bims-drudre 2021-12-26 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2021–12–26
eleven papers selected by
Ceren Kimna, Technical University of Munich

On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles.
Anti-MicroRNA-21 Oligonucleotide Loaded Spermine-Modified Acetalated Dextran Nanoparticles for B1 Receptor-Targeted Gene Therapy and Antiangiogenesis Therapy.
Exosomes derived from immunogenically dying tumor cells as a versatile tool for vaccination against pancreatic cancer.
Self-Assembled Peptide Amphiphile Nanofibers for Controlled Therapeutic Delivery to the Atherosclerotic Niche.
Spatiotemporal Control of Molecular Cascade Reactions by a Reconfigurable DNA Origami Domino Array.
Intracellular Self-Immolative Polyprodrug with Near-Infrared Light Guided Accumulation and in Vivo Visualization of Drug Release.
Support Bath-Free Vertical Extrusion Cryo(bio)printing for Anisotropic Tissue Manufacturing.
Design of Smart Size-, Surface-, and Shape-Switching Nanoparticles to Improve Therapeutic Efficacy.
Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue.
The Impact of MicroRNAs during Inflammatory Bowel Disease: Effects on the Mucus Layer and Intercellular Junctions for Gut Permeability.
Spatial discordances between mRNAs and proteins in the intestinal epithelium.

Proc Natl Acad Sci U S A. 2021 Dec 28. pii: e2109256118. [Epub ahead of print]118(52):

On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles.

Sean A Dilliard, Qiang Cheng, Daniel J Siegwart.

  Lipid nanoparticles (LNPs) are a clinically mature technology for the delivery of genetic medicines but have limited therapeutic applications due to liver accumulation. Recently, our laboratory developed selective organ targeting (SORT) nanoparticles that expand the therapeutic applications of genetic medicines by enabling delivery of messenger RNA (mRNA) and gene editing systems to non-liver tissues. SORT nanoparticles include a supplemental SORT molecule whose chemical structure determines the LNP's tissue-specific activity. To understand how SORT nanoparticles surpass the delivery barrier of liver hepatocyte accumulation, we studied the mechanistic factors which define their organ-targeting properties. We discovered that the chemical nature of the added SORT molecule controlled biodistribution, global/apparent pKa, and serum protein interactions of SORT nanoparticles. Additionally, we provide evidence for an endogenous targeting mechanism whereby organ targeting occurs via 1) desorption of poly(ethylene glycol) lipids from the LNP surface, 2) binding of distinct proteins to the nanoparticle surface because of recognition of exposed SORT molecules, and 3) subsequent interactions between surface-bound proteins and cognate receptors highly expressed in specific tissues. These findings establish a crucial link between the molecular composition of SORT nanoparticles and their unique and precise organ-targeting properties and suggest that the recruitment of specific proteins to a nanoparticle's surface can enable drug delivery beyond the liver.

Keywords:  endogenous targeting; gene editing; lipid nanoparticles; mRNA delivery

DOI:  https://doi.org/10.1073/pnas.2109256118
Adv Sci (Weinh). 2021 Dec 22. e2103812

Anti-MicroRNA-21 Oligonucleotide Loaded Spermine-Modified Acetalated Dextran Nanoparticles for B1 Receptor-Targeted Gene Therapy and Antiangiogenesis Therapy.

Tao Zheng, Wentao Wang, Mohsen Mohammadniaei, Jon Ashley, Ming Zhang, Ninglin Zhou, Jian Shen, Yi Sun.

