drugs as examples in the present review.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Nefropatias Diabéticas/tratamento farmacológico , Endotélio Vascular , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico Sintase Tipo III/farmacologia , Óxido Nítrico Sintase Tipo III/uso terapêutico , Estresse Oxidativo , Ácido Peroxinitroso/metabolismo , Ácido Peroxinitroso/farmacologia , Ácido Peroxinitroso/uso terapêuticoRESUMO
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
Nanoparticulate drug delivery systems (nano-DDSs) are required to reliably arrive and persistently reside at the tumor site with minimal off-target side effects for clinical theranostics. However, due to the complicated environment and high interstitial pressure in tumor tissue, they can return to the bloodstream and cause secondary side effects in normal organs. Recently, a number of nanogatekeepers have been engineered via structure-transformable/stable strategies to overcome this undesirable dilemma. The emerging structure-transformable nanogatekeepers for tumor imaging and therapy are first overviewed here, particularly for nanogatekeepers undergoing structural transformation in tumor microenvironments, cell membranes, and organelles. Thereafter, intelligent structure-stable nanogatekeepers through reversible activation and artificial individualization receptors are overviewed. Finally, the ongoing challenges and prospects of nanogatekeepers for clinical translation are briefly discussed.
Assuntos
Neoplasias , Medicina de Precisão , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Microambiente TumoralRESUMO
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
A valine carbamate prodrug of naringenin (NAR) called 4'V was synthesized to enhance its oral bioavailability because of low water solubility and poor membrane permeability of NAR. This study developed and fully validated a sensitive, rapid, and robust HPLC-MS/MS method for the simultaneous determination of NAR and 4'V in plasma. The analytes were treated using liquid-liquid extraction, separated on a Phenomenex Kinetex XB-C18 column, and detected using a triple-quadrupole tandem mass spectrometer equipped with an electrospray ionization interface. The analytes were eluted within only 4 min by gradient procedure. The excellent linear correlations were validated over the range of 4-400 ng/mL (r = 0.9990) for NAR and 2-2000 ng/mL (r = 0.9951) for 4'V, with lower limits of quantification of 4 and 2 ng/mL, respectively. For all quality control samples, the intra-day and inter-day precision and accuracy were within ±15%. The validated method was economical, high throughput, and reliable and was first successfully applied to a pharmacokinetic study of NAR and 4'V after oral administration to Sprague-Dawley rats. The results of the pharmacokinetic study demonstrated that the idea of amino acid carbamate prodrug is a promising strategy to improve the bioavailability of NAR.
Assuntos
Carbamatos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Flavanonas/sangue , Espectrometria de Massas em Tandem/métodos , Valina/sangue , Animais , Disponibilidade Biológica , Carbamatos/química , Carbamatos/farmacocinética , Flavanonas/química , Flavanonas/farmacocinética , Modelos Lineares , Masculino , Pró-Fármacos , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Valina/química , Valina/farmacocinéticaRESUMO
Combination therapy is one of the most common clinical practices in the treatment of malignancies. Synergistic effects, however, are produced only when optimal ratios of combined drugs were delivered to tumor cells. Thus, carriers co-encapsulating of multiple drugs are widely utilized for coordinated delivery. Herein, co-encapsulated pegylated liposomal formulation of mitoxantrone (MIT) and berberine (BER) at an optimal ratio has been developed (MBL) with high encapsulation efficiency (EE) and drug loading in order to achieve the purpose of ratiometric loading and delivery. MBL can not only extend blood circulation but also enhance tumor accumulation for both MIT and BER. More importantly, MBL can maintain the originally desired drug ratio in tumors within 48 h of intravenous injection for synergistic therapy. Compared with the liposomal formulation of MIT-treated group (ML), the progression of tumor growth was inhibited significantly in murine 4T1 breast tumor model after the treatment of MBL, as well as a lower cardiac toxicity. In addition, MBL evidently prolonged the survival of mice with L1210 ascitic tumor model. In summary, such a strategy of co-encapsulated liposomes could improve the clinical applications against multiple cancers.