bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒01‒30
fourteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Adv Mater. 2022 Jan 22. e2109789
      Intracellular bacteria in latent or dormant states tolerate high-dose antibiotics. Fighting against these opportunistic bacteria has been a long-standing challenge. Herein, we design a cascade-targeting drug delivery system (DDS) that can sequentially target macrophages and intracellular bacteria, exhibiting on-site drug delivery. The DDS is fabricated by encapsulating rifampicin (Rif) into mannose-decorated poly(α-N-acryloyl-phenylalanine)-block-poly(β-N-acryloyl-D-aminoalanine) nanoparticles, denoted as Rif@FAM NPs. The mannose units on Rif@FAM NPs guide the initial macrophage-specific uptake and intracellular accumulation. After the uptake, the detachment of mannose in acidic phagolysosome via Schiff base cleavage exposes the D-aminoalanine moieties, which subsequently steer the NPs to escape from lysosomes and target intracellular bacteria through peptidoglycan-specific binding, as evidenced by the in-situ/ex-situ co-localization using confocal, flow cytometry, and TEM. Through the on-site Rif delivery, Rif@FAM NPs show superior in vitro and in vivo elimination efficiency than the control groups of free Rif or the DDSs lacking the macrophages- or bacteria-targeting moieties. Furthermore, Rif@FAM NPs remodel the innate immune response of the infected macrophages by up-regulating the M1/M2 polarization, resulting in a reinforced antibacterial capacity. Therefore, this biocompatible DDS enabling macrophages and bacteria targeting in a cascade manner provides a new outlook for the therapy of intracellular pathogen infection. This article is protected by copyright. All rights reserved.
    Keywords:  cascade-targeting drug delivery system; intracellular bacteria targeting; macrophages polarization; on-site antibiotic delivery; poly(N-acryloyl amino acid)
  2. Acta Biomater. 2022 Jan 24. pii: S1742-7061(22)00056-3. [Epub ahead of print]
      Mounting evidence shows that tumor hypoxia stress promotes tumor invasion and metastasis and induces therapeutic resistance. Oxygen-independent Fenton reaction, which refers to the iron-catalyzed conversion of endogenous hydrogen peroxide (H2O2) to hydroxyl radical (•OH), has been designed for ferroptosis therapy. Nevertheless, the treatment efficiency is compromised by limited H2O2 content and limited tumor retention and penetration of nanoparticles. Herein, we designed a tumor-acidity and bioorthogonal chemistry mediated construction and deconstruction of drug depots for tumor ferroptosis under normoxia and hypoxia. Briefly, the dendritic poly(amidoamine) (PAMAM, G4) was modified using cinnamaldehyde (CA) to deplete GSH and increase H2O2 levels, and ferrocene (Ferr) served as Fenton reaction catalyst to generate PFC. Subsequently, PFC was modified with maleic acid amide with slow pH-response rate and poly(2-azepane ethyl methacrylate) (PAEMA) with rapid pH-response rate, accompanied with highly efficient bioorthogonal chemistry to construct and deconstruct drug depots for enhanced tumor retention and penetration. The small-sized PFC potentially induced H2O2 self-supplied ferroptosis under normoxia and hypoxia. In sum, this work utilizes two tumoral acidity-responsive groups with different response rates and highly efficient bioorthogonal click chemistry, which paves a way for ferroptosis and provides a general drug delivery strategy with enhanced tumor retention and penetration. STATEMENT OF SIGNIFICANCE: : Oxygen independent Fenton reaction refers to the conversion of endogenous H2O2 to •OH which has been designed for ferroptosis therapy. Nevertheless, limited H2O2 level and abundant GSH in tumor cells could both compromise the treatment efficiency. Herein, we developed a tumor-acidity and bioorthogonal chemistry mediated construction and deconstruction of drug depots, which elevate the intracellular H2O2 level and deplete GSH for tumor ferroptosis under normoxia and hypoxia microenvironment. This work utilizes two tumoral acidity response groups with different response rates and highly efficient bioorthogonal click reactions, which paves a way for tumor cell ferroptosis and provides a general drug delivery strategy for enhanced tumor accumulation and penetration.