  The use of nanoparticles (NPs) to deliver small inhibiting microRNAs (miRNAs) has shown great promise for treating cancer. However, constructing a miRNA delivery system that targets brain cancers, such as glioblastoma multiforme (GBM), remains technically challenging due to the existence of the blood-tumor barrier (BTB). In this work, a novel targeted antisense miRNA-21 oligonucleotide (ATMO-21) delivery system is developed for GBM treatment. Bradykinin ligand agonist-decorated spermine-modified acetalated dextran NPs (SpAcDex NPs) could temporarily open the BTB by activating G-protein-coupled receptors that are expressed in tumor blood vessels and tumor cells, which increase transportation to and accumulation in tumor sites. ATMO-21 achieves high loading in the SpAcDex NPs (over 90%) and undergoes gradual controlled release with the degradation of the NPs in acidic lysosomal compartments. This allows for cell apoptosis and inhibition of the expression of vascular endothelial growth factor by downregulating hypoxia-inducible factor (HIF-1α) protein. An in vivo orthotopic U87MG glioma model confirms that the released ATMO-21 shows significant therapeutic efficacy in inhibiting tumor growth and angiogenesis, demonstrating that agonist-modified SpAcDex NPs represent a promising strategy for GBM treatment combining targeted gene therapy and antiangiogenic therapy.

Keywords:  anti-microRNA-21 oligonucleotide; antiangiogenesis therapy; gene therapy; glioblastoma multiforme; targeted delivery

DOI:  https://doi.org/10.1002/advs.202103812
Biomaterials. 2021 Dec 02. pii: S0142-9612(21)00662-1. [Epub ahead of print]280 121306

Exosomes derived from immunogenically dying tumor cells as a versatile tool for vaccination against pancreatic cancer.

Wenxi Zhou, Xinli Chen, Yu Zhou, Si Shi, Chen Liang, Xianjun Yu, Hongyi Chen, Qin Guo, Yiwen Zhang, Peixin Liu, Chao Li, Yongchao Chu, Yifan Luo, Yu Wang, Zheng Zhou, Zhenhao Zhao, Qinjun Chen, Tao Sun, Chen Jiang.

  Despite tremendous progress achieved in immunotherapy, many critical challenges in treating pancreatic ductal adenocarcinoma (PDAC) persist. Considering the poor vascularization of PDAC, after intramuscular administration exosomes can targeted deliver "cargos" to pancreatic tumors and bypass obstructions of the intrinsic overexpressed stroma through lymphatics. Herein, we propose a strategy to derive exosomes from immunogenically dying tumor cells and exploit their properties for several purposes, including antigen presentation, adjuvant supply, and "cargo" delivery of vaccines against pancreatic cancer via intramuscular injection. To enhance the immunostimulatory effects, the MART-1 peptide is modified to the exosomes to expand T-cell-related responses. Furthermore, CCL22 siRNA is electroporated into the exosomes (referred to as spMEXO) to hinder the CCR4/CCL22 axis between DCs and Tregs, thereby suppressing Treg expansion. Both in vitro and in vivo studies demonstrate that spMEXO can serve as an effective prophylactic vaccine to delay tumor growth, whereas combining spMEXO with PDAC first-line chemotherapeutics (co-administration of gemcitabine with albumin-paclitaxel) demonstrated significantly enhanced therapeutic effects in established PANC-02 tumors. Therefore, the present work provides an effective strategy to employ cancer vaccines through intramuscular injection in PDAC and highlights the potential of exosomes derived from immunogenically dying tumor cells as a versatile tool to develop nanovaccines for immunotherapy.

Keywords:  CCR4/CCL22 axis; Exosomes; Lymphatics; Nanovaccines; Pancreatic cancer immunotherapy

DOI:  https://doi.org/10.1016/j.biomaterials.2021.121306
Adv Ther (Weinh). 2021 Sep;pii: 2100103. [Epub ahead of print]4(9):

Self-Assembled Peptide Amphiphile Nanofibers for Controlled Therapeutic Delivery to the Atherosclerotic Niche.

Erica B Peters, Mark R Karver, Kui Sun, David C Gillis, Suvendu Biswas, Tristan D Clemons, Wenhan He, Nick D Tsihlis, Samuel I Stupp, Melina R Kibbe.

