RESUMEN
There has been growing interest in polymeric systems that break down or undergo property changes in response to stimuli. Such polymers can play important roles in biological systems, where they can be used to control the release of therapeutics, modulate imaging signals, actuate movement, or direct the growth of cells. In this Perspective, after discussing the most important stimuli relevant to biological applications, we will present a selection of recent exciting developments. The growing importance of stimuli-responsive polysaccharides will be discussed, followed by a variety of stimuli-responsive polymeric systems for the delivery of small molecule drugs and nucleic acids. Switchable polymers for the emerging area of therapeutic response measurement in theranostics will be described. Then, the diverse functions that can be achieved using hydrogels cross-linked covalently, as well as by various dynamic approaches will be presented. Finally, we will discuss some of the challenges and future perspectives for the field.
Asunto(s)
Hidrogeles , Polímeros de Estímulo Receptivo , Humanos , Polímeros de Estímulo Receptivo/química , Hidrogeles/química , Sistemas de Liberación de Medicamentos/métodos , Polisacáridos/química , Polímeros/química , AnimalesRESUMEN
The silencing of disease-causing genes with small interfering RNA (siRNA) offers a particularly effective therapeutic strategy for different disorders; however, its clinical efficacy relies on the development of nontoxic and tissue-specific delivery vehicles. Herein, we report that bioresponsive chimaeric polymersomes (BCP) with short poly(ethylenimine) as inner shell mediate highly efficacious, sustained, and liver-specific siRNA transfection in vivo. BCP exhibited remarkable encapsulation efficiencies of siRNA (95-100%) at siRNA-feeding contents of 15-25 wt %, to afford stable, small-sized (55-64 nm), and neutral-charged BCP-siRNA. siApoB-Loaded BCP (BCP-siApoB) outperformed lipofectamine counterparts and silenced 93% of ApoB mRNA in HepG2 cells at 50 nM siApoB without inducing cytotoxicity. Intriguingly, the in vivo studies using wild-type C57BL/6 mice revealed that BCP-siApoB preferentially accumulated in the liver, and a single dose of 4.5 mg/kg achieved over 90% downregulation of ApoB mRNA for at least 10 days. The systemic administration of BCP-siApoB at 4.5 mg/kg every 2 weeks or 1.5 mg/kg weekly in diet-induced obese mice could also achieve up to 80% silencing of ApoB mRNA. The liver specificity and silencing efficacy of BCP-siApoB could further be improved by decorating it with the trivalent N-acetylgalactosamine (TriGalNAc) ligand. These bioresponsive and liver-specific chimaeric polymersomes provide an enabling technology for siRNA therapy of various liver-related diseases.
Asunto(s)
Apolipoproteínas B , Hígado , Animales , Ratones , ARN Interferente Pequeño/genética , Ratones Endogámicos C57BL , Apolipoproteínas B/genética , Transfección , ARN MensajeroRESUMEN
Targeted molecular therapy, for example, with sorafenib (SF) is considered as a new and potent strategy for glioblastoma (GBM) that remains hard to treat today. Several clinical trials with SF, as monotherapy or combination therapy with current treatments, have not met the clinical endpoints, likely as a result of the blood-brain barrier (BBB) and inferior GBM delivery. Here, we designed and explored small, smart, and LDLR-specific micelles to load SF (LDLR-mSF) and to improve SF therapy of GBM by enhancing BBB penetration, GBM accumulation, and cell uptake. LDLR-mSF with 2.5% ApoE peptide functionality based on poly(ethylene glycol)-poly(ε-caprolactone-co-dithiolane trimethylene carbonate)-mefenamate exhibited nearly quantitative SF loading, small size (24 nm), high colloidal stability, and glutathione-activated SF release. The in vitro and in vivo studies certified that LDLR-mSF greatly enhanced BBB permeability and U-87 MG cell uptake and caused 10.6- and 12.9-fold stronger anti-GBM activity and 6.0- and 2.5-fold higher GBM accumulation compared with free SF and non-LDLR mSF controls, respectively. The treatment of an orthotopic human GBM tumor model revealed that LDLR-mSF at a safe dosage of 15 mg of SF/kg significantly retarded tumor progression and improved the survival rate by inducing tumor cell apoptosis and inhibiting tumor angiogenesis. These small, smart, and LDLR-specific micelles provide a potential solution to enhance targeted molecular therapy of GBM.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Barrera Hematoencefálica , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Glioblastoma/tratamiento farmacológico , Humanos , Micelas , Sorafenib/farmacologíaRESUMEN
The mucus layer and cell membrane are two major barriers against pulmonary siRNA delivery. Commonly used polycationic gene vectors can hardly penetrate the mucus layer due to the adsorption of mucin glycoproteins that trap and destabilize the polyplexes. Herein, guanidinated and fluorinated bifunctional helical polypeptides were developed to synchronizingly overcome these two barriers. The guanidine domain and α-helix facilitated trans-membrane siRNA delivery into macrophages, whereas fluorination of the polypeptides dramatically enhanced the mucus permeation capability by â¼240 folds, because incorporated fluorocarbon segments prevented adsorption of mucin glycoproteins onto polyplexes surfaces. Thus, when delivering TNF-α siRNA intratracheally, the top-performing polypeptide P7F7 provoked highly efficient gene knockdown by â¼96% at 200 µg/kg siRNA and exerted pronounced anti-inflammatory effect against acute lung injury. This study thus provides an effective strategy for transmucosal gene delivery, and it also renders promising utilities for the noninvasive, localized treatment of inflammatory pulmonary diseases.
