bims-drudre 2021-08-29 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2021–08–29
twelve papers selected by
Ceren Kimna, Technical University of Munich

Macrophage-Disguised Manganese Dioxide Nanoparticles for Neuroprotection by Reducing Oxidative Stress and Modulating Inflammatory Microenvironment in Acute Ischemic Stroke.
Selective Thrombosis of Tumor for Enhanced Hypoxia-Activated Prodrug Therapy.
Visible-Light-Driven Photocatalysis-Enhanced Nanozyme of TiO2 Nanotubes@MoS2 Nanoflowers for Efficient Wound Healing Infected with Multidrug-Resistant Bacteria.
Pathologically Responsive Mitochondrial Gene Therapy in an Allotopic Expression-Independent Manner Cures Leber's Hereditary Optic Neuropathy.
Multifunctional Parachute-like Nanomotors for Enhanced Skin Penetration and Synergistic Antifungal Therapy.
Immune Microenvironment Landscape in CNS Tumors and Role in Responses to Immunotherapy.
An Injectable Meta-Biomaterial: From Design and Simulation to In Vivo Shaping and Tissue induction.
Dysregulation of miRNAs Targeting the IGF-1R Pathway in Pancreatic Ductal Adenocarcinoma.
High Antibacterial Activity and Selectivity of the Versatile Polysulfoniums that Combat Drug Resistance.
Tuning the Elasticity of Polymersomes for Brain Tumor Targeting.
Implantable optical fibers for immunotherapeutics delivery and tumor impedance measurement.
Autonomous DNA nanostructures instructed by hierarchically concatenated chemical reaction networks.

Adv Sci (Weinh). 2021 Aug 26. e2101526

Macrophage-Disguised Manganese Dioxide Nanoparticles for Neuroprotection by Reducing Oxidative Stress and Modulating Inflammatory Microenvironment in Acute Ischemic Stroke.

Chao Li, Zhenhao Zhao, Yifan Luo, Tingting Ning, Peixin Liu, Qinjun Chen, Yongchao Chu, Qin Guo, Yiwen Zhang, Wenxi Zhou, Hongyi Chen, Zheng Zhou, Yu Wang, Boyu Su, Haoyu You, Tongyu Zhang, Xuwen Li, Haolin Song, Chufeng Li, Tao Sun, Chen Jiang.

  Reperfusion injury is still a major challenge that impedes neuronal survival in ischemic stroke. However, the current clinical treatments are remained on single pathological process, which are due to lack of comprehensive neuroprotective effects. Herein, a macrophage-disguised honeycomb manganese dioxide (MnO2 ) nanosphere loaded with fingolimod (FTY) is developed to salvage the ischemic penumbra. In particular, the biomimetic nanoparticles can accumulate actively in the damaged brain via macrophage-membrane protein-mediated recognition with cell adhesion molecules that are overexpressed on the damaged vascular endothelium. MnO2 nanosphere can consume excess hydrogen peroxide (H2 O2 ) and convert it into desiderated oxygen (O2 ), and can be decomposed in acidic lysosome for cargo release, so as to reduce oxidative stress and promote the transition of M1 microglia to M2 type, eventually reversing the proinflammatory microenvironment and reinforcing the survival of damaged neuron. This biomimetic nanomedicine raises new strategy for multitargeted combined treatment of ischemic stroke.

Keywords:  O2 generation; biomimetic nanoparticles; inflammatory microenvironment; microglia polarization; neuroprotection; reactive oxygen species (ROS) consumption; reperfusion injury

DOI:  https://doi.org/10.1002/advs.202101526
Adv Mater. 2021 Aug 26. e2104504

Selective Thrombosis of Tumor for Enhanced Hypoxia-Activated Prodrug Therapy.

Zhaoyu Ma, Yifan Zhang, Xinxin Dai, Weiyun Zhang, Mohamed F Foda, Jin Zhang, Yanli Zhao, Heyou Han.

