RESUMEN
Brain disorders are at the leading edge of global disease burden worldwide. Effective therapies are lagging behind because most drugs cannot reach their targets in the brain because of the blood-brain barrier (BBB). The new development of a BBB transport vehicle may bring us a step closer to solve this problem.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Encefalopatías/patología , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Barrera Hematoencefálica/efectos de los fármacos , Encefalopatías/metabolismo , Portadores de Fármacos/química , Humanos , Inmunoconjugados/química , Inmunoconjugados/inmunología , Inmunoconjugados/farmacología , Receptores de Transferrina/inmunología , Receptores de Transferrina/metabolismo , TranscitosisRESUMEN
The membrane translocation of hydrophilic substances constitutes a challenge for their application as therapeutic compounds and labelling probes1-4. To remedy this, charged amphiphilic molecules have been classically used as carriers3,5. However, such amphiphilic carriers may cause aggregation and non-specific membrane lysis6,7. Here we show that globular dodecaborate clusters, and prominently B12Br122-, can function as anionic inorganic membrane carriers for a broad range of hydrophilic cargo molecules (with molecular mass of 146-4,500 Da). We show that cationic and neutral peptides, amino acids, neurotransmitters, vitamins, antibiotics and drugs can be carried across liposomal membranes. Mechanistic transport studies reveal that the carrier activity is related to the superchaotropic nature of these cluster anions8-12. We demonstrate that B12Br122- affects cytosolic uptake of different small bioactive molecules, including the antineoplastic monomethyl auristatin F, the proteolysis targeting chimera dBET1 and the phalloidin toxin, which has been successfully delivered in living cells for cytoskeleton labelling. We anticipate the broad and distinct delivery spectrum of our superchaotropic carriers to be the starting point of conceptually distinct cell-biological, neurobiological, physiological and pharmaceutical studies.
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Boro , Péptidos , Aniones/química , Transporte Biológico , Cationes , Portadores de Fármacos/química , Interacciones Hidrofóbicas e Hidrofílicas , Péptidos/química , Preparaciones FarmacéuticasRESUMEN
The recent emergence of nanomedicine has revolutionized the therapeutic landscape and necessitated the creation of more sophisticated drug delivery systems. Polymeric nanoparticles sit at the forefront of numerous promising drug delivery designs, due to their unmatched control over physiochemical properties such as size, shape, architecture, charge, and surface functionality. Furthermore, polymeric nanoparticles have the ability to navigate various biological barriers to precisely target specific sites within the body, encapsulate a diverse range of therapeutic cargo and efficiently release this cargo in response to internal and external stimuli. However, despite these remarkable advantages, the presence of polymeric nanoparticles in wider clinical application is minimal. This review will provide a comprehensive understanding of polymeric nanoparticles as drug delivery vehicles. The biological barriers affecting drug delivery will be outlined first, followed by a comprehensive description of the various nanoparticle designs and preparation methods, beginning with the polymers on which they are based. The review will meticulously explore the current performance of polymeric nanoparticles against a myriad of diseases including cancer, viral and bacterial infections, before finally evaluating the advantages and crucial challenges that will determine their wider clinical potential in the decades to come.
Asunto(s)
Sistemas de Liberación de Medicamentos , Nanopartículas , Polímeros , Polímeros/química , Nanopartículas/química , Humanos , Animales , Portadores de Fármacos/química , Neoplasias/tratamiento farmacológicoRESUMEN
The design of stimuli-responsive systems in nanomedicine arises from the challenges associated with the unsolved needs of current molecular drug delivery. Here, we present a delivery system with high spatiotemporal control and tunable release profiles. The design is based on the combination of an hydrophobic synthetic molecular rotary motor and a PDMS-b-PMOXA diblock copolymer to create a responsive self-assembled system. The successful incorporation and selective activation by low-power visible light (λ = 430 nm, 6.9 mW) allowed to trigger the delivery of a fluorescent dye with high efficiencies (up to 75%). Moreover, we proved the ability to turn on and off the responsive behavior on demand over sequential cycles. Low concentrations of photoresponsive units (down to 1 mol% of molecular motor) are shown to effectively promote release. Our system was also tested under relevant physiological conditions using a lung cancer cell line and the encapsulation of an Food and Drug Administration (FDA)-approved drug. Similar levels of cell viability are observed compared to the free given drug showing the potential of our platform to deliver functional drugs on request with high efficiency. This work provides an important step for the application of synthetic molecular machines in the next generation of smart delivery systems.