Asunto(s)
Lesión Pulmonar Aguda , Macrófagos/metabolismo , Moco/metabolismo , Péptidos , ARN Interferente Pequeño , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/genética , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Sistemas de Liberación de Medicamentos , Técnicas de Silenciamiento del Gen , Halogenación , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Péptidos/química , Péptidos/farmacología , Conformación Proteica en Hélice alfa , Células RAW 264.7 , ARN Interferente Pequeño/química , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacologíaRESUMEN
Designer particles that are embued with nanomachinery for autonomous motion have great potential for biomedical applications; however, their development is highly demanding with respect to biodegradability/compatibility. Previously, biodegradable propulsive machinery based on enzymes has been presented. However, enzymes are highly susceptible to proteolysis and deactivation in biological milieu. Biodegradable hybrid nanomotors powered by catalytic inorganic nanoparticles provide a proteolytically stable alternative to those based upon enzymes. Herein we describe the assembly of hybrid biodegradable nanomotors capable of transducing chemical energy into motion. Such nanomotors are constructed through a process of compartmentalized synthesis of inorganic MnO2 nanoparticles (MnPs) within the cavity of organic stomatocytes. We show that the nanomotors remain active in cellular environments and do not compromise cell viability. Effective tumor penetration of hybrid nanomotors is also demonstrated in proof-of-principle experiments. Overall, this work represents a new prospect for engineering of nanomotors that can retain their functionality within biological contexts.
Asunto(s)
Compuestos de Manganeso , Nanopartículas , Movimiento (Física) , ÓxidosRESUMEN
Biodegradable nanostructures displaying aggregation-induced emission (AIE) are desirable from a biomedical point of view, due to the advantageous features of loading capacity, emission brightness, and fluorescence stability. Herein, biodegradable polymers comprising poly (ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-P(CLgTMC)), with tetraphenylethylene pyridinium-TMC (PAIE) side chains have been developed, which self-assembled into well-defined polymersomes. The resultant AIEgenic polymersomes are intrinsically fluorescent delivery vehicles. The presence of the pyridinium moiety endows the polymersomes with mitochondrial targeting ability, which improves the efficiency of co-encapsulated photosensitizers and improves therapeutic index against cancer cells both in vitro and in vivo. This contribution showcases the ability to engineer AIEgenic polymersomes with structure inherent fluorescence and targeting capacity for enhanced photodynamic therapy.
Asunto(s)
Antineoplásicos/farmacología , Plásticos Biodegradables/farmacología , Colorantes Fluorescentes/farmacología , Fármacos Fotosensibilizantes/farmacología , Poliésteres/farmacología , Polietilenglicoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/efectos de la radiación , Compuestos de Bencilideno/síntesis química , Compuestos de Bencilideno/farmacología , Compuestos de Bencilideno/efectos de la radiación , Plásticos Biodegradables/síntesis química , Plásticos Biodegradables/efectos de la radiación , Compuestos de Boro/síntesis química , Compuestos de Boro/farmacología , Compuestos de Boro/efectos de la radiación , Línea Celular Tumoral , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/efectos de la radiación , Humanos , Luz , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/efectos de la radiación , Poliésteres/síntesis química , Poliésteres/efectos de la radiación , Polietilenglicoles/síntesis química , Polietilenglicoles/efectos de la radiación , Compuestos de Piridinio/síntesis química , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/efectos de la radiaciónRESUMEN
Sorafenib (SF) is an FDA-approved molecular-targeted drug for treating hepatocellular carcinoma (HCC). SF, however, suffers from poor water solubility, low bioavailability, dose-limiting side effects, and possible drug resistance. Here, we report on apolipoprotein E peptide-decorated disulfide-cross-linked micellar SF (ApoE-Ms-SF) as a targeted and intelligent formulation for HCC therapy. ApoE-Ms-SF was prepared with a good SF loading of 7.0 wt %, small size (37 nm), high stability, and reduction-triggered drug release from poly(ethylene glycol)-b-poly(ε-caprolactone-co-dithiolane trimethylene carbonate)-mefenamate (PEG-P(CL-DTC)-MA) and ApoE-modified ApoE-PEG-P(CL-DTC) block copolymers. MTT assays in low-density lipoprotein receptors (LDLRs) overexpressing SMMC-7721 human liver cancer cells showed ApoE density-dependent antitumor potency of ApoE-Ms-SF, in which 7.5% ApoE led to the best antitumor effect (IC50: 8.5 vs 23.3 µg/mL for free SF). Confocal studies, flow cytometry, western blot, and apoptotic assays illustrated clearly a more efficient uptake of ApoE-Ms than nontargeted Ms by SMMC-7721 cells as well as lower phosphorylated extracellular signal-regulated kinase protein level and better cell apoptosis caused by ApoE-Ms-SF compared with Ms-SF and free SF. ApoE-Ms-SF revealed a long circulation time (elimination half-life = 6.8 h). DiR-loaded ApoE-Ms showed a significantly higher accumulation in SMMC-7721 tumor than the nontargeted counterpart. The therapeutic outcomes in the orthotopic SMMC-7721 tumor models demonstrated that ApoE-Ms-SF reduced SF-associated side effects and brought about enhanced angiogenesis inhibition and tumor apoptosis compared to free SF and Ms-SF controls, leading to a better treatment of HCC.
