bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒04‒11
thirteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Nat Chem. 2021 Apr 08.
      The encoding of chemical compounds with amplifiable DNA tags facilitates the discovery of small-molecule ligands for proteins. To investigate the impact of stereo- and regiochemistry on ligand discovery, we synthesized a DNA-encoded library of 670,752 derivatives based on 2-azido-3-iodophenylpropionic acids. The library was selected against multiple proteins and yielded specific ligands. The selection fingerprints obtained for a set of protein targets of pharmaceutical relevance clearly showed the preferential enrichment of ortho-, meta- or para-regioisomers, which was experimentally verified by affinity measurements in the absence of DNA. The discovered ligands included novel selective enzyme inhibitors and binders to tumour-associated antigens, which enabled conditional chimeric antigen receptor T-cell activation and tumour targeting.
  2. Small. 2021 Apr 07. e2100287
      Ovarian cancer is an aggressive tumor owing to its ability to metastasize from stage II onward. Herein, lipid nanoparticles (LNPs) that encapsulate combination of small interfering RNAs (siRNAs), polo-like kinase-1 (PLK1), and eukaryotic translation-initiation factor 3c (eIF3c), to target different cellular pathways essential for ovarian cancer progression are generated. The LNPs are further modified with hyaluronan (tNPs) to target cluster of differentiation 44 (CD44) expressing cells. Interestingly, hyaluronan-coated LNPs (tNPs) prolong functional activity and reduce growth kinetics of spheroids in in vitro assay as compared to uncoated LNPs (uNPs) due to ≈1500-fold higher expression of CD44. Treatment of 2D and 3D cultured ovarian cancer cells with LNPs encapsulating both siRNAs result in 85% cell death and robust target gene silencing. In advanced orthotopic ovarian cancer model, intraperitoneal administration of LNPs demonstrates CD44 specific tumor targeting of tNPs compared to uNPs and robust gene silencing in tissues involved in ovarian cancer pathophysiology. At very low siRNA dose, enhanced overall survival of 60% for tNPs treated mice is observed compared to 10% and 20% for single siRNA-, eIF3c-tNP, and PLK1-tNP treatment groups, respectively. Overall, LNPs represent promising platform in the treatment of advanced ovarian cancer by improving median- and overall-survival.
    Keywords:  gene delivery; lipid nanoparticle; ovarian cancer; small interfering RNA; targeting
  3. Sci Adv. 2021 Apr;pii: eabe6374. [Epub ahead of print]7(15):
      Treating osteoarthritis (OA) remains a major clinical challenge. Despite recent advances in drug discovery and development, no disease-modifying drug for knee OA has emerged with any notable clinical success, in part, due to the lack of valid and responsive therapeutic targets and poor drug delivery within knee joints. In this work, we show that the amount of secretory phospholipase A2 (sPLA2) enzyme increases in the articular cartilage in human and mouse OA cartilage tissues. We hypothesize that the inhibition of sPLA2 activity may be an effective treatment strategy for OA. To develop an sPLA2-responsive and nanoparticle (NP)-based interventional platform for OA management, we incorporated an sPLA2 inhibitor (sPLA2i) into the phospholipid membrane of micelles. The engineered sPLA2i-loaded micellar NPs (sPLA2i-NPs) were able to penetrate deep into the cartilage matrix, prolong retention in the joint space, and mitigate OA progression. These findings suggest that sPLA2i-NPs can be promising therapeutic agents for OA treatment.
  4. Nat Commun. 2021 04 06. 12(1): 2041
      An effective tumor vaccine vector that can rapidly display neoantigens is urgently needed. Outer membrane vesicles (OMVs) can strongly activate the innate immune system and are qualified as immunoadjuvants. Here, we describe a versatile OMV-based vaccine platform to elicit a specific anti-tumor immune response via specifically presenting antigens onto OMV surface. We first display tumor antigens on the OMVs surface by fusing with ClyA protein, and then simplify the antigen display process by employing a Plug-and-Display system comprising the tag/catcher protein pairs. OMVs decorated with different protein catchers can simultaneously display multiple, distinct tumor antigens to elicit a synergistic antitumour immune response. In addition, the bioengineered OMVs loaded with different tumor antigens can abrogate lung melanoma metastasis and inhibit subcutaneous colorectal cancer growth. The ability of the bioengineered OMV-based platform to rapidly and simultaneously display antigens may facilitate the development of these agents for personalized tumour vaccines.
