bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022–08–14
nine papers selected by
Ceren Kimna, Technical University of Munich
  1. Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics.
  2. Size-Controllable DNA Origami-Stacked Gold Nanoparticles for Deep Tumor-Penetrating Therapy.
  3. Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems.
  4. miRacle of microRNA-Driven Cancer Nanotherapeutics.
  5. Adenosine triphosphate-activated prodrug system for on-demand bacterial inactivation and wound disinfection.
  6. Circulation Time-Optimized Albumin Nanoplatform for Quantitative Visualization of Lung Metastasis via Targeting of Macrophages.
  7. Programmable RNA targeting by bacterial Argonaute nucleases with unconventional guide binding and cleavage specificity.
  8. Controlled tough bioadhesion mediated by ultrasound.
  9. mRNA Vaccines Against SARS-CoV-2 Variants Delivered by Lipid Nanoparticles Based on Novel Ionizable Lipids.
  1. Mol Ther. 2022 Aug 06. pii: S1525-0016(22)00436-1. [Epub ahead of print]
    Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics.
    John G Yuen, Andrew Fesler, Ga-Ram Hwang, Lan-Bo Chen, Jingfang Ju.
      MicroRNA (miRNAs) are pleiotropic post-transcriptional modulators of gene expression. Their inherently pleiotropic nature makes miRNAs strong candidates for the development of cancer therapeutics, yet despite their potential, there remains a challenge to deliver nucleic acid-based therapies into cancer cells. We developed a novel approach to modify miRNAs by replacing the uracil bases with 5-fluorouracil (5-FU) in the guide strand of tumor suppressor miRNAs, thereby combining the therapeutic effect of 5-FU with tumor-suppressive effect of miRNAs to create a potent, multi-targeted therapeutic molecule without altering its native RNAi function. To demonstrate the general applicability of this approach to other tumor-suppressive miRNAs, we screened a panel of 12 novel miRNA mimetics in several cancer types, including leukemia, breast, gastric, lung, and pancreatic cancer. Our results show that 5-FU-modified miRNA mimetics have increased potency (low nanomolar range) in inhibiting cancer cell proliferation and that these mimetics can be delivered into cancer cells without delivery vehicle both in vitro and in vivo, thus representing significant advancements in the development of therapeutic miRNAs for cancer. This work demonstrates the potential of fluoropyrimidine modifications that can be broadly applicable and may serve as a platform technology for future miRNA and nucleic acid-based therapeutics.
    Keywords:  RNA delivery; breast cancer; cancer; colon cancer; gene therapy; lung cancer; microRNA; oligonucleotide-based therapies
    DOI:  https://doi.org/10.1016/j.ymthe.2022.07.015
  2. ACS Appl Mater Interfaces. 2022 Aug 11.
    Size-Controllable DNA Origami-Stacked Gold Nanoparticles for Deep Tumor-Penetrating Therapy.
    Dening Gu, Yanqi Qiao, Hongli Fu, Hongjie Zhao, Xinmin Yue, Shuo Wang, Yongmei Yin, Rimo Xi, Xiaoling Fu, Xiujie Zhao, Meng Meng.
      With the rapid development of nanotechnology, researchers have designed a variety of intelligent nanodelivery systems to enhance tumor targeting of anticancer drugs. However, increased tumor accumulation does not indicate deeper penetration in the tumor tissue, without which the tumor cells in the core area cannot be sufficiently killed. Herein, we develop a size-controllable nanoparticle system for deep-penetrating cancer therapy, which will be programmably disassembled with the decrease of the pH from the normal tissue to the tumor microenvironment and to the intracellular area. The integrated nanoparticle is composed of a gold nanoparticle (GNP, ∼30 nm) and a tetrahedral DNA nanostructure (TDN, ∼25 nm) loaded with doxorubicin (DOX). Initially, the nanoparticles maintain a larger size (∼100 nm) to accumulate in the tumor through the enhanced permeability and retention effect. At a pH of about 6.5 at the tumor microenvironment, with the linkage of DNA sequences converting into a triplex structure, the TDNs detach from the GNP and penetrate deeply into the tumor interstitium and then are internalized into the cells. Finally, in acidic lysosomes with pH 5.0, the TDNs release DOX by forming an i-motif structure. This nanosmart delivery system thus shows effective deep penetration into the tumor core with good antitumor efficacy and satisfactory biocompatibility and provides new insights into the development of intelligent nanosystems for anti-cancer treatment.