Asunto(s)
Antineoplásicos/metabolismo , Apolipoproteínas E/metabolismo , Carcinoma Hepatocelular/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Neoplasias Hepáticas/metabolismo , Micelas , Sorafenib/metabolismo , Animales , Antineoplásicos/administración & dosificación , Apolipoproteínas E/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Reactivos de Enlaces Cruzados/administración & dosificación , Reactivos de Enlaces Cruzados/metabolismo , Disulfuros/administración & dosificación , Disulfuros/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Sorafenib/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Future healthcare requires development of novel theranostic agents that are capable of not only enhancing diagnosis and monitoring therapeutic responses but also augmenting therapeutic outcomes. Here, a versatile and stable nanoagent is reported based on poly(ethylene glycol)-b-poly(l-thyroxine) (PEG-PThy) block copolypeptide for enhanced single photon emission computed tomography/computed tomography (SPECT/CT) dual-modality imaging and targeted tumor radiotherapy in vivo. PEG-PThy acquired by polymerization of l-thyroxine-N-carboxyanhydride (Thy-NCA) displays a controlled Mn , high iodine content of ≈49.2 wt%, and can spontaneously form 65 nm-sized nanoparticles (PThyN). In contrast to clinically used contrast agents like iohexol and iodixanol, PThyN reveals iso-osmolality, low viscosity, and long circulation time. While PThyN exhibits comparable in vitro CT attenuation efficacy to iohexol, it greatly enhances in vivo CT imaging of vascular systems and soft tissues. PThyN allows for surface decoration with the cRGD peptide achieving enhanced CT imaging of subcutaneous B16F10 melanoma and orthotopic A549 lung tumor. Taking advantages of a facile iodine exchange reaction, 125 I-labeled PThyN enables SPECT/CT imaging of tumors and monitoring of PThyN biodistribution in vivo. Besides, 131 I-labeled and cRGD-functionalized PThyN displays remarkable growth inhibition of the B16F10 tumor in mice (tumor inhibition rate > 89%). These poly(l-thyroxine) nanoparticles provide a unique and versatile theranostic platform for varying diseases.
Asunto(s)
Péptidos/química , Polietilenglicoles/química , Radioterapia/métodos , Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Medios de Contraste/química , Humanos , Nanomedicina Teranóstica/métodosRESUMEN
Engineering biodegradable nanostructures with precise morphological characteristics is a key objective in nanomedicine. In particular, asymmetric (i.e., nonspherical) nanoparticles are desirable due to the advantageous effects of shape in a biomedical context. Using molecular engineering, it is possible to program unique morphological features into the self-assembly of block copolymers (BCPs). However, the criteria of biocompatibility and scalability limit progress due to the prevalence of nondegradable components and the use of toxic solvents during fabrication. To address this shortfall, a robust strategy for the fabrication of morphologically asymmetric nanoworms, comprising biodegradable BCPs, has been developed. Modular BCPs comprising poly (ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-PCLgTMC), with a terminal chain of quaternary ammonium-TMC (PTMC-Q), undergo self-assembly via direct hydration into well-defined nanostructures. By controlling the solution ionic strength during hydration, particle morphology switches from spherical micelles to nanoworms (of varying aspect ratio). This ionically-induced switch is driven by modulation of chain packing with salts screening interchain repulsions, leading to micelle elongation. Nanoworms can be loaded with cytotoxic cargo (e.g., doxorubicin) at high efficiency, preferentially interact with cancer cells, and increase tumor penetration. This work showcases the ability to program assembly of BCPs and the potential of asymmetric nanosystems in anticancer drug delivery.