    Keywords:  Bioorthogonal chemistry; drug delivery; ferroptosis; pH-response; tumor penetration
  3. J Biomed Mater Res A. 2022 Jan 25.
      Lipid nanoparticles (LNPs) play a crucial role in delivering messenger RNA (mRNA) therapeutics for clinical applications, including COVID-19 mRNA vaccines. While mRNA can be chemically modified to become immune-silent and increase protein expression, LNPs can still trigger innate immune responses and cause inflammation-related adverse effects. Inflammation can in turn suppress mRNA translation and reduce the therapeutic effect. Dexamethasone (Dex) is a widely used anti-inflammatory corticosteroid medication that is structurally similar to cholesterol, a key component of LNPs. Here, we developed LNP formulations with anti-inflammatory properties by partially substituting cholesterol with Dex as a means to reduce inflammation. We demonstrated that Dex-incorporated LNPs effectively abrogated the induction of tumor necrosis factor alpha (TNF-ɑ) in vitro and significantly reduced its expression in vivo. Reduction of inflammation using this strategy improved in vivo mRNA expression in mice by 1.5-fold. Thus, we envision that our Dex-incorporated LNPs could potentially be used to broadly to reduce the inflammatory responses of LNPs and enhance protein expression of a range of mRNA therapeutics.
    Keywords:  anti-inflammation; dexamethasone; gene delivery; lipid nanoparticles; mRNA
  4. Adv Mater. 2022 Jan 22. e2109609
      DNA materials have emerged as potential nanocarriers for targeted cancer therapy with superior biological applications to precisely deliver cargo with specific purpose. However, many DNA carriers have constrained ability to carry sufficient dose of drugs, and their short half-life and low bioavailability due to the interception by the reticuloendothelial system and blood clearance further limit their clinical translations. To address these issues, our study employed a HER2-targeted DNA aptamer modified tetrahedral framework nucleic acid (HApt-tFNA) as a drug delivery system, and combined maytansine (DM1) and HApt-tFNA to develop the HApt-DNA tetrahedron/DM1 conjugate (HApt-tFNA@DM1, HTD, HApDC) nanomedicine for targeted therapy of HER2-positive cancer. To optimize the pharmacokinetics and tumor-aggregation of HTD, a biomimetic camouflage was applied to embed HTD. The biomimetic camouflage was constructed by merging the red blood cell (RBC) membrane with pH-responsive functionalized synthetic liposomes thus with excellent performance of chemotherapeutic drug delivery and tumor-stimulated drug release. In xenograft mice models, the hybrid erythrosome-based nanoparticles showed better inhibition of HER2-positive cancer than other drug formulations. More importantly, not like other therapeutics, this novel nanomedicine exhibited superior biosafety and did not induce any overt side effects. With the strengths of precise delivery, increased drug loading, more sensitive tumor probing and prolonged circulation time to exert long-lasting anti-tumor effects, the HApDC represents a promising nanomedicine to treat HER2-positive tumors. Notably, this study is the first to develop a dual-targeting nanoparticle by combining pH-sensitive biomimetic camouflage and HApDC, initiating an important step towards the developments and applications of DNA-based medicine and biomimetic cell membrane materials in cancer treatment and other potential biological applications in the future. This article is protected by copyright. All rights reserved.
    Keywords:  Anti-HER2 aptamer; DNA tetrahedra nanostructures; HER2-positive breast cancer; Maytansine; Red blood cell membrane
  5. J Control Release. 2022 Jan 22. pii: S0168-3659(22)00037-2. [Epub ahead of print]
      Local, sustained drug delivery of potent therapeutics holds promise for the treatment of a myriad of localized diseases while eliminating systemic side effects. However, introduction of drug delivery depots such as viscous hydrogels or polymer-based implants is highly limited in stiff tissues such as desmoplastic tumors. Here, we present a method to create materials-free intratumoral drug depots through Tissue-Reactive Anchoring Pharmaceuticals (TRAPs). TRAPs diffuse into tissue and attach locally for sustained drug release. In TRAPs, potent drugs are modified with ECM-reactive groups and then locally injected to quickly react with accessible amines within the ECM, creating local drug depots. We demonstrate that locally injected TRAPs create dispersed, stable intratumoral depots deep within mouse and human pancreatic tumor tissues. TRAPs depots based on ECM-reactive paclitaxel (TRAP paclitaxel) had better solubility than free paclitaxel and enabled sustained in vitro and in vivo drug release. TRAP paclitaxel induced higher tumoral apoptosis and sustained better antitumor efficacy than the free drug. By providing continuous drug access to tumor cells, this material-free approach to sustained drug delivery of potent therapeutics has the potential in a wide variety of diseases where current injectable depots fall short.