Asunto(s)
Sistemas de Liberación de Medicamentos , Polímeros , Polímeros/química , Colorantes Fluorescentes , Línea Celular , Interacciones Hidrofóbicas e Hidrofílicas , Portadores de Fármacos/químicaRESUMEN
Human serum albumin (HSA) is a highly water-soluble protein with 67% alpha-helix content and three distinct domains (I, II, and III). HSA offers a great promise in drug delivery with enhanced permeability and retention effect. But it is hindered by protein denaturation during drug entrapment or conjugation that result in distinct cellular transport pathways and reduction of biological activities. Here we report using a protein design approach named reverse-QTY (rQTY) code to convert specific hydrophilic alpha-helices to hydrophobic to alpha-helices. The designed HSA undergo self-assembly of well-ordered nanoparticles with highly biological actives. The hydrophilic amino acids, asparagine (N), glutamine (Q), threonine (T), and tyrosine (Y) in the helical B-subdomains of HSA were systematically replaced by hydrophobic leucine (L), valine (V), and phenylalanine (F). HSArQTY nanoparticles exhibited efficient cellular internalization through the cell membrane albumin binding protein GP60, or SPARC (secreted protein, acidic and rich in cysteine)-mediated pathways. The designed HSArQTY variants displayed superior biological activities including: i) encapsulation of drug doxorubicin, ii) receptor-mediated cellular transport, iii) tumor cell targeting, and iv) antitumor efficiency compare to denatured HSA nanoparticles. HSArQTY nanoparticles provided superior tumor targeting and antitumor therapeutic effects compared to the albumin nanoparticles fabricated by antisolvent precipitation method. We believe that the rQTY code is a robust platform for specific hydrophobic modification of functional hydrophilic proteins with clear-defined binding interfaces.
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Antineoplásicos , Nanopartículas , Humanos , Animales , Ratones , Albúmina Sérica Humana/química , Antineoplásicos/farmacología , Antineoplásicos/química , Doxorrubicina/farmacología , Doxorrubicina/química , Sistemas de Liberación de Medicamentos , Albúminas , Nanopartículas/química , Línea Celular Tumoral , Portadores de Fármacos/químicaRESUMEN
For the delivery of drugs, different nanosized drug carriers (e.g., liposomes, lipid nanoparticles, and micelles) have been developed in order to treat diseases that afflict society. Frequently, these vehicles are formed by the self-assembly of small molecules to encapsulate the therapeutic cargo of interest. Over decades, nanoparticles have been optimized to make them more efficient and specific to fulfill tailor-made tasks, such as specific cell targeting or enhanced cellular uptake. In recent years, lipid-based nanoparticles in particular have taken center stage; however, off-targeting side effects and poor endosomal escape remain major challenges since therapies require high efficacy and acceptable toxicity.To overcome these issues, many different approaches have been explored to make drug delivery more specific, resulting in reduced side effects, to achieve an optimal therapeutic effect and a lower required dose. The fate of nanoparticles is largely dependent on size, shape, and surface charge. A common approach to designing drug carriers with targeting capability is surface modification. Different approaches to functionalize nanoparticles have been investigated since the attachment of targeting moieties plays a significant role in whether they can later interact with surface-exposed receptors of cells. To this end, various strategies have been used involving different classes of biomolecules, such as small molecules, nucleic acids, antibodies, aptamers, and peptides.Peptides in particular are often used since there are many receptors overexpressed in different specific cell types. Furthermore, peptides can be produced and modified at a low cost, enabling high therapeutic screening. Cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs) are frequently used for this purpose. Less studied in this context are fusogenic coiled-coil peptides. Lipid-based nanoparticles functionalized with these peptides are able to avoid the endolysosomal pathway; instead such particles can be taken up by membrane fusion, resulting in increased delivery of payload. Furthermore, they can be used for targeting cells/organs but are not directed at surface-exposed receptors. Instead, they recognize complementary peptide sequences, facilitating their uptake into cells.In this Account, we will discuss peptides as moieties for enhanced cytosolic delivery, targeted uptake, and how they can be attached to lipid-based nanoparticles to alter their properties. We will discuss the properties imparted to the particles by peptides, surface modification approaches, and recent examples showing the power of peptides for in vitro and in vivo drug delivery. The main focus will be on the functionalization of lipid-based nanoparticles by fusogenic coiled-coil peptides, highlighting the relevance of this concept for the development of future therapeutics.