    Keywords:  deep penetration; gold nanoparticles; pH response; size-controllable; tetrahedral DNA nanostructure (TDN)
    DOI:  https://doi.org/10.1021/acsami.2c05750
  3. J Nanobiotechnology. 2022 Aug 06. 20(1): 362
    Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems.
    Deepak A Subramanian, Robert Langer, Giovanni Traverso.
      Oral delivery of therapeutics is the preferred route of administration due to ease of administration which is associated with greater patient medication adherence. One major barrier to oral delivery and intestinal absorption is rapid clearance of the drug and the drug delivery system from the gastrointestinal (GI) tract. To address this issue, researchers have investigated using GI mucus to help maximize the pharmacokinetics of the therapeutic; while mucus can act as a barrier to effective oral delivery, it can also be used as an anchoring mechanism to improve intestinal residence. Nano-drug delivery systems that use materials which can interact with the mucus layers in the GI tract can enable longer residence time, improving the efficacy of oral drug delivery. This review examines the properties and function of mucus in the GI tract, as well as diseases that alter mucus. Three broad classes of mucus-interacting systems are discussed: mucoadhesive, mucus-penetrating, and mucolytic drug delivery systems. For each class of system, the basis for mucus interaction is presented, and examples of materials that inform the development of these systems are discussed and reviewed. Finally, a list of FDA-approved mucoadhesive, mucus-penetrating, and mucolytic drug delivery systems is reviewed. In summary, this review highlights the progress made in developing mucus-interacting systems, both at a research-scale and commercial-scale level, and describes the theoretical basis for each type of system.
    Keywords:  Gastrointestinal tract; Mucoadhesive; Mucus; Mucus penetration; Oral delivery
    DOI:  https://doi.org/10.1186/s12951-022-01539-x
  4. Cancers (Basel). 2022 Aug 06. pii: 3818. [Epub ahead of print]14(15):
    miRacle of microRNA-Driven Cancer Nanotherapeutics.
    Goknur Kara, Banu Arun, George A Calin, Bulent Ozpolat.
      MicroRNAs (miRNAs) are non-protein-coding RNA molecules 20-25 nucleotides in length that can suppress the expression of genes involved in numerous physiological processes in cells. Accumulating evidence has shown that dysregulation of miRNA expression is related to the pathogenesis of various human diseases and cancers. Thus, stragegies involving either restoring the expression of tumor suppressor miRNAs or inhibiting overexpressed oncogenic miRNAs hold potential for targeted cancer therapies. However, delivery of miRNAs to tumor tissues is a challenging task. Recent advances in nanotechnology have enabled successful tumor-targeted delivery of miRNA therapeutics through newly designed nanoparticle-based carrier systems. As a result, miRNA therapeutics have entered human clinical trials with promising results, and they are expected to accelerate the transition of miRNAs from the bench to the bedside in the next decade. Here, we present recent perspectives and the newest developments, describing several engineered natural and synthetic novel miRNA nanocarrier formulations and their key in vivo applications and clinical trials.
    Keywords:  cancer; miRNA; miRNA inhibitors; miRNA mimics; nanoparticles
    DOI:  https://doi.org/10.3390/cancers14153818
  5. Nat Commun. 2022 Aug 11. 13(1): 4712
    Adenosine triphosphate-activated prodrug system for on-demand bacterial inactivation and wound disinfection.
