bims-drudre 2022-05-01 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2022–05–01
eleven papers selected by
Ceren Kimna, Technical University of Munich

Three-dimensional imaging for the quantification of spatial patterns in microbiota of the intestinal mucosa.
Development of a Microenvironment-Responsive Hydrogel Promoting Chronically Infected Diabetic Wound Healing through Sequential Hemostatic, Antibacterial, and Angiogenic Activities.
Changeable net charge on nanoparticles facilitates intratumor accumulation and penetration.
Prediction and Design of Nanozymes Using Explainable Machine Learning.
Bacterial toxin-triggered release of antibiotics from capsosomes protects a fly model from lethal methicillin-resistant Staphylococcus aureus (MRSA) infection.
Nanodelivery of nucleic acids.
Injectable and Self-Healing Probiotics-Loaded Hydrogel for Promoting Superbacteria-Infected Wound Healing.
Engineering DNA-Guided Hydroxyapatite Bulk Materials with High Stiffness and Outstanding Antimicrobial Ability for Dental Inlay Applications.
Needleless administration of advanced therapies into the skin via the appendages using a hypobaric patch.
A multi-organ chip with matured tissue niches linked by vascular flow.
Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer.

Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2118483119

Three-dimensional imaging for the quantification of spatial patterns in microbiota of the intestinal mucosa.

Octavio Mondragón-Palomino, Roberta Poceviciute, Antti Lignell, Jessica A Griffiths, Heli Takko, Rustem F Ismagilov.

  SignificanceMany human diseases are causally linked to the gut microbiota, yet the field still lacks mechanistic understanding of the underlying complex interactions, because existing tools cannot simultaneously quantify microbial communities and their native context. In this work, we provide an approach to tissue clearing and preservation that enables 3D visualization of the biogeography of the host-microbiota interface. We combine this tool with sequencing and multiplexed microbial labeling to provide the field with a platform on which to discover patterns in the spatial distribution of microbes. We validated this platform by quantifying bacterial distribution in cecal mucosa at different stages of antibiotic exposure. This approach may enable researchers to formulate and test new hypotheses about host-microbe and microbe-microbe interactions.

Keywords:  microbiota; quantitative biogeography; tissue clearing

DOI:  https://doi.org/10.1073/pnas.2118483119
ACS Appl Mater Interfaces. 2022 Apr 25.

Development of a Microenvironment-Responsive Hydrogel Promoting Chronically Infected Diabetic Wound Healing through Sequential Hemostatic, Antibacterial, and Angiogenic Activities.

Chuan Guo, Ye Wu, Weilong Li, Yu Wang, Qingquan Kong.

  Microenvironment-responsive hydrogels present high potential in treating refractory wounds due to their capability of on-demand drug release. In this study, a specially designed hydrogel with smart targeting of refractory wound characteristics was designed to treat chronically infected diabetic wounds. Aminated gelatin reacted with oxidized dextran, forming a hydrogel cross-linked with a dynamic Schiff base, which is sensitive to the low-pH environment in refractory wounds. Nano-ZnO was loaded into the hydrogel for killing microbes. A Paeoniflorin-encapsulated micelle with a ROS-responsive property was fixed to the skeleton of the hydrogel via a Schiff base bond for low-pH- and ROS-stimulated angiogenic activity. The sequential responsiveness of the novel hydrogel enabled smart rescue of the deleterious microenvironment in refractory wounds. This highly biocompatible hydrogel demonstrated antibacterial and angiogenic abilities in vitro and significantly promoted healing of chronically infected diabetic wounds via sequential hemostatic, microbe killing, and angiogenic activities. This microenvironment-responsive hydrogel loaded with nZnO and Pf-encapsulated micelles holds great potential as a location-specific dual-response delivery platform for curing refractory, chronically infected diabetic wounds.

