bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022–11–20
twelve papers selected by
Ceren Kimna, Technical University of Munich
  1. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer.
  2. Dual "unlocking" strategy to overcome inefficient nanomedicine delivery and tumor hypoxia for enhanced photodynamic-immunotherapy.
  3. An Enzymatically Gated Catalytic Hairpin Assembly Delivered by Lipid Nanoparticles for the Tumor-Specific Activation of Signal Amplification in miRNA Imaging.
  4. Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation.
  5. Lipid-mRNA nanoparticles landscape for cancer therapy.
  6. Natural Shaping of Acellular Dermal Matrices for Implant-based Breast Reconstruction via Expansile Kirigami.
  7. Programming Non-Nucleic Acid Molecules into Computational Nucleic Acid Systems.
  8. Oral vaccination using microdevices to deliver α-GalCer adjuvanted vaccine afford mucosal immunity.
  9. Folate Receptor-Mediated Delivery of Cas9 RNP for Enhanced Immune Checkpoint Disruption in Cancer Cells.
  10. Flash drug release from nanoparticles accumulated in the targeted blood vessels facilitates the tumour treatment.
  11. Tumor-derived miRNAs as tumor microenvironment regulators for synergistic therapeutic options.
  12. Multiplexed Ultrasensitive Sample-to-Answer RT-LAMP Chip for the Identification of SARS-CoV-2 and Influenza Viruses.
  1. Nature. 2022 Nov 16.
    Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer.
    Jorge Luis Galeano Niño, Hanrui Wu, Kaitlyn D LaCourse, Andrew G Kempchinsky, Alexander Baryiames, Brittany Barber, Neal Futran, Jeffrey Houlton, Cassie Sather, Ewa Sicinska, Alison Taylor, Samuel S Minot, Christopher D Johnston, Susan Bullman.
      The tumour-associated microbiota is an intrinsic component of the tumour microenvironment across human cancer types1,2. Intratumoral host-microbiota studies have so far largely relied on bulk tissue analysis1-3, which obscures the spatial distribution and localized effect of the microbiota within tumours. Here, by applying in situ spatial-profiling technologies4 and single-cell RNA sequencing5 to oral squamous cell carcinoma and colorectal cancer, we reveal spatial, cellular and molecular host-microbe interactions. We adapted 10x Visium spatial transcriptomics to determine the identity and in situ location of intratumoral microbial communities within patient tissues. Using GeoMx digital spatial profiling6, we show that bacterial communities populate microniches that are less vascularized, highly immuno‑suppressive and associated with malignant cells with lower levels of Ki-67 as compared to bacteria-negative tumour regions. We developed a single-cell RNA-sequencing method that we name INVADEseq (invasion-adhesion-directed expression sequencing) and, by applying this to patient tumours, identify cell-associated bacteria and the host cells with which they interact, as well as uncovering alterations in transcriptional pathways that are involved in inflammation, metastasis, cell dormancy and DNA repair. Through functional studies, we show that cancer cells that are infected with bacteria invade their surrounding environment as single cells and recruit myeloid cells to bacterial regions. Collectively, our data reveal that the distribution of the microbiota within a tumour is not random; instead, it is highly organized in microniches with immune and epithelial cell functions that promote cancer progression.
    DOI:  https://doi.org/10.1038/s41586-022-05435-0
  2. Adv Healthc Mater. 2022 Nov 15. e2202467
    Dual "unlocking" strategy to overcome inefficient nanomedicine delivery and tumor hypoxia for enhanced photodynamic-immunotherapy.
    Xianglong Li, Cong Jiang, Xinlin Jia, Yuanyuan Cao, Yuanqing Mao, Ji-Na Hao, Yang Yang, Peng Zhang, Yongsheng Li.