    Keywords:  Extracellular matrix; Materials-free delivery; N-hydroxysuccinimide ester; Paclitaxel; Pancreatic cancer; Sustained release
  6. Nano Lett. 2022 Jan 24.
      Inefficient tumor accumulation and penetration remain as the main challenges to therapy efficacy of lung cancer. Local delivery of smart nanoclusters can increase drug penetration and provide superior antitumor effects than systemic routes. Here, we report self-assembled pH-sensitive superparamagnetic iron oxide nanoclusters (SPIONCs) that enhance in situ ferroptosis and apoptosis with radiotherapy and chemodynamic therapy. After pulmonary delivery in orthotopic lung cancer, SPIONCs disintegrate into smaller nanoparticles and release more iron ions in an acidic microenvironment. Under single-dose X-ray irradiation, endogenous superoxide dismutase converts superoxide radicals produced by mitochondria to hydrogen peroxide, which in turn generates hydroxyl radicals by the Fenton reaction from iron ions accumulated inside the tumor. Finally, irradiation and iron ions enhance tumor lipid peroxidation and induce cell apoptosis and ferroptosis. Thus, rationally designed pulmonary delivered nanoclusters provide a promising strategy for noninvasive imaging of lung cancer and synergistic therapy.
    Keywords:  Chemodynamic therapy; Ferroptosis; Lipid peroxide; Lung cancer; Radiotherapy
  7. Adv Mater. 2022 Jan 25. e2108848
      Mucosa is a protective and lubricating barrier in biological tissue, which has a great clinical inspiration because of its slippery, soft, and hydrophilic surface. However, mimicking mucosal traits on complex surface remains an enormous challenge. Herein, a novel approach to create mucosa-like conformal hydrogel coating is developed. A thin conformal hydrogel layer mimicking the epithelial layer is obtained by first absorbing micelles, followed by forming covalent interlinks with the polymer substrate via interface-initiated hydrogel polymerization. The resulting coating exhibits uniform thickness (∼ 15 μm), mucosa-matched compliance (Young's modulus = 1.1 ± 0.1 kPa) and lubrication (coefficients of friction = 0.018 ± 0.003), robust interfacial bonding against peeling (peeling strength = 1218.0 ± 187.9 J m-2 ), as well as high water absorption capacity. It effectively resists adhesion of proteins and bacteria without compromising biocompatibility. As demonstrated by a in vivo cynomolgus monkey model and clinical trial, applications of the mucosa-like conformal hydrogel coating on the endotracheal tube significantly reduces intubation-related complications, such as invasive stimuli, mucosal lesions, laryngeal oedema, inflammation, and postoperative pain. This work offers a promising prototype for surface decoration of biomedical devices and holds great prospects for clinical translation to enable interventional operations with minimally invasive impacts . This article is protected by copyright. All rights reserved.
    Keywords:  aqueous lubrication; conformal decoration; hydrogel coatings; mechanical match; mucosa
  8. Proc Natl Acad Sci U S A. 2022 Jan 25. pii: e2115523119. [Epub ahead of print]119(4):
      The exceptional elastic resilience of some protein materials underlies essential biomechanical functions with broad interest in biomedical fields. However, molecular design of elastic resilience is restricted to amino acid sequences of a handful of naturally occurring resilient proteins such as resilin and elastin. Here, we exploit non-resilin/elastin sequences that adopt kinetically stabilized, random coil-dominated conformations to achieve near-perfect resilience comparable with that of resilin and elastin. We also show a direct correlation between resilience and Raman-characterized protein conformations. Furthermore, we demonstrate that metastable conformation of proteins enables the construction of mechanically graded protein materials that exhibit spatially controlled conformations and resilience. These results offer insights into molecular mechanisms of protein elastomers and outline a general conformation-driven strategy for developing resilient and functional protein materials.