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Caproatos/química , Sistemas de Liberación de Medicamentos/métodos , Lactonas/química , Nanomedicina/métodos , Nanoestructuras/química , Micelas , Polímeros/químicaRESUMEN
Ovarian cancer as a recurrent disease is often refractory to treatment including pegylated liposomal doxorubicin hydrochloride (Lipo-Dox). Here, GE11 peptide-modified reversibly cross-linked polymersomal doxorubicin (GE11-PS-Dox) was investigated as an advanced treatment for SKOV3 human ovarian tumors, which overexpress epidermal growth factor receptor (EGFR). The in vitro experiments using SKOV3 cancer cells demonstrated that GE11-PS-Dox induced obviously higher cellular uptake, Dox delivery to the nuclei, and antitumor activity than the nontargeted PS-Dox and Lipo-Dox controls. In vivo biodistribution experiments displayed 2.5-fold higher tumor accumulation for GE11-PS-Dox as compared to Lipo-Dox. Notably, GE11-PS-Dox could effectively suppress the progression of SKOV3 tumors and cause little adverse effects at 12 mg of Dox equiv/kg, leading to a remarkably increased survival rate of 100% over 78 days. In contrast, continued tumor growth and body weight loss were discerned for Lipo-Dox treated mice at 6 mg of Dox equiv/kg. Moreover, a single dose of GE11-PS-Dox at 60 mg of Dox equiv/kg showed also effective treatment and low toxicity toward SKOV3-tumor bearing mice. GE11-directed reversibly cross-linked polymersomal doxorubicin has emerged as an advanced alternative to Lipo-Dox for treatment of EGFR-overexpressing ovarian cancers.
Asunto(s)
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/uso terapéutico , Doxorrubicina/análogos & derivados , Sistemas de Liberación de Medicamentos/métodos , Liposomas/química , Péptidos/química , Animales , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Receptores ErbB/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Polietilenglicoles/química , Polietilenglicoles/uso terapéutico , Distribución AleatoriaRESUMEN
The ring opening copolymerization of trimethylene carbonate (TMC) and dithiolane trimethylene carbonate (DTC) using acidic and basic organocatalysts, i.e., diphenyl phosphate (DPP) and triazabicyclo[4.4.0]dec-5-ene (TBD), was systemically investigated. Interestingly, DPP and TBD gave rise to completely different polymerization kinetics and copolymer sequences. The copolymerization of TMC and DTC using methoxy poly(ethylene glycol) (mPEG-OH) as an initiator and DPP as a catalyst proceeded in a first-order manner and to near completion in 72 h for both monomers, yielding well-controlled copolymers with random sequences, predictable molar mass, and low dispersity ( Mw/ Mn = 1.09-1.19). By contrast, TBD brought about much faster copolymerization of TMC and DTC under similar conditions (high monomer conversion achieved in 2-4 h), to furnish copolymers with controlled molar mass and moderate dispersity ( Mw/ Mn = 1.27-1.80). Moreover, polymerization kinetics revealed that DTC was preferentially polymerized followed by first-order polymerization of TMC, leading to blocky copolymers. These results signify that type of organocatalysts has a critical influence on polymerization kinetics of cyclic carbonates, copolymer sequence, and molar mass control.
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Dioxanos/química , Polietilenglicoles/química , Polietilenglicoles/síntesis química , Catálisis , CinéticaRESUMEN
PHSCN peptide (licensed as ATN-161) is an effective α5ß1 integrin inhibitor that has advanced to phase II clinical trials to treat solid tumors. Here we developed ATN-161 functionalized self-cross-linkable and intracellularly de-cross-linkable polymersomes (ATN/SCID-Ps) for highly efficient and targeted delivery of doxorubicin hydrochloride (DOX·HCl) into B16F10 melanoma-bearing C57BL/6 mice. ATN/SCID-Ps exhibited a high loading capacity of DOX·HCl. The size of DOX-loaded ATN/SCID-Ps (DOX-ATN/SCID-Ps) decreased from 150 to 88 nm with increasing ATN surface densities from 0 to 100% (mol/mol). DOX-ATN/SCID-Ps were robust with low drug leakage under physiological conditions while quickly releasing DOX with the addition of 10 mM glutathione. MTT assay results displayed that DOX-ATN/SCID-Ps induced ATN density-dependent antitumor activity to α5ß1 integrin overexpressing B16F10 melanoma cells, in which 56% ATN-161 was optimal. Flow cytometry and CLSM studies revealed significantly more efficient internalization and cytoplasmic DOX release in B16F10 cells for DOX-ATN/SCID-Ps than for DOX-SCID-Ps (nontargeting control) as well as clinically used pegylated liposomal doxorubicin (DOX-LPs). DOX-ATN/SCID-Ps displayed a long blood circulation time (elimination half-life = 4.13 h) and 4 times higher DOX accumulation in B16F10 bearing C57BL/6 mice than DOX-LPs. Interestingly, DOX-ATN/SCID-Ps exhibited a superior maximum-tolerated dose of over 100 mg DOX·HCl/kg, 10 times higher than DOX-LPs. Remarkably, DOX-ATN/SCID-Ps could significantly inhibit the growth of aggressive B16F10 melanoma with little adverse effects via either multiple or single injection of total dosage of 100 mg DOX·HCl/kg, resulting in greatly improved survival rates as compared to DOX-LPs. ATN/SCID-Ps are appealing nanovehicles for targeted chemotherapy of α5ß1 integrin positive solid tumors.
