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The increasing prevalence of multidrug-resistant bacterial infections necessitates the exploration of novel paradigms for anti-infective therapy. Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), have garnered extensive recognition as immunomodulatory molecules that leverage natural host mechanisms to enhance therapeutic benefits. The unique immune mechanism exhibited by certain HDPs that involves self-assembly into supramolecular nanonets capable of inducing bacterial agglutination and entrapping is significantly important. This process effectively prevents microbial invasion and subsequent dissemination and significantly mitigates selective pressure for the evolution of microbial resistance, highlighting the potential of HDP-based antimicrobial therapy. Recent advancements in this field have focused on developing bio-responsive materials in the form of supramolecular nanonets. A comprehensive overview of the immunomodulatory and bacteria-agglutinating activities of HDPs, along with a discussion on optimization strategies for synthetic derivatives, is presented in this article. These optimized derivatives exhibit improved biological properties and therapeutic potential, making them suitable for future clinical applications as effective anti-infective therapeutics.
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Anti-Infecciosos , Infecções Bacterianas , Humanos , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Bactérias , Infecções Bacterianas/tratamento farmacológico , Farmacorresistência Bacteriana MúltiplaRESUMO
In exploring the challenges of bone repair and regeneration, this review evaluates the potential of bone tissue engineering (BTE) as a viable alternative to traditional methods, such as autografts and allografts. Key developments in biomaterials and scaffold fabrication techniques, such as additive manufacturing and cell and bioactive molecule-laden scaffolds, are discussed, along with the integration of bio-responsive scaffolds, which can respond to physical and chemical stimuli. These advancements collectively aim to mimic the natural microenvironment of bone, thereby enhancing osteogenesis and facilitating the formation of new tissue. Through a comprehensive combination of in vitro and in vivo studies, we scrutinize the biocompatibility, osteoinductivity, and osteoconductivity of these engineered scaffolds, as well as their interactions with critical cellular players in bone healing processes. Findings from scaffold fabrication techniques and bio-responsive scaffolds indicate that incorporating nanostructured materials and bioactive compounds is particularly effective in promoting the recruitment and differentiation of osteoprogenitor cells. The therapeutic potential of these advanced biomaterials in clinical settings is widely recognized and the paper advocates continued research into multi-responsive scaffold systems.
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Materiais Biocompatíveis , Regeneração Óssea , Osso e Ossos , Engenharia Tecidual , Alicerces Teciduais , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Humanos , Animais , Osso e Ossos/metabolismo , Osso e Ossos/fisiologia , Materiais Biocompatíveis/química , Osteogênese , Diferenciação CelularRESUMO
Injectable hydrogels are promising for treatment of bone defects in clinic owing to their minimally invasive procedure. Currently, there is limited emphasis on how to utilize injectable hydrogels to mobilize body's regenerative potential for enhancing bone regeneration. Herein, an injectable bone-mimicking hydrogel (BMH) scaffold assembled from nanocomposite microgel building blocks was developed, in which a highly interconnected microporous structure and an inorganic/organic (methacrylated hydroxyapatite and methacrylated gelatin) interweaved nano structure were well-designed. Compared with hydrogels lacking micro-nano structures or only showing microporous structure, the BMH scaffold enhanced the ingrowth of vessels and promoted the formation of dense cellular networks (including stem cells and M2 macrophages), across the entire scaffold at early stage after subcutaneous implantation. Moreover, the BMH scaffold could not only directly trigger osteogenic differentiation of the infiltrated stem cells, but also provided an instructive osteo-immune microenvironment by inducing macrophages into M2 phenotype. Mechanistically, our results reveal that the nano-rough structure of the BMH plays an essential role in inducing macrophage M2 polarization through activating mechanotransduction related RhoA/ROCK2 pathway. Overall, this work offers an injectable hydrogel with micro-nano structure driven bio-responsive abilities, highlighting harnessing body's inherent regenerative potential to realize bone regeneration.
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Regeneração Óssea , Hidrogéis , Nanocompostos , Osteogênese , Alicerces Teciduais , Regeneração Óssea/efeitos dos fármacos , Hidrogéis/química , Nanocompostos/química , Animais , Alicerces Teciduais/química , Osteogênese/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/citologia , Camundongos , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células RAW 264.7 , Durapatita/química , Engenharia Tecidual/métodos , Injeções , Gelatina/químicaRESUMO
The field of dental materials is undergoing rapid advancements in the pursuit of an innovative generation of dental polymeric restorative materials. There is a growing interest in the development of a distinct category of dental polymers that transcend the conventional role of inertly filling prepared cavities. Instead, these materials possess the capacity to actively detect and respond to alterations within the host environment by undergoing dynamic and controlled molecular changes. Despite the well-established status of stimuli-responsive polymeric systems in other fields, their implementation in dentistry is still in its nascent stages, presenting a multitude of promising opportunities for advancement. These systems revolve around the fundamental concept of harnessing distinctive stimuli inherent in the oral environment to trigger precise, targeted, predictable, and demand-driven responses through molecular modifications within the polymeric network. This review aims to provide a comprehensive overview of the diverse categories of stimuli-responsive polymers, accentuating the critical aspects that must be considered during their design and development phases. Furthermore, it evaluates their current application in the dental field while exploring potential alternatives for future advancements.