  5. Investig Clin Urol. 2021 Mar 16.
      PURPOSE: MicroRNAs (miRNAs) are small non-coding RNAs and are involved in the development, proliferation, and pathogenesis of prostate cancer (PCa). Urinary miRNAs are promising non-invasive biomarkers for PCa diagnosis because of their stability in urine. Here, we evaluated the diagnostic value of urinary miR-1913 to miR-3659 ratio in PCa patients and benign prostate hyperplasia (BPH) controls.MATERIALS AND METHODS: Candidate miRNAs were identified from urinary microarray data and tested by real-time PCR. The urinary miR-1913 to miR-3659 expression ratio was selected and tested in 83 urine samples (44 PCa and 39 BPH) to confirm its validity as a non-invasive diagnostic biomarker for PCa.
    RESULTS: The expression ratio of urinary miR-1913 to miR-3659 was significantly higher in PCa than in BPH (p=0.002) and showed a higher area under the receiver operating characteristic curve than prostate-specific antigen (PSA; 0.821 vs. 0.518) in patients within the PSA gray zone (tPSA: 3-10 ng/mL), with sensitivity of 75.0% and specificity of 78.6% (p=0.003).
    CONCLUSIONS: The urinary miR-1913 to miR-3659 expression ratio was increased in PCa and may serve as a useful supplemental biomarker to PSA for the diagnosis of PCa, particularly in patients within the PSA gray zone.
    Keywords:  Biomarkers; Diagnosis; Gene expression; MicroRNA; Prostate neoplasms
  6. Small. 2021 Apr 10. e2100257
      Methicillin-resistant Staphylococcus aureus (MRSA) causes diseases ranging from skin infections to lethal sepsis and has become a serious threat to human health due to multiple-drug resistance (MDR). Therefore, a resistance-free antibacterial therapy is necessary to overcome MDR MRSA infections. In this study, an antibacterial nanorobot (Ab-nanobot) is developed wherein a cell wall-binding domain (CBD)-endolysin, acting as a sensor, is covalently conjugated with an actuator consisting of an iron oxide/silica core-shell. The CBD-endolysin sensor shows an excellent specificity to detect, bind, and accumulate on the S. aureus USA300 cell surface even in a bacterial consortium, and in host cell infections. Ab-nanobot specifically captures and kills MRSA in response to medically approved radiofrequency (RF) electromagnetic stimulation (EMS) signal. When Ab-nanobot receives the RF-EMS signal on the cell surface, actuator induces cell death in MRSA with 99.999% removal within 20 min by cell-wall damage via generation of localized heat and reactive oxygen species. The in vivo efficacy of Ab-nanobot is proven using a mice subcutaneous skin infection model. Collectively, this study offers a nanomedical resistance-free strategy to overcome MDR MRSA infections by providing a highly specific nanorobot for S. aureus.
    Keywords:  USA300; ab-nanobot; antimicrobial resistance; electromagnetic-stimulation; mice subcutaneous skin infection model; radiofrequency; staphylococcus aureus
  7. Adv Mater. 2021 Apr 08. e2100599
      A systematic combination strategy is proposed for overcoming cisplatin resistance using near-infrared (NIR)-light-triggered hyperthermia. A new photothermal polymer DAP-F is complexed with a reduction-sensitive amphiphilic polymer P1 to form F-NPs with photothermal effect. Subsequently, to build the final nanosystem F-Pt-NPs, F-NPs are combined with Pt-NPs, which are obtained by encapsulating a Pt(IV) prodrug with P1. Mild hyperthermia (43 °C), generated from F-Pt-NPs induced by an 808 nm NIR laser, have various effects such as: i) enhancing the cellular membrane permeability to promote the uptake of drugs; ii) activating cisplatin by accelerating the glutathione consumption; iii) increasing the Pt-DNA adducts formation and possibly the formation of a portion of irreparable Pt-DNA interstrand crosslinks, thereby inhibiting the repair of DNA. In vitro, it is found that even on cisplatin-resistant A549DDP cells, the IC50 of F-Pt-NPs (43 °C) is only 7.0 × 10-6 m Pt mL-1 . In vivo, on a patient-derived xenograft model of multidrug resistant lung cancer, the efficacy of the F-Pt-NPs (43 °C) treatment group shows a tumor inhibition rate of 94%. Taken together, here, an important perspective of resolving cascade drug resistance with the assistance of mild hyperthermia triggered by NIR light is presented, which can be of great significance for clinic translation.