Asunto(s)
Doxorrubicina/química , Doxorrubicina/uso terapéutico , Melanoma/tratamiento farmacológico , Péptidos/química , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Femenino , Citometría de Flujo , Semivida , Dosis Máxima Tolerada , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
6-Mercaptopurine (6-MP) is an essential medicine used for treating leukemia in the clinics. 6-MP suffers, however, from poor water solubility, low bioavailability, and significant side effects. Here, we designed CD44-targeted glutathione-sensitive hyaluronic acid-mercaptopurine prodrug (HA-GS-MP) linked via carbonyl vinyl sulfide for safer and enhanced treatment of acute myeloid leukemia (AML). HA-GS-MP obtained with 50 kDa HA and 6-MP conjugation content of 6.9 wt % showed excellent water solubility with a hydrodynamic size of ca. 15 nm. Intriguingly, HA-GS-MP was extremely stable, without any drug leakage, under physiological environment while rapidly releasing 6-MP in response to 10 mM glutathione. HA-GS-MP exhibited obvious targetability and markedly enhanced antitumor effect to OCI/AML-2 human AML cells (IC50 = 16.9 µg 6-MP equiv./mL). The pharmacokinetic studies displayed that Cy5-labeled HA-GS-MP had a long circulation time in mice (elimination half-life = 4.37 h). The in vivo fluorescence images demonstrated strong and persistent accumulation of Cy5-labeled HA-GS-MP from 4 to 48 h post injection in the subcutaneous OCI/AML-2 tumor in nude mice. Notably, HA-GS-MP while causing little side effects induced significantly enhanced growth inhibition of OCI/AML-2 tumor and better survival rate of OCI/AML-2 tumor-bearing mice as compared to free 6-MP. Carbonyl vinyl sulfide-linked hyaluronic acid-mercaptopurine prodrug has appeared to be a simple and smart nanomedicine for targeted treatment of AML.
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Antimetabolitos Antineoplásicos/química , Glutatión/química , Receptores de Hialuranos/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Mercaptopurina/química , Nanopartículas/química , Profármacos/química , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Línea Celular Tumoral , Humanos , Ácido Hialurónico/química , Mercaptopurina/administración & dosificación , Mercaptopurina/farmacocinética , Ratones , Profármacos/farmacocinética , Eliminación Renal , Distribución Tisular , Compuestos de Vinilo/químicaRESUMEN
Combinatorial chemotherapy, which has emerged as a promising treatment modality for intractable cancers, is challenged by a lack of tumor-targeting, robust and ratiometric dual drug release systems. Here, docetaxel-loaded cRGD peptide-decorated redox-activable micellar mertansine prodrug (DTX-cRGD-MMP) was developed for targeted and synergistic treatment of B16F10 melanoma-bearing C57BL/6 mice. DTX-cRGD-MMP exhibited a small size of ca. 49 nm, high DTX and DM1 loading, low drug leakage under physiological conditions, with rapid release of both DTX and DM1 under a cytoplasmic reductive environment. Notably, MTT and flow cytometry assays showed that DTX-cRGD-MMP brought about a synergistic antitumor effect to B16F10 cancer cells, with a combination index of 0.37 and an IC50 over 3- and 13-fold lower than cRGD-MMP (w/o DTX) and DTX-cRGD-Ms (w/o DM1) controls, respectively. In vivo studies revealed that DTX-cRGD-MMP had a long circulation time and a markedly improved accumulation in the B16F10 tumor compared with the non-targeting DTX-MMP control (9.15 versus 3.13% ID/g at 12 h post-injection). Interestingly, mice treated with DTX-cRGD-MMP showed almost complete growth inhibition of B16F10 melanoma, with tumor inhibition efficacy following an order of DTX-cRGD-MMP > DTX-MMP (w/o cRGD) > cRGD-MMP (w/o DTX) > DTX-cRGD-Ms (w/o DM1) > free DTX. Consequently, DTX-cRGD-MMP significantly improved the survival rates of B16F10 melanoma-bearing mice. Importantly, DTX-cRGD-MMP caused little adverse effects as revealed by mice body weights and histological analyses. The combination of two mitotic inhibitors, DTX and DM1, appears to be an interesting approach for effective cancer therapy.