    Keywords:  conformation; elasticity; polymorphism; protein; silk
  9. J Control Release. 2022 Jan 22. pii: S0168-3659(22)00041-4. [Epub ahead of print]
      Lipid Nanoparticles (LNPs) are a promising drug delivery vehicle for clinical siRNA delivery. Modified mRNA (modRNA) has recently gained great attention as a therapeutic molecule in cardiac regeneration. However, for mRNA to be functional, it must first reach the diseased myocardium, enter the target cell, escape from the endosomal compartment into the cytosol and be translated into a functional protein. However, it is unknown if LNPs can effectively deliver mRNA, which is much larger than siRNA, to the ischemic myocardium. Here, we evaluated the ability of LNPs to deliver mRNA to the myocardium upon ischemia-reperfusion injury functionally. By exploring the bio-distribution of fluorescently labeled LNPs, we observed that, upon reperfusion, LNPs accumulated in the infarct area of the heart. Subsequently, the functional delivery of modRNA was evaluated by the administration of firefly luciferase encoding modRNA. Concomitantly, a significant increase in firefly luciferase expression was observed in the heart upon myocardial reperfusion when compared to sham-operated animals. To characterize the targeted cells within the myocardium, we injected LNPs loaded with Cre modRNA into Cre-reporter mice. Upon LNP infusion, Tdtomato+ cells, derived from Cre mediated recombination, were observed in the infarct region as well as the epicardial layer upon LNP infusion. Within the infarct area, most targeted cells were cardiac fibroblasts but also some cardiomyocytes and macrophages were found. Although the expression levels were low compared to LNP-modRNA delivery into the liver, our data show the ability of LNPs to functionally deliver modRNA therapeutics to the damaged myocardium, which holds great promise for modRNA-based cardiac therapies.
    Keywords:  Lipid nanoparticles; Modified modRNA; Myocardial infarction; Reperfusion injury; Systemic delivery
  10. Angew Chem Int Ed Engl. 2022 Jan 25.
      The lowly expressed analyte in complex cytoplasmic milieu necessitates the development of non-enzymatic autocatalytic DNA circuits with high amplification and anti-interference performance. Herein, we engineered a versatile and robust stimuli-responsive autocatalytic hybridization assembly (AHA) circuit for high performance in vivo bioanalysis. Under a moderately confined condition, the initiator motivated the autonomous and cooperative cross-activation of cascade hybridization reaction and catalytic DNA assembly for generating an exponentially amplified readout without the parasite steric hindrance and random diffusion side effects. The AHA circuit was systematically investigated by a series of experimental studies and theoretical simulations. The successively guaranteed target-recognition and synergistically accelerated signal-amplification enables the sensitive and selective detection of analyte, and realized the robust miRNA imaging in living cells and mice. This autocatalytic DNA circuit could substantially expand the toolbox for accurate diagnosis and programmable therapeutics.
    Keywords:  Autocatalysis; DNA circuit; fluorescence; imaging; microRNA
  11. Biomaterials. 2022 Jan 05. pii: S0142-9612(22)00003-5. [Epub ahead of print]281 121364
      Delivering drugs directly to the inflamed intestinal sites to treat inflammatory bowel disease (IBD), particularly Crohn's and ulcerative colitis, is highly challenging. Recent advances in colitis therapy medications are expanding opportunities for improving local on-site drug availability by minimising the associated systemic side-effects. Drug delivery with targeted carrier systems has shown the potential to increase site-specificity, stability, and therapeutic efficacy. Herein, we report the development of a strong anionic charged inflammation targeted nanocarriers (IT-NCs) loaded with an immunosuppressant model drug. This system showed preferential adhesion on a charge-modified surface in vitro, and in both dextran sulfate sodium (DSS) and TNBS colitis mice in vivo models. IT-NCs showed improved colitis phenotype therapeutic efficacy in both animal models compared to free drug. Furthermore, ex vivo study of colon tissue biopsies from patients with colitis revealed that IT-NCs adhered preferentially to inflamed biopsies compared to normal. Together, our results suggest that IT-NCs have promising therapeutic potential as delivery carriers' in colitis management.