Keywords:  angiogenesis; antimicrobial; drug-loaded micelles; hemostasis; microenvironment-responsive; wound healing

DOI:  https://doi.org/10.1021/acsami.2c02725
J Control Release. 2022 Apr 21. pii: S0168-3659(22)00221-8. [Epub ahead of print]

Changeable net charge on nanoparticles facilitates intratumor accumulation and penetration.

Aziz Awaad, Hiroyasu Takemoto, Muneaki Iizuka, Koichi Ogi, Yuki Mochida, Abdul-Hackam Ranneh, Masahiro Toyoda, Makoto Matsui, Takahiro Nomoto, Yuto Honda, Kotaro Hayashi, Keishiro Tomoda, Tomoyuki Ohtake, Yutaka Miura, Nobuhiro Nishiyama.

  The Enhanced Permeability and Retention (EPR) effect is a golden strategy for the nanoparticle (NP)-based targeting of solid tumors, and the surface property of NPs might be a determinant on their targeting efficiency. Poly(ethylene glycol) (PEG) is commonly used as a shell material; however, it has been pointed out that PEG-coated NPs may exhibit accumulation near tumor vasculature rather than having homogenous intratumor distribution. The PEG shell plays a pivotal role on prolonged blood circulation of NPs but potentially impairs the intratumor retention of NPs. In this study, we report on a shell material to enhance tumor-targeted delivery of NPs by maximizing the EPR effect: polyzwitterion based on ethylenediamine-based carboxybetaine [PGlu(DET-Car)], which shows the changeable net charge responding to surrounding pH. The net charge of PGlu(DET-Car), is neutral at physiological pH 7.4, allowing it to exhibit a stealth property during the blood circulation; however, it becomes cationic for tissue-interactive performance under tumorous acidic conditions owing to the stepwise protonation behavior of ethylenediamine. Indeed, the PGlu(DET-Car)-coated NPs (i.e., gold NPs in the present study) exhibited prolonged blood circulation and remarkably enhanced tumor accumulation and retention than PEG-coated NPs, achieving 32.1% of injected dose/g of tissue, which was 4.2 times larger relative to PEG-coated NPs. Interestingly, a considerable portion of PGlu(DET-Car)-coated NPs clearly penetrated into deeper tumor sites and realized the effective accumulation in hypoxic regions, probably because the cationic net charge of PGlu(DET-Car) is augmented in more acidic hypoxic regions. This study suggests that the changeable net charge on the NP surface in response to tumorous acidic conditions is a promising strategy for tumor-targeted delivery based on the EPR effect.

Keywords:  EPR effect; Hypoxic region; Nanoparticles (NPs); Polyzwitterions; Surface charge; pH responsiveness

DOI:  https://doi.org/10.1016/j.jconrel.2022.04.025
Adv Mater. 2022 Apr 29. e2201736

Prediction and Design of Nanozymes Using Explainable Machine Learning.

Yonghua Wei, Jin Wu, Yixuan Wu, Hongjiang Liu, Fanqiang Meng, Qiqi Liu, Adam C Midgley, Xiangyun Zhang, Tianyi Qi, Helong Kang, Rui Chen, Deling Kong, Jie Zhuang, Xiyun Yan, Xinglu Huang.

  An abundant number of nanomaterials have been discovered to possess enzyme-like catalytic activity, termed nanozymes. It was identified that a variety of internal and external factors influence the catalytic activity of nanozymes. However, there is a lack of essential methodologies to uncover the hidden mechanisms between nanozyme features and enzyme-like activity. Here we demonstrated a data-driven approach that utilized machine learning algorithms to understand particle-property relationships, allowing for classification and quantitative predictions of enzyme-like activity exhibited by nanozymes. High consistency between predicted outputs and the observations was confirmed by accuracy (90.6%) and R2 (up to 0.80). Furthermore, sensitive analysis of the models revealed the central roles of transition metals in determining nanozyme activity. As an example, the models were successfully applied to predict or design desirable nanozymes by uncovering the hidden relationship between different periods of transition metals and their enzyme-like performance. This study offers a promising strategy to develop nanozymes with desirable catalytic activity and demonstrates the potential of machine learning within the field of material science. This article is protected by copyright. All rights reserved.