  One of the main challenges for tumor vascular infarction in combating cancer lies in failing to produce sustained complete thrombosis. Inspired by the capability of vascular infarction in blocking the delivery of oxygen to aggravate tumor hypoxia, the performance of selective tumor thrombus inducing hypoxia activation therapy to improve the therapeutic index of coagulation-based tumor therapy is presented. By encapsulating coagulation-inducing protease thrombin and a hypoxia-activated prodrug (HAP) tirapazamine into metal-organic framework nanoparticles with a tumor-homing ligand, the obtained nanoplatform selectively activates platelet aggregation at the tumor to induce thrombosis and vascular obstruction therapy by the exposed thrombin. Meanwhile, the thrombus can cut off the blood oxygen supply and potentiate the hypoxia levels to enhance the HAP therapy. This strategy not only addresses the dissatisfaction of vascular therapy, but also conquers the dilemma of inadequate hypoxia in HAP treatment. Since clinical operations such as surgery can be used to induce coagulation, coagulation-based synergistic therapy is promising for translation into a clinical combination regimen.

Keywords:  cancer treatment; metal-organic frameworks; prodrug therapy; thrombosis; tumor hypoxia

DOI:  https://doi.org/10.1002/adma.202104504
Small. 2021 Aug 21. e2103348

Visible-Light-Driven Photocatalysis-Enhanced Nanozyme of TiO2 Nanotubes@MoS2 Nanoflowers for Efficient Wound Healing Infected with Multidrug-Resistant Bacteria.

Yu Lin, Xiangyong Liu, Zengxu Liu, Yuanhong Xu.

  To enhance the catalytic activity of the nanozymes for efficient wound healing infected with multidrug-resistant bacteria, photo-based motivations have been suggested, but attention is mainly focused on the external stimulus of near-infrared light, while the inexhaustible visible one is promising but lack of study. Herein, an efficient visible light-stimulated peroxidase-like nanozyme system, TiO2 nanotubes coated with MoS2 nanoflowers (TiO2 NTs@MoS2 ), is discovered for efficient bacterial treatment. Based on the synergetic effects between the two components, the bandgap of the TiO2 NTs can be narrowed from 3.2 to 2.97 eV due to the MoS2 loading, which extended the light response of TiO2 to visible-light range and enhanced the photocatalytic activity accordingly. Meanwhile, the peroxidase-like activity of MoS2 can be significantly enhanced due to the combination with TiO2 NTs in return. Especially, the peroxidase-like activity of the TiO2 NTs@MoS2 nanocomposite can be further improved under the sunlight irradiation, rendering much more hydroxyl radical (•OH) generation. Accordingly, the as-obtained TiO2 NTs@MoS2 shows an outstanding antibacterial effect against drug-resistance extended spectrum β-lactamases producing Escherichia coli and methicillin-resistant Staphylococcus aureus under the visible light. In vivo wound healing test further confirms the high antimicrobial efficiency and good biocompatibility of the synergistic antimicrobial system.

Keywords:  antimicrobial; enzyme mimics; nanomaterials; photocatalytic; wound healing

DOI:  https://doi.org/10.1002/smll.202103348
Adv Mater. 2021 Aug 25. e2103307

Pathologically Responsive Mitochondrial Gene Therapy in an Allotopic Expression-Independent Manner Cures Leber's Hereditary Optic Neuropathy.

Yi Wang, Li-Fan Hu, Peng-Fei Cui, Lian-Yu Qi, Lei Xing, Hu-Lin Jiang.

  Leber's hereditary optic neuropathy (LHON) is a rare inherited blindness caused by mutations in the mitochondrial DNA (mtDNA). The disorder is untreatable and tricky, as the existing chemotherapeutic agent Idebenone alleviates symptoms rather than overcoming the underlying cause. Although some studies have made progress on allotopic expression for LHON, in situ mitochondrial gene therapy remains challenging, which may simplify delivery procedures to be a promising therapeutic for LHON. LHON becomes more difficult to manage in the changed mitochondrial microenvironment, including increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP). Herein, a pathologically responsive mitochondrial gene delivery vector named [triphenylphosphine-terminated poly(sulfur-containing thioketal undecafluorohexylamine histamine) and Ide-terminated poly(sulfur-containing thioketal undecafluorohexylamine histamine)] (TISUH) is reported to facilitate commendable in situ mitochondrial gene therapy for LHON. TISUH directly targets diseased mitochondria via triphenylphosphine and fluorination addressing the decreasing MMP. In addition, TISUH can be disassembled by high mitochondrial ROS levels to release functional genes for enhancing gene transfection efficiency and fundamentally correcting genetic abnormalities. In both traditional and gene-mutation-induced LHON mouse models, TISUH-mediated gene therapy shows satisfactory curative effect through the sustained therapeutic protein expression in vivo. This work proposes a novel pathologically responsive in situ mitochondrial delivery platform and provides a promising approach for refractory LHON as well as other mtDNA mutated diseases treatments.