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Maitansina , Micelas , Neoplasias/tratamiento farmacológico , Péptidos Cíclicos , Profármacos , Línea Celular Tumoral , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Sinergismo Farmacológico , Humanos , Maitansina/química , Maitansina/farmacología , Neoplasias/metabolismo , Neoplasias/patología , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Profármacos/química , Profármacos/farmacologíaRESUMEN
Poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles have attracted an enormous interest for controlled drug delivery. Their clinical applications are, however, partly hindered by lack of biocompatible, biodegradable and functional surfactants. Here, we designed and developed a novel biocompatible surfactant based on amphiphilic vitamin E-oligo(methyl diglycol l-glutamate) (VEOEG) for facile fabrication of robust and tumor-targeting PLGA-based nanomedicines. VEOEG was prepared with controlled Mn of 1.7-2.6 kg/mol and low molecular weight distribution (D = 1.04-1.16) via polymerization of methyl diglycol l-glutamate N-carboxyanhydride using vitamin E-ethylenediamine derivative (VE-NH2) as an initiator. VEOEG had a hydrophile-lipophile balance data of 13.8-16.1 and critical micellar concentration of 189.3-203.8 mg/L depending on lengths of oligopeptide. Using VEOEG as a surfactant, PLGA nanoparticles could be obtained via nanoprecipitation method with a small and uniform hydrodynamic size of 135 nm and positive surface charge of +26.6 mV, in accordance with presence of amino groups at the surface. The resulting PLGA nanoparticles could be readily coated with hyaluronic acid (HA) to form highly stable, small-sized (143 nm), monodisperse, and negatively charged nanoparticles (HA-PLGA NPs). Notably, paclitaxel-loaded HA-PLGA NPs (PTX-HA-PLGA NPs) exhibited better antitumor effects in CD44-positive MCF-7 breast tumor cells than Taxol (a clinical paclitaxel formulation). The in vivo pharmacokinetics assay in nude mice displayed that PTX-HA-PLGA NPs possessed a long plasma half-life of 3.14 h. The in vivo biodistribution studies revealed that PTX-HA-PLGA NPs had a high tumor PTX level of 8.4% ID/g, about 6 times better than that of Taxol. Interestingly, therapeutic studies showed that PTX-HA-PLGA NPs caused significantly more effective tumor growth inhibition, better survival rate and lower adverse effect than Taxol. VEOEG has emerged as a versatile and functional surfactant for the fabrication of advanced anticancer nanomedicines.
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Materiales Biocompatibles/química , Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Ácido Láctico/química , Nanopartículas/química , Paclitaxel/farmacología , Ácido Poliglicólico/química , Tensoactivos/química , Vitamina E/química , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/patología , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos , Femenino , Ácido Glutámico/química , Glicoles/química , Humanos , Ratones , Nanopartículas/administración & dosificación , Paclitaxel/administración & dosificación , Paclitaxel/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Células Tumorales Cultivadas , Vitamina E/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Low tolerability and tumor selectivity restricts many potent anticancer drugs including mertansine from wide clinical use. Here, glutathione-activatable hyaluronic acid-SS-mertansine prodrug (HA-SS-DM1) was designed and developed to achieve enhanced tolerability and targeted therapy of CD44+ human breast tumor xenografts. DM1 was readily conjugated to HA using 2-(2-pyridyldithio)-ethylamine as a linker. Notably, HA-SS-DM1 with a high DM1 content of 20 wt % had a mean size of â¼170 nm at concentrations above 0.2 mg/mL while transformed into unimers upon dilution to 0.04 mg/mL. HA-SS-DM1 exhibited a superior targetability to MCF-7 cancer cells with an exceptionally low IC50 of 0.13 µg DM1/mL. The pharmacokinetic studies displayed that Cy5-labeled HA-SS-DM1 had an elimination half-life of 2.12 h. Notably, HA-SS-DM1 displayed better tolerability with a maximum-tolerated dose 4-fold higher than free DM1. Cy5-labeled HA-SS-DM1 quickly accumulated in the MCF-7 tumor, the fluorescence intensity of which was maximized at 24 h post injection and kept strong in 48 h. The tumor Cy5 level reached 8.17%ID/g at 24 h. The therapeutic results demonstrated that HA-SS-DM1 effectively inhibited tumor growth at 800 µg DM1 equiv/kg while causing reduced side effects as compared to free DM1. Glutathione-cleavable HA-SS-DM1 prodrug with superior drug content, excellent targetability, enhanced tolerability, and easy large-scale synthesis appears to be a highly promising alternative to clinically used Trastuzumab emtansine (T-DM1) for targeted breast tumor therapy.