Keywords:  machine learning; nanomaterials; nanozyme

DOI:  https://doi.org/10.1002/adma.202201736
Adv Healthc Mater. 2022 Apr 28. e2200036

Bacterial toxin-triggered release of antibiotics from capsosomes protects a fly model from lethal methicillin-resistant Staphylococcus aureus (MRSA) infection.

Renée L Tonkin, Anna Klöckner, Adrian Najer, Carolina J Simoes da Silva, Cécile Echalier, Marc S Dionne, Andrew M Edwards, Molly M Stevens.

  Antibiotic resistance is a severe global health threat and hence demands rapid action to develop novel therapies, including microscale drug delivery systems. Herein, a hierarchical microparticle system is developed to achieve bacteria-activated single- and dual-antibiotic drug delivery for preventing methicillin-resistant Staphylococcus aureus (MRSA) bacterial infections. The designed system is based on a capsosome structure, which consisted of a mesoporous silica microparticle coated in alternating layers of oppositely charged polymers and antibiotic-loaded liposomes. The capsosomes are engineered and shown to release their drug payloads in the presence of MRSA toxins controlled by the Agr quorum sensing system. MRSA-activated single drug delivery of vancomycin and synergistic dual delivery of vancomycin together with an antibacterial peptide successfully killed MRSA in vitro. The capability of capsosomes to selectively deliver their cargo in the presence of bacteria, producing a bactericidal effect to protect the host organism, is confirmed in vivo using a Drosophila melanogaster MRSA infection model. Thus, our capsosomes serve as a versatile multi-drug, subcompartmentalized microparticle system for preventing antibiotic-resistant bacterial infections, with potential applications to protect wounds or medical device implants from infections. This article is protected by copyright. All rights reserved.

Keywords:  MRSA; antibiotic delivery; capsosomes; microparticle; vancomycin

DOI:  https://doi.org/10.1002/adhm.202200036
Nat Rev Methods Primers. 2022 ;pii: 24. [Epub ahead of print]2

Nanodelivery of nucleic acids.

Bárbara B Mendes, João Conniot, Aviram Avital, Dongbao Yao, Xingya Jiang, Xiang Zhou, Noga Sharf-Pauker, Yuling Xiao, Omer Adir, Haojun Liang, Jinjun Shi, Avi Schroeder, João Conde.

There is growing need for a safe, efficient, specific and non-pathogenic means for delivery of gene therapy materials. Nanomaterials for nucleic acid delivery offer an unprecedented opportunity to overcome these drawbacks; owing to their tunability with diverse physico-chemical properties, they can readily be functionalized with any type of biomolecules/moieties for selective targeting. Nucleic acid therapeutics such as antisense DNA, mRNA, small interfering RNA (siRNA) or microRNA (miRNA) have been widely explored to modulate DNA or RNA expression Strikingly, gene therapies combined with nanoscale delivery systems have broadened the therapeutic and biomedical applications of these molecules, such as bioanalysis, gene silencing, protein replacement and vaccines. Here, we overview how to design smart nucleic acid delivery methods, which provide functionality and efficacy in the layout of molecular diagnostics and therapeutic systems. It is crucial to outline some of the general design considerations of nucleic acid delivery nanoparticles, their extraordinary properties and the structure-function relationships of these nanomaterials with biological systems and diseased cells and tissues.

DOI: https://doi.org/10.1038/s43586-022-00104-y
ACS Appl Mater Interfaces. 2022 Apr 26.

Injectable and Self-Healing Probiotics-Loaded Hydrogel for Promoting Superbacteria-Infected Wound Healing.

Li Mei, Dongjie Zhang, Huarong Shao, Yuanping Hao, Ting Zhang, Weiping Zheng, Yanjing Ji, Peixue Ling, Yun Lu, Qihui Zhou.