Keywords:  Idebenone; Leber's hereditary optic neuropathy; fluorination; in situ mitochondrial gene therapy; pathologically responsive polymers

DOI:  https://doi.org/10.1002/adma.202103307
ACS Nano. 2021 Aug 26.

Multifunctional Parachute-like Nanomotors for Enhanced Skin Penetration and Synergistic Antifungal Therapy.

Xin Ji, Haiyuan Yang, Wen Liu, Yandong Ma, Jinpei Wu, Xiaoqing Zong, Pengfei Yuan, Xinjie Chen, Caiqi Yang, Xiaodi Li, Hongsheng Lin, Wei Xue, Jian Dai.

  Fungal infections in skin are extremely stubborn and seriously threaten human health. In the process of antifungal treatment, it is a huge challenge that the stratum corneum of the skin and fungal biofilms form the drug transport barrier. Herein, a near-infrared (NIR) laser-propelled parachute-like nanomotor loaded with miconazole nitrate (PNM-MN) is fabricated to enhance transdermal drug delivery for synergistic antifungal therapy. Due to asymmetrically spatial distribution, PNM can generate a thermal gradient under NIR laser irradiation, thereby forming effective self-thermophoretic propulsion. The self-propulsion and photothermal effect of PNM play a major role in promoting fungal uptake and biofilm adhesion. Moreover, under laser irradiation, PNM-MN can obliterate plankton Candida albicans and mature biofilms by combining pharmacological therapy and photothermal therapy. More importantly, the drug effectively penetrated the skin to reach the infected site using the nanomotor with NIR laser irradiation. Moreover, PNM-MN with a NIR laser can eradicate fungal infections caused by C. albicans and facilitate the abscess ablation, showing a therapeutic effect in vivo better than that of PNM with a NIR laser or free MN groups, with negligible histological toxicity. Taken together, NIR laser-propelled PNM-MN, as an antifungal nanoagent, provides a promising strategy for transdermal delivery and antifungal therapy.

Keywords:  NIR laser propulsion; enhanced skin penetration; nanomotor; parachute-like nanohybrid; synergistic antifungal therapy

DOI:  https://doi.org/10.1021/acsnano.1c01379
Cells. 2021 Aug 09. pii: 2032. [Epub ahead of print]10(8):

Immune Microenvironment Landscape in CNS Tumors and Role in Responses to Immunotherapy.

Hinda Najem, Mustafa Khasraw, Amy B Heimberger.

  Despite the important evolution of immunotherapeutic agents, brain tumors remain, in general, refractory to immune therapeutics. Recent discoveries have revealed that the glioma microenvironment includes a wide variety of immune cells in various states that play an important role in the process of tumorigenesis. Anti-tumor immune activity may be occurring or induced in immunogenic hot spots or at the invasive edge of central nervous system (CNS) tumors. Understanding the complex heterogeneity of the immune microenvironment in gliomas will likely be the key to unlocking the full potential of immunotherapeutic strategies. An essential consideration will be the induction of immunological effector responses in the setting of the numerous aspects of immunosuppression and evasion. As such, immune therapeutic combinations are a fundamental objective for clinical studies in gliomas. Through immune profiling conducted on immune competent murine models of glioma and ex vivo human glioma tissue, we will discuss how the frequency, distribution of immune cells within the microenvironment, and immune modulatory processes, may be therapeutically modulated to lead to clinical benefits.

Keywords:  CNS metastasis; T cells; glioma; immune checkpoints; immune composition; immune therapy; tumor associated macrophages/microglia; tumor microenvironment

DOI:  https://doi.org/10.3390/cells10082032
Adv Mater. 2021 Aug 27. e2102350

An Injectable Meta-Biomaterial: From Design and Simulation to In Vivo Shaping and Tissue induction.

Amélie Béduer, Fabien Bonini, Connor A Verheyen, Martina Genta, Mariana Martins, Joé Brefie-Guth, Josefine Tratwal, Aleksandra Filippova, Patrick Burch, Olaia Naveiras, Thomas Braschler.