    Keywords:  cascade drug resistance; cisplatin; combination therapy; mild hyperthermia; patient-derived xenograft models
  8. Sci Transl Med. 2021 Apr 07. pii: eaaz6804. [Epub ahead of print]13(588):
      Insufficient T cell infiltration into noninflamed tumors, such as hepatocellular carcinoma (HCC), restricts the effectiveness of immune-checkpoint blockade (ICB) for a subset of patients. Epigenetic therapy provides further opportunities to rewire cancer-associated transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune-excluded phenotype remain incompletely defined. Here, we showed that pharmacological inhibition of histone deacetylase 8 (HDAC8), a histone H3 lysine 27 (H3K27)-specific isozyme overexpressed in a variety of human cancers, thwarts HCC tumorigenicity in a T cell-dependent manner. The tumor-suppressive effect of selective HDAC8 inhibition was abrogated by CD8+ T cell depletion or regulatory T cell adoptive transfer. Chromatin profiling of human HDAC8-expressing HCCs revealed genome-wide H3K27 deacetylation in 1251 silenced enhancer-target gene pairs that are enriched in metabolic and immune regulators. Mechanistically, down-regulation of HDAC8 increased global and enhancer acetylation of H3K27 to reactivate production of T cell-trafficking chemokines by HCC cells, thus relieving T cell exclusion in both immunodeficient and humanized mouse models. In an HCC preclinical model, selective HDAC8 inhibition increased tumor-infiltrating CD8+ T cells and potentiated eradication of established hepatomas by anti-PD-L1 therapy without evidence of toxicity. Mice treated with HDAC8 and PD-L1 coblockade were protected against subsequent tumor rechallenge as a result of the induction of memory T cells and remained tumor-free for greater than 15 months. Collectively, our study demonstrates that selective HDAC8 inhibition elicits effective and durable responses to ICB by co-opting adaptive immunity through enhancer reprogramming.
  9. ACS Nano. 2021 Apr 05.
      The development of a theragnostic platform integrating precise diagnosis and effective treatment is significant but still extremely challenging. Herein, an integrated smart nanodevice composed of Au@Cu2-xS@polydopamine nanoparticles (ACSPs) and fuel DNA-conjugated tetrahedral DNA nanostructures (fTDNs) was constructed, in which the ACSP nanoprobe played multiple key roles in antitumor therapy as well as in situ monitoring of microRNAs (miRNAs) in cancer cells. Regarding the analysis, the ACSP probe contained two optical properties: excellent surface-enhanced Raman scattering (SERS) enhancement and high fluorescence (FL) quenching performance. Employing the ACSPs as the high-efficiency detection substrate combined with the fTDN-assisted DNA walking nanomachines as the superior amplification strategy, a SERS-FL dual-spectrum biosensor was constructed, which achieved an ultralow background signal and excellent sensitivity with detection limits of 0.11 pM and 4.95 aM by FL and SERS, respectively. Moreover, the rapid FL imaging and precise SERS quantitative detection for miRNA in cancer cells were also achieved by dual-signal ratio strategy, improving the accuracy of diagnosis. Regarding the therapeutic application, due to the high reactive oxygen species generation ability and excellent photothermal conversion efficiency, the ACSPs can also act as an all-in-one nanoagent for multimodal collaborative tumor therapy. Significantly, both in vivo and in vitro experiments confirmed its high biological safety and strong anticancer effect, indicating its promising theragnostic applications.
    Keywords:  DNA walking nanomachine; all-in-one nanoagent; dual-spectrum assay; in situ imaging; synergetic therapy
  10. Transl Oncol. 2021 Apr 05. pii: S1936-5233(21)00082-6. [Epub ahead of print]14(7): 101090
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival rate less than 8%, which has remained unchanged over the last 50 years. Early detection is particularly difficult due to the lack of disease-specific symptoms and a reliable biomarker. Multimodality treatment including chemotherapy, radiotherapy (used sparingly) and surgery has become the standard of care for patients with PDAC. Carbohydrate antigen 19-9 (CA 19-9) is the most common diagnostic biomarker; however, it is not specific enough especially for asymptomatic patients. Non-coding RNAs are often deregulated in human malignancies and shown to be involved in cancer-related mechanisms such as cell growth, differentiation, and cell death. Several micro, long non-coding and circular RNAs have been reported to date which are involved in PDAC. Aim of this review is to discuss the roles and functions of non-coding RNAs in diagnosis and treatments of PDAC.