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Glutatión/química , Maitansina/análogos & derivados , Ado-Trastuzumab Emtansina , Animales , Anticuerpos Monoclonales Humanizados/química , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Glutatión/administración & dosificación , Glutatión/síntesis química , Humanos , Receptores de Hialuranos/genética , Ácido Hialurónico/administración & dosificación , Ácido Hialurónico/síntesis química , Ácido Hialurónico/química , Células MCF-7 , Maitansina/administración & dosificación , Maitansina/síntesis química , Maitansina/química , Ratones , Profármacos/administración & dosificación , Profármacos/química , Trastuzumab , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Reductively degradable biopolymers have emerged as a unique class of smart biomedical materials. Here, a functional coupling agent, cystamine diisocyanate (CDI), was designed to offer a facile access to reductively degradable biopolymers via polycondensation with various diols. CDI was readily obtained with a decent yield of 46% by reacting cystamine dihydrochloride with triphosgene. The polycondensation of oligo(ethylene glycol) diol (Mn = 0.4 or 1.5 kg/mol) or oligo(ε-caprolactone) diol (Mn = 0.53 kg/mol) with CDI in N,N-dimethylformamide at 60 °C using dibutyltin dilaurate as a catalyst afforded reductively degradable poly(ethylene glycol) (SSPEG, Mn = 6.2-76.8 kg/mol) or poly(ε-caprolactone) (SSPCL, Mn = 6.8-16.3 kg/mol), in which molecular weights were well controlled by diol/CDI molar ratios. Moreover, PEG-SSPCL-PEG triblock copolymers could be readily prepared by reacting dihydroxyl-terminated SSPCL with PEG-isocyanate derivative. PEG-SSPCL-PEG with an Mn of 5.0-16.3-5.0 kg/mol formed small-sized micelles with an average diameter of about 85 nm in PB buffer. The in vitro release studies using doxorubicin (DOX) as a model drug showed that, in sharp contrast to reduction-insensitive PEG-PCL(HDI)-PEG controls, drug release from PEG-SSPCL-PEG micelles was fast and nearly complete in 24 h under a reductive condition containing 10 mM glutathione. The confocal microscopy experiments in drug-resistant MCF-7 cells (MCF-7/ADR) displayed efficient cytoplasmic DOX release from PEG-SSPCL-PEG micelles. MTT assays revealed that DOX-loaded PEG-SSPCL-PEG micelles were much more potent against MCF-7/ADR cells than reduction-insensitive PEG-PCL(HDI)-PEG controls (IC50: 6.3 vs 55.4 µg/mL). It should further be noted that blank PEG-SSPCL-PEG micelles were noncytotoxic up to a tested concentration of 1 mg/mL. Hence, cystamine diisocyanate appears to be an innovative coupling agent that facilitates versatile synthesis of biocompatible and reductively degradable biopolymers.
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Plásticos Biodegradables/síntesis química , Cistamina/química , Portadores de Fármacos/síntesis química , Micelas , Antineoplásicos/administración & dosificación , Plásticos Biodegradables/efectos adversos , Caproatos/química , Cianatos/química , Doxorrubicina/administración & dosificación , Portadores de Fármacos/efectos adversos , Humanos , Lactonas/química , Células MCF-7 , Polietilenglicoles/químicaRESUMEN
Polyurethanes are a unique class of biomaterials that are widely used in medical devices. In spite of their easy synthesis and excellent biocompatibility, polyurethanes are less explored for controlled drug delivery due to their slow or lack of degradation. In this paper, we report the design and development of novel acid degradable poly(acetal urethane) (PAU) and corresponding triblock copolymer micelles for pH-triggered intracellular delivery of a model lipophilic anticancer drug, doxorubicin (DOX). PAU with Mn ranging from 4.3 to 12.3 kg/mol was conveniently prepared from polycondensation reaction of lysine diisocyanate (LDI) and a novel diacetal-containing diol, terephthalilidene-bis(trimethylolethane) (TPABTME) using dibutyltin dilaurate (DBTDL) as a catalyst in N,N-dimethylformamide (DMF). The thiol-ene click reaction of Allyl-PAU-Allyl with thiolated PEG (Mn = 5.0 kg/mol) afforded PEG-PAU-PEG triblock copolymers that readily formed micelles with average sizes of about 90-120 nm in water. The dynamic light scattering (DLS) measurements revealed fast swelling and disruption of micelles under acidic pH. UV/vis spectroscopy corroborated that acetal degradation was accelerated at pH 4.0 and 5.0. The in vitro release studies showed that doxorubicin (DOX) was released in a controlled and pH-dependent manner, in which ca. 96%, 73%, and 30% of drug was released within 48 h at pH 4.0, 5.0, and 7.4, respectively. Notably, MTT assays displayed that DOX-loaded PEG-PAU-PEG micelles had a high in vitro antitumor activity in both RAW 264.7 and drug-resistant MCF-7/ADR cells. The confocal microscopy and flow cytometry experiments demonstrated that PEG-PAU-PEG micelles mediated efficient cytoplasmic delivery of DOX. Importantly, blank PEG-PAU-PEG micelles were shown to be nontoxic to RAW 264.7 and MCF-7/ADR cells even at a high concentration of 1.5 mg/mL. Hence, micelles based on poly(acetal urethane) have appeared as a new class of biocompatible and acid-degradable nanocarriers for efficient intracellular drug delivery.