Asunto(s)
Péptidos de Penetración Celular , Nanopartículas , Liposomas/química , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Portadores de Fármacos , Péptidos de Penetración Celular/química , Lípidos/químicaRESUMEN
Polymer prodrugs are based on the covalent linkage of therapeutic molecules to a polymer structure which avoids the problems and limitations commonly encountered with traditional drug-loaded nanocarriers in which drugs are just physically entrapped (e.g., burst release, poor drug loadings). In the past few years, reversible-deactivation radical polymerization (RDRP) techniques have been extensively used to design tailor-made polymer prodrug nanocarriers. This synthesis strategy has received a lot of attention due to the possibility of fine tuning their structural parameters (e.g., polymer nature and macromolecular characteristics, linker nature, physico-chemical properties, functionalization, etc.), to achieve optimized drug delivery and therapeutic efficacy. In particular, adjusting the nature of the drug-polymer linker has enabled the easy synthesis of stimuli-responsive polymer prodrugs for efficient spatiotemporal drug release. In this context, this review article will give an overview of the different stimuli-sensitive polymer prodrug structures designed by RDRP techniques, with a strong focus on the synthesis strategies, the macromolecular architectures and in particular the drug-polymer linker, which governs the drug release kinetics and eventually the therapeutic effect. Their biological evaluations will also be discussed.
Asunto(s)
Portadores de Fármacos , Polimerizacion , Profármacos , Profármacos/química , Profármacos/farmacología , Profármacos/síntesis química , Portadores de Fármacos/química , Humanos , Polímeros/química , Polímeros/síntesis química , Nanopartículas/química , Liberación de Fármacos , Radicales Libres/químicaRESUMEN
Micro/nanorobots hold the potential to revolutionize biomedicine by executing diverse tasks in hard-to-reach biological environments. Nevertheless, achieving precise drug delivery to unknown disease sites using swarming micro/nanorobots remains a significant challenge. Here we develop a heterogeneous swarm comprising sensing microrobots (sensor-bots) and drug-carrying microrobots (carrier-bots) with collaborative tasking capabilities for precise drug delivery toward unknown sites. Leveraging robust interspecific hydrodynamic interactions, the sensor-bots and carrier-bots spontaneously synchronize and self-organize into stable heterogeneous microswarms. Given that the sensor-bots can create real-time pH maps employing pH-responsive structural-color changes and the doxorubicin-loaded carrier-bots exhibit selective adhesion to acidic targets via pH-responsive charge reversal, the sensor-carrier microswarm, when exploring unknown environments, can detect and localize uncharted acidic targets, guide itself to cover the area, and finally deploy therapeutic carrier-bots precisely there. This versatile platform holds promise for treating diseases with localized acidosis and inspires future theranostic microsystems with expandability, task flexibility, and high efficiency.