  Atherosclerotic plaque remains the leading contributor to cardiovascular disease and requires invasive surgical procedures for its removal. Nanomedicine offers a minimally invasive approach to alleviate plaque burden by targeted therapeutic delivery. However, nanocarriers are limited without the ability to sense and respond to the diseased microenvironment. In this study, targeted self-assembled peptide amphiphile (PA) nanofibers were developed that cleave in response to biochemical cues expressed in atherosclerotic lesions-reactive oxygen species (ROS) and intracellular glutathione-to deliver a liver X receptor agonist (LXR) to enhance macrophage cholesterol efflux. The PAs released LXR in response to physiological levels of ROS and reducing agents and could be co-assembled with plaque-targeting PAs to form nanofibers. The resulting LXR PA nanofibers promoted cholesterol efflux from macrophages in vitro as well as LXR alone and with lower cytotoxicity. Further, the ApoA1-LXR PA nanofibers targeted plaque within an atherosclerotic mouse model in vivo and activated ATP-binding cassette A1 (ABCA1) expression as well as LXR alone with reduced liver toxicity. Taken together, these results demonstrate the potential of self-assembled PA nanofibers for controlled therapeutic delivery to the atherosclerotic niche.

Keywords:  Nanotechnology; cardiovascular disease; drug delivery; nanomedicine; peptide amphiphiles

DOI:  https://doi.org/10.1002/adtp.202100103
Angew Chem Int Ed Engl. 2021 Dec 21.

Spatiotemporal Control of Molecular Cascade Reactions by a Reconfigurable DNA Origami Domino Array.

Sisi Fan, Bin Ji, Yan Liu, Kexuan Zou, Zhijin Tian, Bin Dai, Daxiang Cui, Pengfei Zhang, Yonggang Ke, Jie Song.

  Inspired by efficient biomolecular reactions in the cell, versatile DNA nanostructures have been explored for manipulating the spatial position and regulating reactions at the molecular level. Spatially controlled arrangement of molecules on the artificial scaffolds generally leads to enhanced reaction activities. Especially, the rich toolset of dynamic DNA nanostructures provides a potential route towards more sophisticated and vigorous regulation of molecular reactions. Herein, reconfigurable DNA origami domino array (DODA) as dynamic scaffolds was adopted in this work for temporal-controlled and switchable molecular cascade reactions. Dynamic regulation of the assembly of G-quadruplex, hybridization of parallel-stranded duplex and assembly of binary DNAzyme were demonstrated. Molecular cascade reactions proceed on the triggered reconfiguration of DODAs were realized, resulting in more complex, dynamic, and switchable control over the reactions.

Keywords:  reconfigurable DNA origami * dynamic regulation * cascade reactions * spatial control

DOI:  https://doi.org/10.1002/anie.202116324
Adv Mater. 2021 Dec 21. e2109528

Intracellular Self-Immolative Polyprodrug with Near-Infrared Light Guided Accumulation and in Vivo Visualization of Drug Release.

Dong-Bing Cheng, Xue-Hao Zhang, Si-Yi Chen, Xiao-Xue Xu, Hao Wang, Zeng-Ying Qiao.

  The selective accumulation and real-time monitoring of drug release at tumor site are the key bottlenecks to the clinical translation of polyprodrug. Herein, we exploit an intracellular self-immolative polyprodrug (PMTO), which not only shows the enhanced cellular internalization and selective accumulation in tumor site under the mild hyperthermia triggered by laser irradiation, but also possesses the self-monitoring drug release ability in vivo. The polyprodrug amphiphiles are synthesized by sequential esterification reaction, and hydrophilic poly(ethylene glycol) serves as blocking agent. On account of the mild hyperthermia produced by PMTO under the laser irradiation at tumor site, the cell membranous permeability increases, resulting in the enhanced cellular internalization and drug accumulation in tumor. After internalized by cells, the self-immolative PMTO nanoparticles can release free mitoxantrone (MTO) in intracellular reductive environment, and ratiometric photoacoustic (RPA) imaging based on distinct signals between MTO and PMTO is presented to trace the drug release in vivo. Finally, this self-monitoring polyprodrug presents significant tumor suppression efficacy, which exhibits great potential for guiding the clinical medication in cancer treatment. This article is protected by copyright. All rights reserved.