    Yuhao Weng, Huihong Chen, Xiaoqian Chen, Huilin Yang, Chia-Hung Chen, Hongliang Tan.
      The prodrug approach has emerged as a promising solution to combat bacterial resistance and enhance treatment efficacy against bacterial infections. Here, we report an adenosine triphosphate (ATP)-activated prodrug system for on-demand treatment of bacterial infection. The prodrug system benefits from the synergistic action of zeolitic imidazolate framework-8 and polyacrylamide hydrogel microsphere, which simultaneously transports indole-3-acetic acid and horseradish peroxidase in a single carrier while preventing the premature activation of indole-3-acetic acid. The ATP-responsive characteristic of zeolitic imidazolate framework-8 allows the prodrug system to be activated by the ATP secreted by bacteria to generate reactive oxygen species (ROS), displaying exceptional broad-spectrum antimicrobial ability. Upon disruption of the bacterial membrane by ROS, the leaked intracellular ATP from dead bacteria can accelerate the activation of the prodrug system to further enhance antibacterial efficiency. In vivo experiments in a mouse model demonstrates the applicability of the prodrug system for wound disinfection with minimal side effects.
    DOI:  https://doi.org/10.1038/s41467-022-32453-3
  6. ACS Nano. 2022 Aug 09.
    Circulation Time-Optimized Albumin Nanoplatform for Quantitative Visualization of Lung Metastasis via Targeting of Macrophages.
    Hyewon Chung, Ji Yong Park, Kyuwan Kim, Ran Ji Yoo, Minseok Suh, Gyo Jeong Gu, Jin Sil Kim, Tae Hyeon Choi, Jung Woo Byun, Young Wook Ju, Wonshik Han, Han Suk Ryu, Gehoon Chung, Do Won Hwang, Yujin Kim, Hye-Ryun Kang, Yi Rang Na, Hongyoon Choi, Hyung-Jun Im, Yun-Sang Lee, Seung Hyeok Seok.
      The development of molecular imaging probes to identify key cellular changes within lung metastases may lead to noninvasive detection of metastatic lesions in the lung. In this study, we constructed a macrophage-targeted clickable albumin nanoplatform (CAN) decorated with mannose as the targeting ligand using a click reaction to maintain the intrinsic properties of albumin in vivo. We also modified the number of mannose molecules on the CAN and found that mannosylated serum albumin (MSA) harboring six molecules of mannose displayed favorable pharmacokinetics that allowed high-contrast imaging of the lung, rendering it suitable for in vivo visualization of lung metastases. Due to the optimized control of functionalization and surface modification, MSA enhanced blood circulation time and active/passive targeting abilities and was specifically incorporated by mannose receptor (CD206)-expressing macrophages in the metastatic lung. Moreover, extensive in vivo imaging studies using single-photon emission computed tomography (SPECT)/CT and positron emission tomography (PET) revealed that blood circulation of time-optimized MSA can be used to discern metastatic lesions, with a strong correlation between its signal and metastatic burden in the lung.
    Keywords:  albumin nanoplatform; blood circulation; lung metastasis; macrophage; noninvasive imaging
    DOI:  https://doi.org/10.1021/acsnano.2c03075
  7. Nat Commun. 2022 Aug 08. 13(1): 4624
    Programmable RNA targeting by bacterial Argonaute nucleases with unconventional guide binding and cleavage specificity.
    Lidiya Lisitskaya, Yeonoh Shin, Aleksei Agapov, Anna Olina, Ekaterina Kropocheva, Sergei Ryazansky, Alexei A Aravin, Daria Esyunina, Katsuhiko S Murakami, Andrey Kulbachinskiy.