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Doxorrubicina , Sistemas de Liberación de Medicamentos , Doxorrubicina/química , Doxorrubicina/farmacología , Concentración de Iones de Hidrógeno , Acidosis , Humanos , Portadores de Fármacos/química , RobóticaRESUMEN
Polymeric nanoparticles are a highly promising drug delivery formulation. However, a lack of understanding of the molecular mechanisms that underlie their drug solubilization and controlled release capabilities has hindered the efficient clinical translation of such technologies. Polyethylene glycol-poly(lactic-co-glycolic) acid (PEG-PLGA) nanoparticles have been widely studied as cancer drug delivery vehicles. In this letter, we use unbiased coarse-grained molecular dynamics simulations to model the self-assembly of a PEG-PLGA nanoparticle and its solubulization of the anticancer peptide, EEK, with good agreement with previously reported experimental structural data. We applied unsupervised machine learning techniques to quantify the conformations that polymers adopt at various locations within the nanoparticle. We find that the local microenvironments formed by the various polymer conformations promote preferential EEK solubilization within specific regions of the NP. This demonstrates that these microenvironments are key in controlling drug storage locations within nanoparticles, supporting the rational design of nanoparticles for therapeutic applications.
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Nanopartículas , Poliésteres , Polímeros , Polímeros/química , Ácido Láctico/química , Polietilenglicoles/química , Sistemas de Liberación de Medicamentos/métodos , Péptidos , Nanopartículas/química , Portadores de Fármacos/químicaRESUMEN
Nanostructures of drug carriers play a crucial role in nanomedicine due to their ability to influence drug delivery. There is yet no clear consensus regarding the optimal size and shape (e.g., aspect ratio) of nanoparticles for minimizing macrophage uptake, given the difficulties in controlling the shape and size of nanoparticles while maintaining identical surface properties. Here, we employed graft copolymer self-assembly to prepare polymer micelles with aspect ratios ranging from 1.0 (spherical) to 10.8 (cylindrical) and closely matched interfacial properties. Notably, our findings emphasize that cylindrical micelles with an aspect ratio of 2.4 are the least susceptible to macrophage uptake compared with both their longer counterparts and spherical micelles. This reduced uptake of the short cylindrical micelles results in a 3.3-fold increase in blood circulation time compared with their spherical counterparts. Controlling the aspect ratio of nanoparticles is crucial for improving drug delivery efficacy through better nanoparticle design.
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Macrófagos , Micelas , Polímeros , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Animales , Polímeros/química , Ratones , Portadores de Fármacos/química , Nanopartículas/química , Células RAW 264.7 , Tamaño de la Partícula , Sistemas de Liberación de Medicamentos , Propiedades de SuperficieRESUMEN
Stroke is a leading cause of global mortality and severe disability. However, current strategies used for treating ischemic stroke lack specific targeting capabilities, exhibit poor immune escape ability, and have limited drug release control. Herein, we developed an ROS-responsive nanocarrier for targeted delivery of the neuroprotective agent rapamycin (RAPA) to mitigate ischemic brain damage. The nanocarrier consisted of a sulfated chitosan (SCS) polymer core modified with a ROS-responsive boronic ester enveloped by a red blood cell membrane shell incorporating a stroke homing peptide. When encountering high levels of intracellular ROS in ischemic brain tissues, the release of SCS combined with RAPA from nanoparticle disintegration facilitates effective microglia polarization and, in turn, maintains blood-brain barrier integrity, reduces cerebral infarction, and promotes cerebral neurovascular remodeling in a mouse stroke model involving transient middle cerebral artery occlusion (tMCAO). This work offers a promising strategy to treat ischemic stroke therapy.