      Lacking blood vessels is one of the main characteristics of most solid tumors due to their rapid and unrestricted growth, which thus remarkably causes the inefficient delivery efficiency of nanomedicine and tumor hypoxia. Herein, a dual "unlocking" strategy to overcome these obstacles is proposed by combining the engineered hybrid nanoparticles (named ZnPc@FOM-Pt) with dexamethasone (DXM). It is verified that pretreatment of tumors with DXM can increase intratumorally micro-vessel density (delivery "unlocking") to enhance the tumor delivery efficiency of ZnPc@FOM-Pt and decrease HIF-1α expression. Correspondingly, more Pt can catalyze tumor-overexpressed H2 O2 to produce oxygen to further cause hypoxia "unlocking", ultimately achieving boosted ZnPc-based photodynamic therapy in vivo (Tumor inhibition rate: 99.1%). Moreover, the immunosuppressive tumor microenvironment is efficiently reversed and the therapeutic effect of anti-PD-L1-based immunotherapy is promoted by this newly designed nanomedicine. This dual "unlocking" strategy provides an innovative paradigm on simultaneously enhancing nanomedicine delivery efficacy and hypoxia relief for tumor therapy. This article is protected by copyright. All rights reserved.
    Keywords:  Immunotherapy; Nanomedicine delivery; Photodynamic therapy; Tumor micro-vessel density modulation; anti-programmed death-ligand 1
    DOI:  https://doi.org/10.1002/adhm.202202467
  3. Angew Chem Int Ed Engl. 2022 Nov 16. e202214230
    An Enzymatically Gated Catalytic Hairpin Assembly Delivered by Lipid Nanoparticles for the Tumor-Specific Activation of Signal Amplification in miRNA Imaging.
    Qing Liu, Yuanyu Huang, Zhengping Li, Lele Li, Yuliang Zhao, Mengyuan Li.
      MicroRNA (miRNA) imaging in disease sites is vital to elucidate their role in cancer progression. However, limited tumor specificity remains a major barrier for traditional amplification approaches due to associated background signal leakage. Here, we report a generalizable approach via the combination of enzymatically triggered catalytic hairpin assembly with lipid nanoparticles (LNPs)-based delivery strategy for tumor-specific activation of signal amplification and therefore sensitive miRNA imaging. The signal amplification is established via engineering of traditional catalytic hairpin assembly with enzymatically activated motifs to achieve triggable miRNA imaging in cancer cells. Furthermore, by the introduction of LNPs to combat biological barriers, we demonstrate that the system enables amplified miRNA imaging in vivo with reduced off-tumor signal, leading to enhanced tumor-to-background contrast compared with traditional methods. This approach that relies on specific triggers and controlled delivery to distinguish miRNA in cancer cells from normal cells should be useful in tumor diagnosis.
    Keywords:  Enzyme; In Vivo; Lipid Nanoparticles; MiRNA Imaging; Signal Amplification
    DOI:  https://doi.org/10.1002/anie.202214230
  4. Nat Commun. 2022 Nov 14. 13(1): 6951
    Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation.
    Chengyu Shi, Ying Wang, Minjie Wu, Yu Chen, Fangzhou Liu, Zheyuan Shen, Yiran Wang, Shaofang Xie, Yingying Shen, Lingjie Sang, Zhen Zhang, Zerui Gao, Luojia Yang, Lei Qu, Zuozhen Yang, Xinyu He, Yu Guo, Chenghao Pan, Jinxin Che, Huaiqiang Ju, Jian Liu, Zhijian Cai, Qingfeng Yan, Luyang Yu, Liangjing Wang, Xiaowu Dong, Pinglong Xu, Jianzhong Shao, Yang Liu, Xu Li, Wenqi Wang, Ruhong Zhou, Tianhua Zhou, Aifu Lin.
      Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target.
    DOI:  https://doi.org/10.1038/s41467-022-34346-x
  5. Front Bioeng Biotechnol. 2022 ;10 1053197
    Lipid-mRNA nanoparticles landscape for cancer therapy.
    Yin Li, Hengtong Fang, Tao Zhang, Yu Wang, Tingting Qi, Bai Li, Huping Jiao.
      Intracellular delivery of message RNA (mRNA) technique has ushered in a hopeful era with the successive authorization of two mRNA vaccines for the Coronavirus disease-19 (COVID-19) pandemic. A wide range of clinical studies are proceeding and will be initiated in the foreseeable future to treat and prevent cancers. However, efficient and non-toxic delivery of therapeutic mRNAs maintains the key limited step for their widespread applications in human beings. mRNA delivery systems are in urgent demand to resolve this difficulty. Recently lipid nanoparticles (LNPs) vehicles have prospered as powerful mRNA delivery tools, enabling their potential applications in malignant tumors via cancer immunotherapy and CRISPR/Cas9-based gene editing technique. This review discusses formulation components of mRNA-LNPs, summarizes the latest findings of mRNA cancer therapy, highlights challenges, and offers directions for more effective nanotherapeutics for cancer patients.