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Choroidal vascular diseases, such as age-related macular degeneration, are the leading cause of vision impairment and are characterized by pathological angiogenesis. Verteporfin-mediated photodynamic therapy is a current strategy that selectively occludes choroidal neovasculature. However, the clinically used large-dose systemic administration increases the risk of systemic adverse events, such as phototoxicity to superficial tissues. In this study, we developed an in situ verteporfin delivery system with a photoswitching synergistic function that disassembles in response to intraocular inflammatory enzymes. Under light-on conditions, verteporfin-mediated photodynamic therapy effectively occurs and this leads to vascular occlusion. Under light-off conditions, non-photoactive verteporfin negatively regulates vascular endothelial growth factor-induced angiogenesis as a yes-associated protein inhibitor. Taken together, our system serves as an intraocular verteporfin reservoir to improve the bioavailability of verteporfin by innovatively exploiting its photochemical and biological functions. This work provides a promising strategy with synergistic antiangiogenic effects for the treatment of choroidal vascular diseases.
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Glioblastoma is an unmet clinical need. Local treatment strategies offer advantages, such as the possibility to bypass the blood-brain barrier, achieving high drug concentrations at the glioblastoma site, and consequently reducing systemic toxicity. In this study, we evaluated the feasibility of using hyaluronic acid (HA) for the local treatment of glioblastoma. HA was conjugated to doxorubicin (DOX) with distinct bio-responsive linkers (direct amide conjugation HA-NH-DOX), direct hydrazone conjugation (HA-Hz-DOX), and adipic hydrazone (HA-AdpHz-DOX). All HA-DOX conjugates displayed a small size (less than 30 nm), suitable for brain diffusion. HA-Hz-DOX showed the best performance in killing GBM cells in both 2D and 3D in vitro models and displayed superior activity in a subcutaneous GL261 tumor model in vivo compared to free DOX and other HA-DOX conjugates. Altogether, these results demonstrate the feasibility of HA as a polymeric platform for the local treatment of glioblastoma and the importance of rationally designing conjugates.
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Despite the potential of immunotherapy in various solid tumors, the efficiency of immunotherapy is limited by little tumor-infiltrating lymphocytes (TILs) and abundant immunosuppressive M2-type tumor-associated macrophages (M2-TAMs) in the tumor microenvironment (TME). Herein, we design a versatile photo-immunotherapy nanoparticle (termed as HA-AuNR/M-M2pep NP) to conquer above challenges. The HA-AuNR/M-M2pep NP is composed of hyaluronic acid modified gold nanorod (HA-AuNR) surface-modified with matrix metalloproteinase-2 (MMP2)-responsive M2pep fusion peptides (M-M2pep). Upon tumor site, the fabricated HA-AuNR/M-M2pep NP releases M2pep through the cleavage of MMP2-sensitive peptide to selectively deplete M2-TAMs and improve immunoactivity of TME. Meanwhile, HA-AuNR could target to tumor cells and realize precise tumor photothermal therapy (PTT) under near infrared light irradiation, which further triggers immunogenic cell death (ICD) of tumor cells and elicits antitumor immunity. In vivo antitumor studies reveal that HA-AuNR/M-M2pep NPs-mediated PTT and M2-TAMs depletion recruit TILs, activate effector T lymphocytes, secrete antitumor cytokines (e.g. IFN-γ, TNF-α), and effectively inhibit the growth of tumor. Collectively, HA-AuNR/M-M2pep NP-mediated photo-immunotherapy based on dual targeted delivery and bio-responsive drug release holds tremendous promise to enhance antitumor efficacy.