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Barrera Hematoencefálica , Quitosano , Portadores de Fármacos , Accidente Cerebrovascular Isquémico , Nanopartículas , Sirolimus , Animales , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/patología , Ratones , Quitosano/química , Portadores de Fármacos/química , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Sirolimus/farmacología , Sirolimus/química , Sirolimus/uso terapéutico , Nanopartículas/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Modelos Animales de Enfermedad , Polisacáridos/química , Polisacáridos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Sulfatos/química , Sulfatos/farmacología , Microglía/efectos de los fármacos , Microglía/metabolismoRESUMEN
Chemotherapy resistance remains a significant challenge in treating ovarian cancer effectively. This study addresses this issue by utilizing a dual drug-loaded nanomicelle system comprising albendazole (ABZ) and paclitaxel (PTX), encapsulated in a novel carrier matrix of D-tocopheryl polyethylene glycol 1000 succinate vitamin E (TPGS), soluplus and folic acid. Our objective was to develop and optimize this nanoparticulate delivery system using solvent evaporation techniques to enhance the therapeutic efficacy against ovarian cancer. The formulation process involved pre-formulation, formulation, optimization, and comprehensive characterization of the micelles. Optimization was conducted through a 32 factorial design, focusing on the effects of polymer ratios on particle size, zeta potential, polydispersity index (PDI) and entrapment efficiency (%EE). The optimal formulation demonstrated improved dilution stability, as indicated by a critical micelle concentration (CMC) of 0.0015 mg/mL for the TPGS-folic acid conjugate (TPGS-FOL). Extensive characterization included differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), and Fourier-transform infrared spectroscopy (FTIR). The release profile exhibited an initial burst followed by sustained release over 90 h. The cytotoxic potential of the formulated micelles was superior to that of the drugs alone, as assessed by MTT assays on SKOV3 ovarian cell lines. Additionally, in vivo studies confirmed the presence of both drugs in plasma and tumour tissues, suggesting effective targeting and penetration. In conclusion, the developed TPGS-Fol-based nanomicelles for co-delivering ABZ and PTX show promising results in overcoming drug resistance, enhancing solubility, sustaining drug release, and improving therapeutic outcomes in ovarian cancer treatment.
Asunto(s)
Albendazol , Micelas , Neoplasias Ováricas , Paclitaxel , Femenino , Paclitaxel/farmacología , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Paclitaxel/química , Albendazol/química , Albendazol/farmacología , Albendazol/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Humanos , Animales , Línea Celular Tumoral , Portadores de Fármacos/química , Polietilenglicoles/química , Vitamina E/química , Ácido Fólico/química , Ratones , Liberación de Fármacos , Tamaño de la Partícula , Polivinilos/química , Polímeros/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Using functional proteins for therapeutic purposes due to their high selectivity and/or catalytic properties can enable the control of various cellular processes; however, the transport of active proteins inside living cells remains a major challenge. In contrast, intracellular delivery of nucleic acids has become a routine method for a number of applications in gene therapy, genome editing, or immunization. Here we report a functionalizable platform constituting of DNA-protein nanogel carriers cross-linked through streptavidin-biotin or streptactin-biotin interactions and demonstrate its applicability for intracellular delivery of active proteins. We show that the nanogels can be loaded with proteins bearing either biotin, streptavidin, or strep-tag, and the resulting functionalized nanogels can be delivered into living cells after complexation with cationic lipid vectors. We use this approach for delivery of alkaline phosphatase enzyme, which is shown to keep its catalytic activity after internalization by mouse melanoma B16 cells, as demonstrated by the DDAO-phosphate assay. The resulting functionalized nanogels have dimensions on the order of 100 nm, contain around 100 enzyme molecules, and are shown to be transfectable at low lipid concentrations (charge ratio R± = 0.75). This ensures the low toxicity of our system, which in combination with high local enzyme concentration (â¼100 µM) underlines potential interest of this nanoplatform for biomedical applications.
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Biotina , Polietilenglicoles , Animales , Ratones , Nanogeles , Estreptavidina , Proteínas , ADN/metabolismo , Lípidos , Portadores de FármacosRESUMEN
Nanomedicines often rely on noncovalent self-assembly and encapsulation for drug loading and delivery. However, challenges such as reproducibility issues due to the multicomponent nature, off-target activation caused by premature drug release, and complex pharmacokinetics arising from assembly dissociation have hindered their clinical translation. In this study, we introduce an innovative design concept termed single molecular nanomedicine (SMNM) based on macrocyclic carrier-drug conjugates. Through the covalent linkage of two chemotherapy drugs to a hypoxia-cleavable macrocyclic carrier, azocalix[4]arene, we obtained two self-included complexes to serve as SMNMs. The intramolecular inclusion feature of the SMNMs has not only demonstrated comprehensive shielding and protection for the drugs but also effectively prevented off-target drug leakage, thereby significantly reducing their side effects and enhancing their antitumor therapeutic efficacy. Additionally, the attributes of being a single component and molecularly dispersed confer advantages such as ease of preparation and good reproducibility for SMNMs, which is desirable for clinical applications.