    Keywords:  cancer immunotherapy; cancer nano-vaccine; gene editing; ionizable lipids; lipid nanoparticles (LNPs); mRNA delivery
    DOI:  https://doi.org/10.3389/fbioe.2022.1053197
  6. Adv Mater. 2022 Nov 17. e2208088
    Natural Shaping of Acellular Dermal Matrices for Implant-based Breast Reconstruction via Expansile Kirigami.
    Young-Joo Lee, Suhail K Kanchwala, Hyesung Cho, Jason Christopher Jolly, Eric Jablonka, Michael Tanis, Randall D Kamien, Shu Yang.
      To complete a successful and aesthetic breast reconstruction for breast cancer survivors, tissue reinforcing acellular dermal matrices (ADMs) are widely utilized to create slings/pockets to keep breast implants or autologous tissue transfer secured against the chest wall in the desired location. However, ADM sheets are two-dimensional, and cannot completely cover the entire implant without wrinkles. Here, guided by finite element modeling, we present a kirigami strategy to cut the ADM sheets with locally and precisely controlled stretchability, curvature, and elasticity. Upon expansion, a single kirigami ADM sheet can conformally wrap the implant regardless of the shape and size, forming a natural teardrop shape; contour cuts prescribe the topographical height and fractal cuts in the center ensures horizontal expandability and thus conformability. Our kirigami ADM could provide support to the reconstructed breast in the desired regions, potentially offering optimal outcomes and patient-specific reconstruction, while minimizing operative time and cost. This article is protected by copyright. All rights reserved.
    Keywords:  Acellular dermal matrix; Breast reconstruction; Expansile kirigami; Natural and conformal shaping
    DOI:  https://doi.org/10.1002/adma.202208088
  7. Angew Chem Int Ed Engl. 2022 Nov 14.
    Programming Non-Nucleic Acid Molecules into Computational Nucleic Acid Systems.
    Qiu-Long Zhang, Yang Wang, Liang-Liang Wang, Fan Xie, Ruo-Yue Wu, Xu-Yang Ma, Han Li, Yan Liu, Shunchun Yao, Liang Xu.
      Nucleic acid (NA) computation has been widely developed in the past years to solve kinds of logic and mathematic issues in both information technologies and biomedical analysis. However, the difficulty to integrate non-NA molecules limits its power as a universal platform for molecular computation. Here, we report a versatile prototype of hybridized computation integrated with both nucleic acids and non-NA molecules. Employing the conformationally controlled ligand converters, we demonstrate that non-NA molecules, including both small molecules and proteins, can be computed as nucleic acid strands to construct the circuitry with increased complexity and scalability, and can be even programmed to solve arithmetical calculations within the computational nucleic acid system. This study opens a new door for molecular computation in which all-NA circuits can be expanded with integration of various ligands, and meanwhile, ligands can be precisely programmed by the nuclei acid computation.
    Keywords:  Dynamic DNA Nanotechnology; Information Technology; Ligand Integration; Molecular Computation; Nucleic Acid Circuits
    DOI:  https://doi.org/10.1002/anie.202214698
  8. J Control Release. 2022 Nov 10. pii: S0168-3659(22)00759-3. [Epub ahead of print]
    Oral vaccination using microdevices to deliver α-GalCer adjuvanted vaccine afford mucosal immunity.
    Philip H R Carlsen, Rolf Bech Kjeldsen, Gabriel K Pedersen, Dennis Christensen, Line Hagner Nielsen, Anja Boisen.