    Keywords:  Drug delivery; Hyaluronan; Inflammatory bowel disease; Targeted nanocarriers; Ulcerative colitis
  12. Adv Mater. 2022 Jan 22. e2109394
      Four-dimensional (4D) bioprinting is promising to build cell-laden constructs (bioconstructs) with complex geometries and functions for tissue/organ regeneration applications. The development of hydrogel-based 4D bioinks, especially those allowing living cell printing, with easy preparation, defined composition, and controlled physical properties is critically important for 4D bioprinting. Here, a single-component jammed micro-flake hydrogel (MFH) system with heterogeneous size distribution, which differs from the conventional granular microgel, has been developed as a new cell-laden bioink for 4D bioprinting. This jammed cytocompatible MFH features scalable production and straightforward composition with shear-thinning, shear-yielding, and rapid self-healing properties. As such, it can be smoothly printed into stable 3D bioconstructs, which can be further crosslinked to form a gradient in crosslinking density when a photoinitiator and a UV absorber are incorporated. After being subject to shape morphing, a variety of complex bioconstructs with well-defined configurations and high cell viability were obtained. Based on this system, 4D cartilage-like tissue formation was demonstrated as a proof-of-concept. The establishment of this versatile new 4D bioink system may open up a number of applications in tissue engineering. This article is protected by copyright. All rights reserved.
    Keywords:  4D printing; bioink; crosslinking gradient; shape morphing; tissue engineering
  13. Sci Adv. 2022 Jan 28. 8(4): eabh0496
      The endoplasmic reticulum (ER)-localized stimulator of interferon genes (STING) is the core adaptor for the pathogenic-DNA-triggered innate response. Aberrant activation of STING causes autoinflammatory and autoimmune diseases, raising the concern about how STING is finely tuned during innate response to pathogenic DNAs. Here, we report that the transmembrane domain (TM)-containing ER-localized E3 ubiquitin ligase TRIM13 (tripartite motif containing 13) is required for restraining inflammatory response to pathogenic DNAs. TRIM13 deficiency enhances pathogenic-DNA-triggered inflammatory cytokine production, inhibits DNA virus replication, and causes age-related autoinflammation. Mechanistically, TRIM13 interacts with STING via the TM and catalyzes Lys6-linked polyubiquitination of STING, leading to decelerated ER exit and accelerated ER-initiated degradation of STING. STING deficiency reverses the enhanced innate anti-DNA virus response in TRIM13 knockout mice. Our study delineates a potential strategy for controlling the homeostasis of STING by transmembrane ER-associated TRIM13 during the pathogenic-DNA-triggered inflammatory response.
  14. Sci Adv. 2022 Jan 28. 8(4): eabl8379
      Mechanical regulation and electric stimulation hold great promise in skin tissue engineering for manipulating wound healing. However, the complexity of equipment operation and stimulation implementation remains an ongoing challenge in clinical applications. Here, we propose a programmable and skin temperature-activated electromechanical synergistic wound dressing composed of a shape memory alloy-based mechanical metamaterial for wound contraction and an antibacterial electret thin film for electric field generation. This strategy is successfully demonstrated on rats to achieve effective wound healing in as short as 4 and 8 days for linear and circular wounds, respectively, with a statistically significant over 50% improvement in wound closure rate versus the blank control group. The optimally designed electromechanical synergistic stimulation could regulate the wound microenvironment to accelerate healing metabolism, promote wound closure, and inhibit infection. This work provided an effective wound healing strategy in the context of a programmable temperature-responsive, battery-free electromechanical synergistic biomedical device.