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Antineoplásicos , Calixarenos , Portadores de Fármacos , Nanomedicina , Humanos , Portadores de Fármacos/química , Nanomedicina/métodos , Calixarenos/química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Animales , Compuestos Macrocíclicos/química , Ratones , Línea Celular Tumoral , Liberación de FármacosRESUMEN
Hydrogels hold significant promise as drug delivery systems due to their distinct advantage of sustained localized drug release. However, the challenge of regulating the initial burst release while achieving precise control over degradation and drug-release kinetics persists. Herein, we present an ABA-type triblock copolymer-based hydrogel system with precisely programmable degradation and release kinetics. The resulting hydrogels were designed with a hydrophilic poly(ethylene oxide) midblock and a hydrophobic end-block composed of polyethers with varying ratios of ethoxyethyl glycidyl ether and tetrahydropyranyl glycidyl ether acetal pendant possessing different hydrolysis kinetics. This unique side-chain strategy enabled us to achieve a broad spectrum of precise degradation and drug-release profiles under mildly acidic conditions while maintaining the cross-linking density and viscoelastic modulus, which is unlike the conventional polyester-based backbone degradation system. Furthermore, programmable degradation of the hydrogels and release of active therapeutic agent paclitaxel loaded therein are demonstrated in an in vivo mouse model by suppressing tumor recurrence following surgical resection. Tuning of the fraction of two acetal pendants in the end-block provided delicate tailoring of hydrogel degradation and the drug release capability to achieve the desired therapeutic efficacy. This study not only affords a facile means to design hydrogels with precisely programmable degradation and release profiles but also highlights the critical importance of aligning the drug release profile with the target disease.
Asunto(s)
Liberación de Fármacos , Hidrogeles , Hidrogeles/química , Hidrogeles/síntesis química , Animales , Ratones , Acetales/química , Paclitaxel/química , Paclitaxel/farmacocinética , Éteres/química , Polietilenglicoles/química , Polímeros/química , Polímeros/síntesis química , Portadores de Fármacos/químicaRESUMEN
Candidate drugs targeting the central nervous system (CNS) demonstrate extremely low clinical success rates, with more than 98% of potential treatments being discontinued due to poor blood-brain barrier (BBB) permeability. Neurological conditions were shown to be the second leading cause of death globally in 2016, with the number of people currently affected by neurological disorders increasing rapidly. This increasing trend, along with an inability to develop BBB permeating drugs, is presenting a major hurdle in the treatment of CNS-related disorders, like dementia. To overcome this, it is necessary to understand the structure and function of the BBB, including the transport of molecules across its interface in both healthy and pathological conditions. The use of CNS drug carriers is rapidly gaining popularity in CNS research due to their ability to target BBB transport systems. Further research and development of drug delivery vehicles could provide essential information that can be used to develop novel treatments for neurological conditions. This review discusses the BBB and its transport systems and evaluates the potential of using nanoparticle-based delivery systems as drug carriers for CNS disease with a focus on dementia.
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Enfermedades del Sistema Nervioso Central , Demencia , Humanos , Barrera Hematoencefálica , Sistemas de Liberación de Medicamentos , Portadores de Fármacos/química , Portadores de Fármacos/uso terapéutico , Transporte Biológico , Demencia/tratamiento farmacológicoRESUMEN
Small interfering RNA (siRNA) highlights the immense therapeutic potential for cancer treatment. The major challenge in siRNA therapy is the effective RNA nanodrug delivery system, which is facilitated by the ligand and the carrier. In this study, we analyzed the binding specificity of linear RGD and circular RGD to αVß3 integrins by mapping the morphology using super-resolution direct stochastic optical reconstruction microscopy. Meanwhile, the binding dynamics was investigated using single-molecule force spectroscopy. Then, the effects of the ligand and carrier on RNA nanodrug cell entry dynamic parameters were evaluated at the single particle level by the force tracing technique. Furthermore, the delivery efficiency of RNA nanodrugs was assessed using AFM-based nanoindentation at the single cell level. This report will provide valuable insights for rational design strategies aiming to achieve improved efficiency for nanodrug delivery systems.