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Acetales/química , Antibióticos Antineoplásicos/farmacocinética , Materiales Biocompatibles/síntesis química , Doxorrubicina/farmacocinética , Polímeros/química , Poliuretanos/química , Animales , Antibióticos Antineoplásicos/química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7 , Ratones , Micelas , Tamaño de la PartículaRESUMEN
Polycations often suffer from the irreconcilable inconsistency between transfection efficiency and toxicity. Polymers with high molecular weight (MW) and cationic charge feature potent gene delivery capabilities, while in the meantime suffer from strong chemotoxicity, restricted intracellular DNA release, and low stability in vivo. To address these critical challenges, we herein developed pH-responsive, reversibly cross-linked, polyetheleneimine (PEI)-based polyplexes coated with hyaluronic acid (HA) for the effective and targeted gene delivery to cancer cells. Low-MW PEI was cross-linked with the ketal-containing linker, and the obtained high-MW analogue afforded potent gene delivery capabilities during transfection, while rapidly degraded into low-MW segments upon acid treatment in the endosomes, which promoted intracellular DNA release and reduced material toxicity. HA coating of the polyplexes shielded the surface positive charges to enhance their stability under physiological condition and simultaneously reduced the toxicity. Additionally, HA coating allowed active targeting to cancer cells to potentiate the transfection efficiencies in cancer cells in vitro and in vivo. This study therefore provides an effective approach to overcome the efficiency-toxicity inconsistence of nonviral vectors, which contributes insights into the design strategy of effective and safe vectors for cancer gene therapy.
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ADN/administración & dosificación , Técnicas de Transferencia de Gen , Vectores Genéticos/administración & dosificación , Neoplasias/terapia , Animales , Reactivos de Enlaces Cruzados/química , ADN/genética , ADN/toxicidad , Endosomas/metabolismo , Terapia Genética/métodos , Vectores Genéticos/toxicidad , Células HeLa , Humanos , Ácido Hialurónico/química , Masculino , Ratones , Ratones Endogámicos C57BL , Polietileneimina/químicaRESUMEN
pH-Responsive chimaeric polypeptide-based polymersomes (refer to as pepsomes) were designed and developed from asymmetric poly(ethylene glycol)-b-poly(l-leucine)-b-poly(l-glutamic acid) (PEG-PLeu-PGA, PEG is longer than PGA) triblock copolymers for efficient encapsulation and triggered intracellular delivery of doxorubicin hydrochloride (DOX·HCl). PEG-PLeu-PGA was conveniently prepared by sequential ring-opening polymerization of l-leucine N-carboxyanhydride and γ-benzyl-l-glutamate N-carboxyanhydride using PEG-NH2 as an initiator followed by deprotection. Pepsomes formed from PEG-PLeu-PGA had unimodal distribution and small sizes of 64-71 nm depending on PLeu block lengths. Interestingly, these chimaeric pepsomes while stable at pH 7.4 were quickly disrupted at pH 5.0, likely due to alternation of ionization state of the carboxylic groups in PGA that shifts PGA blocks from hydrophilic and random coil structure into hydrophobic and α-helical structure. DOX·HCl could be actively loaded into the watery core of pepsomes with a high loading efficiency. Remarkably, the in vitro release studies revealed that release of DOX·HCl was highly dependent on pH, in which about 24.0% and 75.7% of drug was released at pH 7.4 and 5.0, respectively, at 37 °C in 24 h. MTT assays demonstrated that DOX·HCl-loaded pepsomes exhibited high antitumor activity, similar to free DOX·HCl in RAW 264.7 cells. Moreover, they were also potent toward drug-resistant MCF-7 cancer cells (MCF-7/ADR). Confocal microscopy studies showed that DOX·HCl-loaded pepsomes delivered and released drug into the cell nuclei of MCF-7/ADR cells in 4 h, while little DOX·HCl fluorescence was observed in MCF-7/ADR cells treated with free drug under otherwise the same conditions. These chimaeric pepsomes with facile synthesis, efficient drug loading, and pH-triggered drug release behavior are an attractive alternative to liposomes for targeted cancer chemotherapy.