    Keywords:  Circular RNA; Long non-coding RNA; MicroRNA; Non-coding RNAs; Pancreatic ductal adenocarcinoma
  11. Mol Ther Nucleic Acids. 2021 Jun 04. 24 264-273
      Patients with inflammatory bowel disease are at increased risk for colitis-associated colorectal cancer (CAC). Therefore, controlling intestinal inflammation is a key therapeutic strategy for CAC. MicroRNAs (miRNAs or miRs) are a family of small noncoding RNAs that have the capacity to regulate fundamental biological processes. To date, a number of miRNAs have been identified as critical regulators of inflammation. However, the specific role of miR-26a in colonic inflammation and colitis-associated carcinogenesis is still elusive. Here, we generated mice with miR-26a myeloid-cell-specific overexpression to show that miR-26a suppressed the intestinal inflammatory response in macrophages by decreasing nuclear factor κB (NF-κB)/STAT3 activation and interleukin 6 (IL-6) production. At the molecular level, a number of NF-κB regulators, including TLR3, PTEN, and PKCδ, were identified as potential targets of miR-26a. Our results thus identify a novel miRNA-mediated mechanism that suppresses carcinogenic inflammation in the colon.
    Keywords:  Colitis-associated carcinogenesis; Intestinal inflammation; Macrophage; MiR-26a; NF-κB/STAT3
  12. Adv Mater. 2021 Apr 08. e2006651
      Programming magnetic fields with microscale control can enable automation at the scale of single cells ≈10 µm. Most magnetic materials provide a consistent magnetic field over time but the direction or field strength at the microscale is not easily modulated. However, magnetostrictive materials, when coupled with ferroelectric material (i.e., strain-mediated multiferroics), can undergo magnetization reorientation due to voltage-induced strain, promising refined control of magnetization at the micrometer-scale. This work demonstrates the largest single-domain microstructures (20 µm) of Terfenol-D (Tb0.3 Dy0.7 Fe1.92 ), a material that has the highest magnetostrictive strain of any known soft magnetoelastic material. These Terfenol-D microstructures enable controlled localization of magnetic beads with sub-micrometer precision. Magnetically labeled cells are captured by the field gradients generated from the single-domain microstructures without an external magnetic field. The magnetic state on these microstructures is switched through voltage-induced strain, as a result of the strain-mediated converse magnetoelectric effect, to release individual cells using a multiferroic approach. These electronically addressable micromagnets pave the way for parallelized multiferroics-based single-cell sorting under digital control for biotechnology applications.
    Keywords:  Terfenol-D; magnetoelastic materials; multiferroics; single-cell separation; single-domain materials
  13. Proc Natl Acad Sci U S A. 2021 Mar 16. pii: e2026405118. [Epub ahead of print]118(11):
      Drug delivery systems featuring electrochemical actuation represent an emerging class of biomedical technology with programmable volume/flowrate capabilities for localized delivery. Recent work establishes applications in neuroscience experiments involving small animals in the context of pharmacological response. However, for programmable delivery, the available flowrate control and delivery time models fail to consider key variables of the drug delivery system--microfluidic resistance and membrane stiffness. Here we establish an analytical model that accounts for the missing variables and provides a scalable understanding of each variable influence in the physics of delivery process (i.e., maximum flowrate, delivery time). This analytical model accounts for the key parameters--initial environmental pressure, initial volume, microfluidic resistance, flexible membrane, current, and temperature--to control the delivery and bypasses numerical simulations allowing faster system optimization for different in vivo experiments. We show that the delivery process is controlled by three nondimensional parameters, and the volume/flowrate results from the proposed analytical model agree with the numerical results and experiments. These results have relevance to the many emerging applications of programmable delivery in clinical studies within the neuroscience and broader biomedical communities.
    Keywords:  analytical model; drug delivery; electrochemical actuation; flexible membrane; mechanics