  Superbacteria-induced skin wound infections are huge health challenges, resulting in significant financial and medical costs due to notable morbidity and mortality worldwide. Probiotics are found in the skin and are effective in treating bacterial infection, moderating the microbial dysbiosis and inflammation induced by pathogens, regulating the immune system, as well as even promoting tissue repair. However, improving their colonization efficiency and viability remains a large obstacle for proper applications. Inspired by probiotic therapy and the natural extracellular matrix structure, hyaluronate-adipic dihydrazide/aldehyde-terminated Pluronic F127/fucoidan hydrogels loaded with Lactobacillus rhamnosus (HPF@L.rha) with unique (bio)physicochemical characteristics were developed through the dynamic Schiff-base reaction for superbacteria-infected trauma management. The developed HPF@L.rha exhibit a shortened gelation time, enhanced mechanical strength, and excellent self-healing and liquid-absorption abilities. Importantly, their anti-superbacteria (Pseudomonas aeruginosa) effect was greatly increased in a dose-dependent fashion. Additionally, in vitro evaluation shows that the prepared HPF@L.rha containing appropriate probiotic concentrations (less than 1 × 107 CFU/mL) possess satisfactory cytocompatibility and blood compatibility. Further, compared to the HPF hydrogel, in vivo the hydrogel combined with probiotics significantly inhibits P. aeruginosa infection and inflammation, promotes the formation of re-epithelialization and collagen, and thus accelerates full-thickness superbacteria-infected wound repair, which is comparable to commercial Prontosan gel formulation. This work suggests that the combination of biomimicking hydrogels and probiotic therapy displays the great potential to manage superbug-infected trauma.

Keywords:  antibacterial biomaterial; bioactive hydrogel; probiotics; superbacterial infection; wound healing

DOI:  https://doi.org/10.1021/acsami.1c23713
Adv Mater. 2022 Apr 30. e2202180

Engineering DNA-Guided Hydroxyapatite Bulk Materials with High Stiffness and Outstanding Antimicrobial Ability for Dental Inlay Applications.

Yusai Zhou, Jingjing Deng, Yi Zhang, Cong Li, Zheng Wei, Jianlei Shen, Jingjing Li, Fan Wang, Bing Han, Dong Chen, Chunhai Fan, Hongjie Zhang, Kai Liu, Yan Wei.

  Programmable base pair interactions at the nanoscale make DNA an attractive scaffold for forming hydroxyapatite (HAP) nanostructures. However, engineering macroscale HAP mineralization guided by DNA molecules remains challenging. To overcome this issue, we developed a facile strategy for the fabrication of ultra-stiff DNA-HAP bulk composites. The electrostatic complexation of DNA and a surfactant with a quaternary ammonium salt group enabled the formation of long-range ordered scaffolds using electrospinning. The growth of one- and two-dimensional HAP minerals were thus realized by this DNA template at a macroscale. Remarkably, the as-prepared DNA-HAP composites exhibited an ultra-high Young's modulus of approximately 25 GPa, which is comparable to natural HAP and superior to most artificial mineralized composites. Furthermore, a new type of dental inlay with outstanding antibacterial properties was developed using the stiff DNA-HAP. The encapsulated quaternary ammonium group within the dense HAP endowed the composite with long-lasting and local antibacterial activity. Therefore, this new type of super-stiff biomaterial holds great potential for oral prosthetic applications. This article is protected by copyright. All rights reserved.

Keywords:  DNA templates; antimicrobial; dental inlay; hydroxyapatite; mineralization

DOI:  https://doi.org/10.1002/adma.202202180
Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2120340119

Needleless administration of advanced therapies into the skin via the appendages using a hypobaric patch.

Faiza Benaouda, Ricardo Inacio, Chui Hua Lim, Haeeun Park, Thomas Pitcher, Mohamed A Alhnan, Mazen M S Aly, Khuloud T Al-Jamal, Ka-Lung Chan, Rikhav P Gala, Daniel Sebastia-Saez, Liang Cui, Tao Chen, Julie Keeble, Stuart A Jones.