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ARN Interferente Pequeño , Ligandos , Humanos , ARN Interferente Pequeño/química , ARN Interferente Pequeño/farmacología , Integrina alfaVbeta3/metabolismo , Integrina alfaVbeta3/química , Oligopéptidos/química , Sistemas de Liberación de Medicamentos , Portadores de Fármacos/química , Microscopía de Fuerza Atómica , Nanopartículas/químicaRESUMEN
Nanocarrier drug delivery systems are attractive options for targeted delivery of survival- and regeneration-enhancing therapeutics to neurons damaged by degenerative or traumatic central nervous system (CNS) lesions. Functional groups on nanocarrier surfaces allow derivatization with molecules to target specific cells but may affect cellular interactions and nanocarrier uptake. We synthesized differently sized -COOH and -NH2 surface functionalized polymeric nanocarriers (SFNCs) by emulsion copolymerization and assessed uptake by different cell types in mixed cortical cultures. Following 60-min incubation with SFNCs, mean intensity measurements of fluorescently labeled SFNCs indicated that corticospinal tract motor neurons (CSMNs) took up more COOH- or NH2- functionalized SFNCs with similar sizes (150 nm), compared to glia. However, larger diameter (750 nm) SFNCs were taken up at higher concentrations compared to smaller COOH-derivatized SFNCs (150 nm). These data suggest that larger SFNCs may provide an advantage for enhanced uptake by targeted neurons.
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Neuronas Motoras , Tractos Piramidales , Polímeros , Sistemas de Liberación de Medicamentos , Neuroglía , Portadores de FármacosRESUMEN
The nanomedicine system based on dual drug delivery systems (DDDs) can significantly enhance the efficacy of tumor treatment. Herein, a metal-organic framework, Zeolite imidazole salt frames 8 (ZIF-8), was successfully utilized as a carrier to load the dual chemotherapeutic drugs doxorubicin (DOX) and camptothecin (CPT), named DOX/CPT@ZIF-8 (denoted as DCZ), and their inhibitory effects on 4T1 breast cancer cells were evaluated. The study experimentally demonstrated the synergistic effects of the dual chemotherapeutic drugs within the ZIF-8 carrier and showed that the ZIF-8 nano-carrier loaded with the dual drugs exhibited stronger cytotoxicity and inhibitory effects on 4T1 breast cancer cells compared to single-drug treatment. The use of a ZIF-8-based dual chemotherapeutic drug carrier system highlighted its potential advantages in suppressing 4T1 breast cancer cells.
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Neoplasias de la Mama , Estructuras Metalorgánicas , Nanopartículas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Portadores de Fármacos , Línea Celular TumoralRESUMEN
The brain is a privileged organ, tightly guarded by a network of endothelial cells, pericytes, and glial cells called the blood brain barrier. This barrier facilitates tight regulation of the transport of molecules, ions, and cells from the blood to the brain. While this feature ensures protection to the brain, it also presents a challenge for drug delivery for brain diseases. It is, therefore, crucial to identify molecules and/or vehicles that carry drugs, cross the blood brain barrier, and reach targets within the central nervous system. Biopolymers are large polymeric molecules obtained from biological sources. In comparison with synthetic polymers, biopolymers are structurally more complex and their 3D architecture makes them biologically active. Researchers are therefore investigating biopolymers as safe and efficient carriers of brain-targeted therapeutic agents. In this article, we bring together various approaches toward achieving this objective with a note on the prospects for biopolymer-based neurotherapeutic/neurorestorative/neuroprotective interventions. Finally, as a representative paradigm, we discuss the potential use of nanocarrier biopolymers in targeting protein aggregation diseases.