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Nanopartículas , Neoplasias , Humanos , Imunoterapia , Metaloproteinase 2 da Matriz , Neoplasias/terapia , Microambiente TumoralRESUMO
The long non-coding RNA (lncRNA) MALAT1 acts as an oncogene. RNA interference (RNAi) is an effective method to control the expression of specific genes and can be used for the treatment of tumors, but an effective and safe carrier system is a significant obstacle to gene therapy. Herein, we explored the possibility of constructing an in situ bio-responsive self-assembled fluorescent gold-short hairpin RNA nanocomplex (Au-shRNA NCs) delivery system by co-incubating gold and MALAT1-shRNA for precise hepatocellular carcinoma (HCC) imaging and treatment. Due to the characteristics of the cancer microenvironment, Au-shRNA NCs self-assembled in HCC cells (HepG2) but did not occur in control cells (L02) under the same conditions. The in situ bio-responsive self-assembled Au-shRNA NCs delivery system can realize cancer cell bioimaging and promote cell uptake and endosomal escape mechanism, thereby realizing effective transfection. They effectively silenced target gene MALAT1, and with the downregulation of MALAT1, we found that several molecules involved in autophagic flux were also regulated. In vitro and tumor-bearing mouse model experiments demonstrated that the as-prepared fluorescent Au-shRNA NCs can readily realize tumor bioimaging and effectively silence the target gene MALAT1, and those autophagy-related pathway molecules were significantly downregulated, thereby exerting a tumor suppressor efficiency. This raises the possibility of realizing accurate multi-scale bio-imaging from the molecular-level with targeted gene-recognition to cancer cell imaging as well as in vivo tumor tissue imaging for the simultaneous precise cancer therapy.
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Autofagia , Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Interferente Pequeno , Animais , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Ouro , Células Hep G2 , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Camundongos , RNA Longo não Codificante , RNA Interferente Pequeno/genética , Microambiente TumoralRESUMO
Eyelid plays a vital role in protecting the eye from injury or infection. Inflammation related eyelid diseases, such as blepharitis, are the most common ocular disorders that affect human's vision and quality of life. Due to the physiological barriers and anatomical structures of the eye, the bioavailability of topical administrated therapeutics is typically less than 5%. Herein, we developed a bio-responsive hydrogel drug delivery system using a generally recognized as safe compound, triglycerol monostearate (TG-18), for in-situ eyelid injection with sustained therapeutics release. In vitro, drug release and disassembly time of Rosiglitazone loaded hydrogel (Rosi-hydrogel) were estimated in the presence or absence of MMP-9, respectively. Moreover, the disassembly of TG-18 hydrogel was evaluated with 9-month-old and 12-month-old mice in vivo. Owing to the bio-responsive nature of Rosi-hydrogel, the on-demand Rosiglitazone release is achieved in response to local enzymes. These findings are proved by further evaluation in the age-related meibomian gland dysfunction mice model, and the bio-responsive hydrogel is used as an in-situ injection to treat eyelid diseases. Taken together, the in-situ eyelid injection with sustained drug release opens a window for the therapy of inflammation related eyelid diseases.
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A successful matching of a PEG group size with the EPR effect for an off-to-on responsive NIR-fluorophore conjugate has been accomplished which allows two distinct in vivo tumor imaging periods, the first being the switch on during the initial tumor uptake via enhanced permeability into the ROI (as background is suppressed) and a second, later, due to enhanced retention within the tumor. Methods: Software simulation (https://mihaitodor.github.io/particle_simulation/index.html), synthetic chemistry, with in vitro and in vivo imaging have been synergistically employed to identify an optimal PEG conjugate of a bio-responsive NIR-AZA fluorophore for in vivo tumor imaging. Results: A bio-responsive NIR-AZA fluorophore conjugated to a 10 kDa PEG group has shown excellent in vivo imaging performance with sustained high tumor to background ratios and peak tumor emission within 24 h. Analysis of fluorescence profiles over 7 days has provided evidence for the EPR effect playing a positive role. Conclusion: Preclinical results show that exploiting the EPR effect by utilizing an optimized PEG substituent on a bio-responsive fluorophore may offer a means for intraoperative tumor margin delineation. The off-to-on responsive nature of the fluorophore makes tumor imaging achievable without waiting for clearance from normal tissue.