      Oral vaccination has in the recent years gained a lot of attraction, mainly due to optimized patient compliance and logistics. However, the development of oral vaccines, especially oral subunit vaccines is challenging. Micro technology can be utilized to overcome some of these challenges, by facilitating protection and effective delivery of the vaccine components in the gastrointestinal tract (GI tract). One such technology is Microcontainers (MCs), which can be realized to be mucoadhesive and to target specific regions of the GI tract via oral delivery. Here, we test MCs, for oral delivery of the C. trachomatis vaccine candidate CTH522, in combination with effective mucosal adjuvants. The adjuvants alpha- galactosylceramide (α-GalCer), C-di-GMP and cholera toxin B were compared in vivo, to identify the most prominent adjuvant for formulation with CTH522. Formulations were administered both purely oral and as boosters following a subcutaneous (s.c.) prime with CTH522 in combination with the CAF®01 adjuvant. CTH522 formulated with α-GalCer showed to be the most efficient combination for the oral vaccine, based on the immunological analysis. Lyophilized formulation of CTH522 and α-GalCer was loaded into MCs and these were subsequently coated with Eudragit L100-55 and evaluated in vivo in mice for the ability of MCs to mediate intestinal vaccine delivery and increase immunogenicity of the vaccine. Mice receiving oral prime and boosters did show a significantly enhanced mucosal immune responses compared to naive mice. This indicates the MCs are indeed capable of delivering the vaccine formulation intact and able to stimulate the immune cells. Mice orally boosted with MCs following a s.c. prime with CAF01, demonstrated improved systemic and local Th17 responses, along with increased local IFN-γ and IgA levels compared to both the s.c. prime alone and the homologous oral prime-boost immunization. However, due to the relatively weak observed effect of the MC delivery on the immune responses, it was hypothesized that the MCs are proportionally too large for the GI tract of mice, and thus cleared before an effective immune response can be induced. To investigate this, MCs were loaded with BaSO4, and orally administered to mice. Analysis with X-ray and CT showed a transit time of approximately 1-1.5 h from the stomach to the cecum, corresponding to the standard transit time in mice, and an extremely narrow absorption window. This indicates that mice is not a suitable animal model for evaluation of MCs. These data should be taken into consideration in future in vivo trials with this and similar technologies, where larger animals might be a necessity for proof-of-concept studies.
    Keywords:  Lyophilization.; Oral vaccination microcontainers adjuvants CAF01 Th17
    DOI:  https://doi.org/10.1016/j.jconrel.2022.11.015
  9. Small. 2022 Nov 18. e2205318
    Folate Receptor-Mediated Delivery of Cas9 RNP for Enhanced Immune Checkpoint Disruption in Cancer Cells.
    Yi Lin, Ulrich Wilk, Jana Pöhmerer, Elisa Hörterer, Miriam Höhn, Xianjin Luo, Hongcheng Mai, Ernst Wagner, Ulrich Lächelt.
      The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system offers great opportunities for the treatment of numerous diseases by precise modification of the genome. The functional unit of the system is represented by Cas9/sgRNA ribonucleoproteins (RNP), which mediate sequence-specific cleavage of DNA. For therapeutic applications, efficient and cell-specific transport into target cells is essential. Here, Cas9 RNP nanocarriers are described, which are based on lipid-modified oligoamino amides and folic acid (FolA)-PEG to realize receptor-mediated uptake and gene editing in cancer cells. In vitro studies confirm strongly enhanced potency of receptor-mediated delivery, and the nanocarriers enable efficient knockout of GFP and two immune checkpoint genes, PD-L1 and PVR, at low nanomolar concentrations. Compared with non-targeted nanoparticles, FolA-modified nanocarriers achieve substantially higher gene editing including dual PD-L1/PVR gene disruption after injection into CT26 tumors in vivo. In the syngeneic mouse model, dual disruption of PD-L1 and PVR leads to CD8+ T cell recruitment and distinct CT26 tumor growth inhibition, clearly superior to the individual knockouts alone. The reported Cas9 RNP nanocarriers represent a versatile platform for potent and receptor-specific gene editing. In addition, the study demonstrates a promising strategy for cancer immunotherapy by permanent and combined immune checkpoint disruption.
    Keywords:  cellular delivery; clustered regularly interspaced short palindromic repeats/ clustered regularly interspaced short palindromic repeats-associated protein 9; folate receptors; gene editing; nanocarriers
    DOI:  https://doi.org/10.1002/smll.202205318
  10. Nat Commun. 2022 Nov 14. 13(1): 6910
    Flash drug release from nanoparticles accumulated in the targeted blood vessels facilitates the tumour treatment.