  A novel type of injectable biomaterial with an elastic softening transition is described. The material enables in vivo shaping, followed by induction of 3D stable vascularized tissue. The synthesis of the injectable meta-biomaterial is instructed by extensive numerical simulation as a suspension of irregularly fragmented, highly porous sponge-like microgels. The irregular particle shape dramatically enhances yield strain for in vivo stability against deformation. Porosity of the particles, along with friction between internal surfaces, provides the elastic softening transition. This emergent metamaterial property enables the material to reversibly change stiffness during deformation, allowing native tissue properties to be matched over a wide range of deformation amplitudes. After subcutaneous injection in mice, predetermined shapes can be sculpted manually. The 3D shape is maintained during excellent host tissue integration, with induction of vascular connective tissue that persists to the end of one-year follow-up. The geometrical design is compatible with many hydrogel materials, including cell-adhesion motives for cell transplantation. The injectable meta-biomaterial therefore provides new perspectives in soft tissue engineering and regenerative medicine.

Keywords:  elastic softening; injectable metamaterials; shaping; tissue reconstruction; vascularization

DOI:  https://doi.org/10.1002/adma.202102350
Cells. 2021 Jul 22. pii: 1856. [Epub ahead of print]10(8):

Dysregulation of miRNAs Targeting the IGF-1R Pathway in Pancreatic Ductal Adenocarcinoma.

Maria Dobre, Vlad Herlea, Cătălina Vlăduţ, Mihai Ciocîrlan, Vasile Daniel Balaban, Gabriel Constantinescu, Mircea Diculescu, Elena Milanesi.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), the most prevalent neoplastic lethal pancreatic disease, has a poor prognosis and an increasing incidence. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is considered to be a contributing factor to the progression, metastasis, and therapy resistance of PDAC. Currently available treatment options for PDAC are limited, but microRNAs (miRNAs) may represent a new therapeutic strategy for targeting genes involved in the IGF-1R signaling pathway.
METHOD: We investigated the expression levels of 21 miRNAs involved in the IGF-1R signaling pathway in pancreatic tissue from 38 patients with PDAC and 11 controls (five patients with chronic pancreatitis and six patients with normal pancreatic tissue).
RESULTS: We found 19 differentially expressed miRNAs between the PDAC cases and the controls. In particular, miR-100-5p, miR-145-5p, miR-29c-3p, miR-9-5p, and miR-195-5p were exclusively downregulated in PDAC tissue but not in chronic pancreatitis or normal pancreatic tissues; both control types presented similar levels. We also identified miR-29a-3p, miR-29b-3p, and miR-7-5p as downregulated miRNAs in PDAC tissues as compared with normal tissues but not with pancreatitis tissues.
CONCLUSIONS: We identified a panel of miRNAs that could represent putative therapeutic targets for the development of new miRNA-based therapies for PDAC.

Keywords:  IGF-1R; adenocarcinoma; microRNA; pancreas

DOI:  https://doi.org/10.3390/cells10081856
Adv Mater. 2021 Aug 26. e2104402

High Antibacterial Activity and Selectivity of the Versatile Polysulfoniums that Combat Drug Resistance.

Jing Sun, Min Li, Min Lin, Bo Zhang, Xuesi Chen.

  Sulfonium-ion-containing polymers exhibit significant potential benefits for various applications. An efficient strategy to synthesize a type of antibacterial sulfonium-ion-bearing polypeptoids via a combination of ring-opening polymerization and a post-polymerization functionalization with various functional epoxides is presented. A systematic investigation is further performed in order to explore the influence of the overall hydrophobic/hydrophilic balance on the antimicrobial activity and selectivity of the prepared polysulfoniums. Notably, those chlorepoxypropane-modified polysulfoniums with an optimized amphiphilic balance show higher selectivity toward both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus, than to red blood cells. The polymers also show great efficiency in inhibiting S. aureus biofilm formations, as well as in further eradicating the mature biofilms. Remarkably, negligible antibacterial resistance and cross-resistance to commercial antibiotics is shown in these polymers. The polysulfoniums further show their potent in vivo antimicrobial efficacy in a multidrug-resistant S. aureus infection model that is developed on mouse skin. Similar to the antimicrobial peptides, the polysulfoniums are demonstrated to kill bacteria through membrane disruption. The obtained polypeptoid sulfoniums, with high selectivity and potent antibacterial property, are excellent candidates for antibacterial treatment and open up new possibilities for the preparation of a class of innovative antimicrobials.