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Permeabilidade Capilar , Sistemas de Liberação de Medicamentos , Endotélio Vascular/metabolismo , Corantes Fluorescentes/farmacocinética , Fluorometria/métodos , Polietilenoglicóis/farmacocinética , Cirurgia Assistida por Computador/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Simulação por Computador , Portadores de Fármacos/farmacocinética , Difusão Dinâmica da Luz , Corantes Fluorescentes/administração & dosagem , Concentração de Íons de Hidrogênio , Microscopia Intravital , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Peso Molecular , Neovascularização Patológica/metabolismo , Polietilenoglicóis/administração & dosagem , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Immature manufacturing and sub-optimal control of quality attributes hinder the effective translation of nanoformulations for cancer treatment, being partially responsible for the scarce number of products on the market. The effect of the method of preparation on the performance of complex formulations such as bio-responsive nanomedicines needs further understanding. In this study, we investigated the the influence of the method of preparation on the characteristics and bio-responsiveness of doxorubicin-loaded redox-sensitive nanoparticles (DOX-SS-NPs), formed by a biocompatible cholesterol-based amphiphilic block copolymer (PC5MA-SS-PEO). Two commonly used preparation techniques: (1) cosolvent removal and (2) an O/W emulsion method were compared and the in vitro and in vivo performance of promising formulations was assessed. Besides particle size distribution and drug loading, the response of the nanoparticles to reducing environments and subsequent release kinetics and cytotoxicity were also affected by the method of preparation. The investigation and understanding of this extensive influence, led to a DOX-SS-NPs formulation with significant in vivo efficacy and an improved safety profile when evaluated against free doxorubicin (DOX-HCl) and the commercial pegylated liposomal form (Doxil®). Our findings highlight the importance of formulation optimization and support the use of systematic approaches like Quality by Design to the development of bio-responsive nanomedicines for cancer treatment.
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Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/análogos & derivados , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Células A549 , Animais , Antibióticos Antineoplásicos/farmacocinética , Colesterol/química , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Emulsões , Feminino , Humanos , Injeções Intravenosas , Masculino , Camundongos , Neoplasias/patologia , Oxirredução , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Polímeros/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
: The use of nanoparticulate systems as contrast agents for magnetic resonance imaging (MRI) is well-established and known to facilitate an enhanced image sensitivity within scans of a particular pathological region of interest. Such a capability can enable both a non-invasive diagnosis and the monitoring of disease progression/response to treatment. In this review, magnetic nanoparticles that exhibit a bio-responsive MR relaxivity are discussed, with pH-, enzyme-, biomolecular-, and protein-responsive systems considered. The ability of a contrast agent to respond to a biological stimulus provides not only enriched diagnostic capabilities over corresponding non-responsive analogues, but also an improved longitudinal monitoring of specific physiological conditions.
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Successful application of gene silencing approaches critically depends on systems that are able to safely and efficiently deliver genetic material such as small interfering RNA (siRNA). Due to their beneficial well-defined dendritic nanostructure, self-assembling dendrimers are emerging as promising nanovectors for siRNA delivery. However, these kinds of vectors are plagued with stability issues, especially when considered for in vivo applications. Therefore, in the present study, disulfide-based temporarily fixed micelles are developed that can degrade upon reductive conditions, and thus lead to efficient cargo release. In detail, lipoic acid-derived crosslinked micelles are synthesized based on small polymerizable dendritic amphiphiles. Particularly, one candidate out of this series is able to efficiently release siRNA due to its redox-responsive biodegradable profile when exposed to simulated intracellular environments. As a result, the reduction-triggered disassembly leads to potent gene silencing. In contrast, noncrosslinkable, structurally related constructs fails under the tested assay conditions, thereby confirming the applied rational design approach and demonstrating its large potential for future in vivo applications.
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Dendrímeros/química , Técnicas de Transferência de Genes , RNA Interferente Pequeno/genética , Dendrímeros/administração & dosagem , Humanos , Micelas , Oxirredução , RNA Interferente Pequeno/administração & dosagem , Tensoativos/administração & dosagem , Tensoativos/química , Ácido Tióctico/administração & dosagem , Ácido Tióctico/químicaRESUMO
The overexpression of secretory phospholipase A2 (sPLA2) in tumors has opened new avenues for enzyme-triggered active unloading of liposomal antitumor drug carriers selectively at the target tumor. However, the effects of the liposome composition, drug encapsulation, and tumor microenvironment on the activity of sPLA2 are still not well understood. We carried out a physico-chemical study to characterize the sPLA2-assisted breakdown of liposomes using dye-release assays in the context of drug delivery and under physiologically relevant conditions. The influence of temperature, lipid concentration, enzyme concentration, and drug loading on the hydrolysis of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC, Tm=42°C) liposomes with snake venom sPLA2 was investigated. The sensitivity of human sPLA2 to the liposome composition was checked using binary lipid mixtures of phosphatidylcholine (PC) and phosphatidylglycerol (PG) phospholipids with C14 and C16 acyl chains. Increasing temperature (36-41°C) was found to mainly shorten the enzyme lag-time, whereas the effect on lipid hydrolysis rate was modest. The enzyme lag-time was also found to be inversely dependent on the lipid-to-enzyme ratio. Drug encapsulation can alter the hydrolysis profile of the carrier liposomes. The activity of human sPLA2 was highly sensitive to the phospholipid acyl-chain length and negative surface charge density of the liposomes. We believe our work will prove useful for the optimization of sPLA2-susceptible liposomal formulations as well as will provide a solid ground for predicting the hydrolysis profile of the liposomes in vivo at the target site.