  SignificanceNeedleless delivery into the skin would overcome a major barrier to efficient clinical utilization of advanced therapies such as nanomaterials and macromolecules. This study demonstrates that controlled skin stretching (in porcine, rat, and mouse models) using a patch comprising a hypobaric chamber, to open the skin appendages, can increase the permeability of the tissue and provide a means to enable direct delivery of advanced therapies directly into the skin without the use of a needle or injection system. This technology can facilitate the self-administration of therapeutics including vaccines, RNA, and antigens, thus improving the translation of these products into effective clinical use.

Keywords:  advanced therapeutics; drug delivery; needleless delivery; skin; vaccine

DOI:  https://doi.org/10.1073/pnas.2120340119
Nat Biomed Eng. 2022 Apr;6(4): 351-371

A multi-organ chip with matured tissue niches linked by vascular flow.

Kacey Ronaldson-Bouchard, Diogo Teles, Keith Yeager, Daniel Naveed Tavakol, Yimu Zhao, Alan Chramiec, Somnath Tagore, Max Summers, Sophia Stylianos, Manuel Tamargo, Busub Marcus Lee, Susan P Halligan, Erbil Hasan Abaci, Zongyou Guo, Joanna Jacków, Alberto Pappalardo, Jerry Shih, Rajesh K Soni, Shivam Sonar, Carrie German, Angela M Christiano, Andrea Califano, Karen K Hirschi, Christopher S Chen, Andrzej Przekwas, Gordana Vunjak-Novakovic.

Engineered tissues can be used to model human pathophysiology and test the efficacy and safety of drugs. Yet, to model whole-body physiology and systemic diseases, engineered tissues with preserved phenotypes need to physiologically communicate. Here we report the development and applicability of a tissue-chip system in which matured human heart, liver, bone and skin tissue niches are linked by recirculating vascular flow to allow for the recapitulation of interdependent organ functions. Each tissue is cultured in its own optimized environment and is separated from the common vascular flow by a selectively permeable endothelial barrier. The interlinked tissues maintained their molecular, structural and functional phenotypes over 4 weeks of culture, recapitulated the pharmacokinetic and pharmacodynamic profiles of doxorubicin in humans, allowed for the identification of early miRNA biomarkers of cardiotoxicity, and increased the predictive values of clinically observed miRNA responses relative to tissues cultured in isolation and to fluidically interlinked tissues in the absence of endothelial barriers. Vascularly linked and phenotypically stable matured human tissues may facilitate the clinical applicability of tissue chips.

DOI: https://doi.org/10.1038/s41551-022-00882-6
Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2200143119

Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer.

Daniel R Principe, Alexandre F Aissa, Sandeep Kumar, Thao N D Pham, Patrick W Underwood, Rakesh Nair, Rong Ke, Basabi Rana, Jose G Trevino, Hidayatullah G Munshi, Elizaveta V Benevolenskaya, Ajay Rana.

  SignificancePancreatic cancer is a leading cause of cancer-related death, in part due to incomplete responses to standard-of-care chemotherapy. In this study, using a combination of single-cell RNA sequencing and high-throughput proteomics, we identified the calcium-responsive protein calmodulin as a key mediator of resistance to the first-line chemotherapy agent gemcitabine. Inhibition of calmodulin led to the loss of gemcitabine resistance in vitro, which was recapitulated using a calcium chelator or Food and Drug Administration-approved calcium channel blockers (CCBs), including amlodipine. In animal studies, amlodipine markedly enhanced therapeutic responses to gemcitabine chemotherapy, reducing the incidence of distant metastases and extending survival. Hence, incorporating CCBs may provide a safe and effective means of improving responses to gemcitabine-based chemotherapy in pancreatic cancer patients.

Keywords:  chemotherapy; drug resistance; gemcitabine; pancreatic cancer

DOI:  https://doi.org/10.1073/pnas.2200143119