Keywords:  antibacterial activity; antimicrobial peptides; polypeptoids; sulfonium-containing polymers

DOI:  https://doi.org/10.1002/adma.202104402
Adv Sci (Weinh). 2021 Aug 22. e2102001

Tuning the Elasticity of Polymersomes for Brain Tumor Targeting.

Meng Zheng, Qiuli Du, Xin Wang, Yuan Zhou, Jia Li, Xue Xia, Yiqing Lu, Jinlong Yin, Yan Zou, Jong Bae Park, Bingyang Shi.

  Nanoformulations show great potential for delivering drugs to treat brain tumors. However, how the mechanical properties of nanoformulations affect their ultimate brain destination is still unknown. Here, a library of membrane-crosslinked polymersomes with different elasticity are synthesized to investigate their ability to effectively target brain tumors. Crosslinked polymersomes with identical particle size, zeta potential and shape are assessed, but their elasticity is varied depending on the rigidity of incorporated crosslinkers. Benzyl and oxyethylene containing crosslinkers demonstrate higher and lower Young's modulus, respectively. Interestingly, stiff polymersomes exert superior brain tumor cell uptake, excellent in vitro blood brain barrier (BBB) and tumor penetration but relatively shorter blood circulation time than their soft counterparts. These results together affect the in vivo performance for which rigid polymersomes exerting higher brain tumor accumulation in an orthotopic glioblastoma (GBM) tumor model. The results demonstrate the crucial role of nanoformulation elasticity for brain-tumor targeting and will be useful for the design of future brain targeting drug delivery systems for the treatment of brain disease.

Keywords:  active targeting; brain tumor; elasticity; polymersomes

DOI:  https://doi.org/10.1002/advs.202102001
Nat Commun. 2021 Aug 26. 12(1): 5138

Implantable optical fibers for immunotherapeutics delivery and tumor impedance measurement.

Ai Lin Chin, Shan Jiang, Eungyo Jang, Liqian Niu, Liwu Li, Xiaoting Jia, Rong Tong.

Immune checkpoint blockade antibodies have promising clinical applications but suffer from disadvantages such as severe toxicities and moderate patient-response rates. None of the current delivery strategies, including local administration aiming to avoid systemic toxicities, can sustainably supply drugs over the course of weeks; adjustment of drug dose, either to lower systemic toxicities or to augment therapeutic response, is not possible. Herein, we develop an implantable miniaturized device using electrode-embedded optical fibers with both local delivery and measurement capabilities over the course of a few weeks. The combination of local immune checkpoint blockade antibodies delivery via this device with photodynamic therapy elicits a sustained anti-tumor immunity in multiple tumor models. Our device uses tumor impedance measurement for timely presentation of treatment outcomes, and allows modifications to the delivered drugs and their concentrations, rendering this device potentially useful for on-demand delivery of potent immunotherapeutics without exacerbating toxicities.

DOI: https://doi.org/10.1038/s41467-021-25391-z
Nat Commun. 2021 Aug 26. 12(1): 5132

Autonomous DNA nanostructures instructed by hierarchically concatenated chemical reaction networks.

Jie Deng, Andreas Walther.

Concatenation and communication between chemically distinct chemical reaction networks (CRNs) is an essential principle in biology for controlling dynamics of hierarchical structures. Here, to provide a model system for such biological systems, we demonstrate autonomous lifecycles of DNA nanotubes (DNTs) by two concatenated CRNs using different thermodynamic principles: (1) ATP-powered ligation/restriction of DNA components and (2) input strand-mediated DNA strand displacement (DSD) using energy gains provided in DNA toeholds. This allows to achieve hierarchical non-equilibrium systems by concurrent ATP-powered ligation-induced DSD for activating DNT self-assembly and restriction-induced backward DSD reactions for triggering DNT degradation. We introduce indirect and direct activation of DNT self-assemblies, and orthogonal molecular recognition allows ATP-fueled self-sorting of transient multicomponent DNTs. Coupling ATP dissipation to DNA nanostructures via programmable DSD is a generic concept which should be widely applicable to organize other DNA nanostructures, and enable the design of automatons and life-like systems of higher structural complexity.

DOI: https://doi.org/10.1038/s41467-021-25450-5