Keywords:  Chemotherapy; Photoacoustic Imaging; Polyprodrug; Self-assembly

DOI:  https://doi.org/10.1002/adma.202109528
Adv Mater. 2021 Dec 21. e2108931

Support Bath-Free Vertical Extrusion Cryo(bio)printing for Anisotropic Tissue Manufacturing.

Zeyu Luo, Guosheng Tang, Hossein Ravanbakhsh, Wanlu Li, Mian Wang, Xiao Kuang, Carlos Ezio Garciamendez-Mijares, Liming Lian, Sili Yi, Junlong Liao, Maobin Xie, Jie Guo, Zongke Zhou, Yu Shrike Zhang.

  Due to poor mechanical properties of many hydrogel bioinks, conventional three-dimensional (3D) extrusion bioprinting is usually conducted based on the X-Y plane, where the deposited layers are stacked in the Z direction with or without the support of prior layers. Herein, we report a technique taking advantage of a cryoprotected bioink to enable direct extrusion bioprinting in the vertical direction in the presence of cells, using a freezing plate with precise temperature-control. Of interest, vertical 3D cryobioprinting concurrently allows the user to create freestanding filamentous constructs containing interconnected, anisotropic microchannels featuring gradient sizes aligned in the vertical direction, also associated with enhanced mechanical performances. Skeletal myoblasts within the 3D-cryobioprinted hydrogel constructs show enhanced cell viability, spreading, and alignment, compared to the same cells in the standard hydrogel constructs. This method is further extended to a multi-material format, finding potential applications in interface tissue engineering, such as creation of the muscle-tendon unit and the muscle-microvascular unit. The unique vertical 3D cryobioprinting technique presented here suggests improvements in robustness and versatility to engineer certain tissue types especially those anisotropic in nature, and may extend broad utilities in tissue engineering, regenerative medicine, drug discovery, and personalized therapeutics. This article is protected by copyright. All rights reserved.

Keywords:  3D printing; Bioprinting; directional freezing; musculoskeletal tissue engineering; regenerative medicine; vertical

DOI:  https://doi.org/10.1002/adma.202108931
Small. 2021 Dec 22. e2104632

Design of Smart Size-, Surface-, and Shape-Switching Nanoparticles to Improve Therapeutic Efficacy.

Xiaoyun Li, E Coulter Montague, Angela Pollinzi, Andrew Lofts, Todd Hoare.

  Multiple biological barriers must be considered in the design of nanomedicines, including prolonged blood circulation, efficient accumulation at the target site, effective penetration into the target tissue, selective uptake of the nanoparticles into target cells, and successful endosomal escape. However, different particle sizes, surface chemistries, and sometimes shapes are required to achieve the desired transport properties at each step of the delivery process. In response, this review highlights recent developments in the design of switchable nanoparticles whose size, surface chemistry, shape, or a combination thereof can be altered as a function of time, a disease-specific microenvironment, and/or via an externally applied stimulus to enable improved optimization of nanoparticle properties in each step of the delivery process. The practical use of such nanoparticles in chemotherapy, bioimaging, photothermal therapy, and other applications is also discussed.

Keywords:  drug delivery; nanoparticles; shape switching; size switching; smart materials; surface switching; theranostics

DOI:  https://doi.org/10.1002/smll.202104632
Nat Biomed Eng. 2021 Dec 20.

Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue.

Huawei Wang, Christina N Alarcón, Bei Liu, Felicia Watson, Stephen Searles, Calvin K Lee, Jeremy Keys, Willie Pi, Dale Allen, Jan Lammerding, Jack D Bui, Richard L Klemke.