      Argonaute proteins are programmable nucleases that have defense and regulatory functions in both eukaryotes and prokaryotes. All known prokaryotic Argonautes (pAgos) characterized so far act on DNA targets. Here, we describe a new class of pAgos that uniquely use DNA guides to process RNA targets. The biochemical and structural analysis of Pseudooceanicola lipolyticus pAgo (PliAgo) reveals an unusual organization of the guide binding pocket that does not rely on divalent cations and the canonical set of contacts for 5'-end interactions. Unconventional interactions of PliAgo with the 5'-phosphate of guide DNA define its new position within pAgo and shift the site of target RNA cleavage in comparison with known Argonautes. The specificity for RNA over DNA is defined by ribonucleotide residues at the cleavage site. The analysed pAgos sense mismatches and modifications in the RNA target. The results broaden our understanding of prokaryotic defense systems and extend the spectrum of programmable nucleases with potential use in RNA technology.
    DOI:  https://doi.org/10.1038/s41467-022-32079-5
  8. Science. 2022 Aug 12. 377(6607): 751-755
    Controlled tough bioadhesion mediated by ultrasound.
    Zhenwei Ma, Claire Bourquard, Qiman Gao, Shuaibing Jiang, Tristan De Iure-Grimmel, Ran Huo, Xuan Li, Zixin He, Zhen Yang, Galen Yang, Yixiang Wang, Edmond Lam, Zu-Hua Gao, Outi Supponen, Jianyu Li.
      Tough bioadhesion has important implications in engineering and medicine but remains challenging to form and control. We report an ultrasound (US)-mediated strategy to achieve tough bioadhesion with controllability and fatigue resistance. Without chemical reaction, the US can amplify the adhesion energy and interfacial fatigue threshold between hydrogels and porcine skin by up to 100 and 10 times. Combined experiments and theoretical modeling suggest that the key mechanism is US-induced cavitation, which propels and immobilizes anchoring primers into tissues with mitigated barrier effects. Our strategy achieves spatial patterning of tough bioadhesion, on-demand detachment, and transdermal drug delivery. This work expands the material repertoire for tough bioadhesion and enables bioadhesive technologies with high-level controllability.
    DOI:  https://doi.org/10.1126/science.abn8699
  9. Adv Funct Mater. 2022 Jul 19. 2204692
    mRNA Vaccines Against SARS-CoV-2 Variants Delivered by Lipid Nanoparticles Based on Novel Ionizable Lipids.
    Kepan Chen, Na Fan, Hai Huang, Xin Jiang, Shugang Qin, Wen Xiao, Qian Zheng, Yupei Zhang, Xing Duan, Zeyi Qin, Yongmei Liu, Jun Zeng, Yuquan Wei, Xiangrong Song.
      SARS-CoV-2 variants are now still challenging all the approved vaccines, including mRNA vaccines. There is an urgent need to develop new generation mRNA vaccines with more powerful efficacy and better safety against SARS-CoV-2 variants. In this study, a new set of ionizable lipids named 4N4T are constructed and applied to form novel lipid nanoparticles called 4N4T-LNPs. Leading 4N4T-LNPs exhibit much higher mRNA translation efficiency than the approved SM-102-LNPs. To test the effectiveness of the novel delivery system, the DS mRNA encoding the full-length S protein of the SARS-CoV-2 variant is synthesized and loaded in 4N4T-LNPs. The obtained 4N4T-DS mRNA vaccines successfully trigger robust and durable humoral immune responses against SARS-CoV-2 and its variants including Delta and Omicron. Importantly, the novel vaccines have higher RBD-specific IgG titers and neutralizing antibody titers than SM-102-based DS mRNA vaccine. Besides, for the first time, the types of mRNA vaccine-induced neutralizing antibodies are found to be influenced by the chemical structure of ionizable lipids. 4N4T-DS mRNA vaccines also induce strong Th1-skewed T cell responses and have good safety. This work provides a novel vehicle for mRNA delivery that is more effective than the approved LNPs and shows its application in vaccines against SARS-CoV-2 variants.
    Keywords:  SARS‐CoV‐2 variants; ionizable lipids; lipid nanoparticles; mRNA delivery; mRNA vaccines
    DOI:  https://doi.org/10.1002/adfm.202204692
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