    Ivan V Zelepukin, Olga Yu Griaznova, Konstantin G Shevchenko, Andrey V Ivanov, Ekaterina V Baidyuk, Natalia B Serejnikova, Artur B Volovetskiy, Sergey M Deyev, Andrei V Zvyagin.
      Tumour microenvironment hinders nanoparticle transport deep into the tissue precluding thorough treatment of solid tumours and metastatic nodes. We introduce an anticancer drug delivery concept termed FlaRE (Flash Release in Endothelium), which represents alternative to the existing approaches based on enhanced permeability and retention effect. This approach relies on enhanced drug-loaded nanocarrier accumulation in vessels of the target tumour or metastasised organ, followed by a rapid release of encapsulated drug within tens of minutes. It leads to a gradient-driven permeation of the drug to the target tissue. This pharmaceutical delivery approach is predicted by theoretical modelling and validated experimentally using rationally designed MIL-101(Fe) metal-organic frameworks. Doxorubicin-loaded MIL-101 nanoparticles get swiftly trapped in the vasculature of the metastasised lungs, disassemble in the blood vessels within 15 minutes and release drug, which rapidly impregnates the organ. A significant improvement of the therapeutic outcome is demonstrated in animal models of early and late-stage B16-F1 melanoma metastases with 11-fold and 4.3-fold decrease of pulmonary melanoma nodes, respectively.
    DOI:  https://doi.org/10.1038/s41467-022-34718-3
  11. J Cancer Res Clin Oncol. 2022 Nov 15.
    Tumor-derived miRNAs as tumor microenvironment regulators for synergistic therapeutic options.
    Qiuxing Meng, Yaoming Deng, Yu Lu, Chunfeng Wu, Shifu Tang.
      MicroRNAs (miRNAs) are a class of non-coding RNAs that perform post-transcriptional gene regulation. This review focuses on the role of tumor cell-derived miRNAs in the regulation of the tumor microenvironment (TME) via receptor cell recoding, including angiogenesis, expression of immunosuppressive molecules, formation of radiation resistance, and chemoresistance. Furthermore, we discuss the potential of these molecules as adjuvant therapies in combination with chemotherapy, radiotherapy, or immunotherapy, as well as their advantages as efficacy predictors for personalized therapy. MiRNA-based therapeutic agents for tumors are currently in clinical trials, and while challenges remain, additional research on tumor-derived miRNAs is warranted, which may provide significant clinical benefits to cancer patients.
    Keywords:  Microenvironment; Predictor; Synergistic therapy; Tumor; Tumor-derived miRNA
    DOI:  https://doi.org/10.1007/s00432-022-04432-0
  12. Adv Mater. 2022 Nov 17. e2207138
    Multiplexed Ultrasensitive Sample-to-Answer RT-LAMP Chip for the Identification of SARS-CoV-2 and Influenza Viruses.
    Minsun Song, SoonGweon Hong, Luke P Lee.
      Prompt on-site diagnosis of SARS-CoV-2 with other respiratory infections would have minimized the global impact of the COVID-19 pandemic through rapid, effective management. However, no such multiplex point-of-care (POC) chip has satisfied a suitable sensitivity of gold-standard nucleic acid amplification tests (NAATs). Here, we present a rapid multiplexed ultrasensitive sample-to-answer LAMP (MUSAL) chip operated by simple LED-driven photothermal amplification to detect six targets from single-swab sampling. First, our MUSAL chip allows ultrafast on-chip sample preparation with ∼500-fold preconcentration at a rate of 1.2 mL min-1 . Second, our chip enables contamination-free amplification using autonomous target elution into on-chip reagents by photothermal activation. Finally, our chip accomplishes multiplexed on-chip diagnostics of SARS-CoV-2 and influenza viruses with a limit of detection (LoD) of 0.5 copies μL-1 . Our rapid, ultra-sensitive, cost-effective sample-to-answer chip with a multiplex capability will allow timely management of various pandemics situations we may face shortly. This article is protected by copyright. All rights reserved.
    Keywords:  RT-LAMP; SARS-CoV-2; multiplex; on-chip sample preparation; preconcentration; sample-to-answer; ultrasensitive POC chip
    DOI:  https://doi.org/10.1002/adma.202207138
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