Targeting the delivery of therapeutics specifically to diseased tissue enhances their efficacy and decreases their side effects. Here we show that mesenchymal stromal cells with their nuclei removed by density-gradient centrifugation following the genetic modification of the cells for their display of chemoattractant receptors and endothelial-cell-binding molecules are effective vehicles for the targeted delivery of therapeutics. The enucleated cells neither proliferate nor permanently engraft in the host, yet retain the organelles for energy and protein production, undergo integrin-regulated adhesion to inflamed endothelial cells, and actively home to chemokine gradients established by diseased tissues. In mouse models of acute inflammation and of pancreatitis, systemically administered enucleated cells expressing two types of chemokine receptor and an endothelial adhesion molecule enhanced the delivery of an anti-inflammatory cytokine to diseased tissue (with respect to unmodified stromal cells and to exosomes derived from bone-marrow-derived stromal cells), attenuating inflammation and ameliorating disease pathology. Enucleated cells retain most of the cells' functionality, yet acquire the cargo-carrying characteristics of cell-free delivery systems, and hence represent a versatile delivery vehicle and therapeutic system.

DOI: https://doi.org/10.1038/s41551-021-00815-9
Cells. 2021 Nov 30. pii: 3358. [Epub ahead of print]10(12):

The Impact of MicroRNAs during Inflammatory Bowel Disease: Effects on the Mucus Layer and Intercellular Junctions for Gut Permeability.

Sarah Stiegeler, Kevin Mercurio, Miruna Alexandra Iancu, Sinéad C Corr.

  Research on inflammatory bowel disease (IBD) has produced mounting evidence for the modulation of microRNAs (miRNAs) during pathogenesis. MiRNAs are small, non-coding RNAs that interfere with the translation of mRNAs. Their high stability in free circulation at various regions of the body allows researchers to utilise miRNAs as biomarkers and as a focus for potential treatments of IBD. Yet, their distinct regulatory roles at the gut epithelial barrier remain elusive due to the fact that there are several external and cellular factors contributing to gut permeability. This review focuses on how miRNAs may compromise two components of the gut epithelium that together form the initial physical barrier: the mucus layer and the intercellular epithelial junctions. Here, we summarise the impact of miRNAs on goblet cell secretion and mucin structure, along with the proper function of various junctional proteins involved in paracellular transport, cell adhesion and communication. Knowledge of how this elaborate network of cells at the gut epithelial barrier becomes compromised as a result of dysregulated miRNA expression, thereby contributing to the development of IBD, will support the generation of miRNA-associated biomarker panels and therapeutic strategies that detect and ameliorate gut permeability.

Keywords:  gut epithelial barrier; inflammatory bowel disease; intercellular junctions; microRNAs; mucus layer

DOI:  https://doi.org/10.3390/cells10123358
Nat Metab. 2021 Dec;3(12): 1680-1693

Spatial discordances between mRNAs and proteins in the intestinal epithelium.

Yotam Harnik, Lisa Buchauer, Shani Ben-Moshe, Inna Averbukh, Yishai Levin, Alon Savidor, Raya Eilam, Andreas E Moor, Shalev Itzkovitz.

The use of transcriptomes as reliable proxies for cellular proteomes is controversial. In the small intestine, enterocytes operate for 4 days as they migrate along villi, which are highly graded microenvironments. Spatial transcriptomics have demonstrated profound zonation in enterocyte gene expression, but how this variability translates to protein content is unclear. Here we show that enterocyte proteins and messenger RNAs along the villus axis are zonated, yet often spatially discordant. Using spatial sorting with zonated surface markers, together with a Bayesian approach to infer protein translation and degradation rates from the combined spatial profiles, we find that, while many genes exhibit proteins zonated toward the villus tip, mRNA is zonated toward the villus bottom. Finally, we demonstrate that space-independent protein synthesis delays can explain many of the mRNA-protein discordances. Our work provides a proteomic spatial blueprint of the intestinal epithelium, highlighting the importance of protein measurements for inferring cell states in tissues that operate outside of steady state.

DOI: https://doi.org/10.1038/s42255-021-00504-6