bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒05‒02
nineteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Science. 2021 Apr 30. pii: eabe5601. [Epub ahead of print]372(6541):
      CRISPR-Cas systems provide RNA-guided adaptive immunity in prokaryotes. We report that the multisubunit CRISPR effector Cascade transcriptionally regulates a toxin-antitoxin RNA pair, CreTA. CreT (Cascade-repressed toxin) is a bacteriostatic RNA that sequesters the rare arginine tRNAUCU (transfer RNA with anticodon UCU). CreA is a CRISPR RNA-resembling antitoxin RNA, which requires Cas6 for maturation. The partial complementarity between CreA and the creT promoter directs Cascade to repress toxin transcription. Thus, CreA becomes antitoxic only in the presence of Cascade. In CreTA-deleted cells, cascade genes become susceptible to disruption by transposable elements. We uncover several CreTA analogs associated with diverse archaeal and bacterial CRISPR-cas loci. Thus, toxin-antitoxin RNA pairs can safeguard CRISPR immunity by making cells addicted to CRISPR-Cas, which highlights the multifunctionality of Cas proteins and the intricate mechanisms of CRISPR-Cas regulation.
  2. Biomaterials. 2021 Apr 23. pii: S0142-9612(21)00202-7. [Epub ahead of print]273 120846
      Developing nanocarrier systems with sufficient drug loading ability and efficient drug release behavior in cells is a powerful strategy to maximize therapeutic efficacies and minimize side effects of administered drugs. However, the two aspects are usually contradictory in a single nanocarrier. Herein, polyphenol-DNA nanocomplex with controllable assembly/disassembly behaviors is developed for responsive and sequential drug release in cancer cells. Programmable assembly of branched-DNA achieves multiple-gene loading, afterwards tannic acid (TA), plant-derived polyphenols as drugs mediate assembly of branched-DNA to form nanocomplex. Intracellularly, two-step disassembly process of nanocomplex enables efficient gene/drug release. Lysosomal acidic microenvironment induces the disassembly of nanocomplex to release TA and branched-DNA. Glutathione and DNase I in cytoplasm trigger the precise release of genes from branched-DNA. The efficacy of multiple-gene/chemo-therapy is demonstrated using in vitro and in vivo models. This work provides a controllable assembly/disassembly route to resolve the conflict between sufficient drug loading and efficient drug release in cells for therapeutics.
    Keywords:  DNA nanostructures; DNA nanotechnology; Gene therapy; Natural polyphenol; Self-assembly
  3. Nat Rev Cancer. 2021 Apr 27.
      Therapeutic cancer vaccines have undergone a resurgence in the past decade. A better understanding of the breadth of tumour-associated antigens, the native immune response and development of novel technologies for antigen delivery has facilitated improved vaccine design. The goal of therapeutic cancer vaccines is to induce tumour regression, eradicate minimal residual disease, establish lasting antitumour memory and avoid non-specific or adverse reactions. However, tumour-induced immunosuppression and immunoresistance pose significant challenges to achieving this goal. In this Review, we deliberate on how to improve and expand the antigen repertoire for vaccines, consider developments in vaccine platforms and explore antigen-agnostic in situ vaccines. Furthermore, we summarize the reasons for failure of cancer vaccines in the past and provide an overview of various mechanisms of resistance posed by the tumour. Finally, we propose strategies for combining suitable vaccine platforms with novel immunomodulatory approaches and standard-of-care treatments for overcoming tumour resistance and enhancing clinical efficacy.
  4. Angew Chem Int Ed Engl. 2021 Apr 27.
      Tumor biomarker-based theranostics has achieved broad interest and success in recent years. However, single biomarker-based recognition can cause false-positive feedback, including the on-target off-tumor phenomenon by the absence of tumor-specific antigen. Besides, multi-biomarker-based recognition molecules often elicit nonspecific and undesired internalization when they bind to ''bystander'' cells. Herein, we report a universal DNA tetrahedral scaffold (DTS) that anchors on the cell membrane to load multiple aptamers and therapeutics for precise and effective theranostics. This DNA logic-gated nanorobot (DLGN) not only facilitates the precise discrimination among five cell lines, but also triggers the synergistic killing of effector aptamer-tethered synergistic drugs (EASDs) to target cancer cells. Logic-gated recognition integrated in aptamer-functionalized molecular machines will prompt fast tumor profiling, in situ capture and isolation, and safe delivery of precise medicine.
    Keywords:  DNA nanorobot; Theranostics; logic gate; synergistic therapy; tumor classification
  5. Adv Sci (Weinh). 2021 Apr;8(8): 2003679
      Photodynamic therapy (PDT) of cancer is limited by tumor hypoxia. Platinum nanoparticles (nano-Pt) as a catalase-like nanoenzyme can enhance PDT through catalytic oxygen supply. However, the cytotoxic activity of nano-Pt is not comprehensively considered in the existing methods to exert their multifunctional antitumor effects. Here, nano-Pt are loaded into liposomes via reverse phase evaporation. The clinical photosensitizer verteporfin (VP) is loaded in the lipid bilayer to confer PDT activity. Murine macrophage cell membranes are hybridized into the liposomal membrane to confer biomimetic and targeting features. The resulting liposomal system, termed "nano-Pt/VP@MLipo," is investigated for chemophototherapy in vitro and in vivo in mouse tumor models. At the tumor site, oxygen produced by nano-Pt catalyzation improves the VP-mediated PDT, which in turn triggers the release of nano-Pt via membrane permeabilization. The ultrasmall 3-5 nm nano-Pt enables better penetration in tumors, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy. Chemophototherapy with a single injection of nano-Pt/VP@MLipo and light irradiation inhibits the growth of aggressive 4T1 tumors and their lung metastasis, and prolongs animal survival without overt toxicity.
    Keywords:  biomimetics; liposomes; photodynamic therapy; platinum nanoparticles; tumor penetration
  6. ACS Appl Mater Interfaces. 2021 Apr 28.
      The CRISPR/Cas9 gene-editing system has become a promising strategy for tumor therapy with its powerful oncogene-editing ability. However, the efficient delivery of sgRNA/Cas9 complex into target tumor cells remains a challenge. Herein, we report a facile strategy for the construction of an sgRNA/Cas9 complex co-assembled nanoplatform for targeted gene editing and combined tumor therapy. In our design, the TAT peptide and thiolated DNA linker functionalized gold nanorod can efficiently load the sgRNA/Cas9 complex through the hybridization between the 3' overhang of sgRNA and the DNA linker. Due to the integration of an active cell targeting group (aptamer) and nuclear targeting peptide (TAT), the multifunctional nanoplatform can elicit the targeted cellular internalization and efficient nuclear targeting transportation to realize endogenous RNase H activated gene editing of the tumor-associated gene polo-like kinase 1 (PLK1). With mild photothermal treatment, this sgRNA/Cas9 complex loaded nanoplatform achieved efficient inhibition of tumor cell proliferation. This multifunctional nanocarrier provides a new strategy for the development of combined tumor therapy.
    Keywords:  drug delivery; gene editing; gold nanorod; nucleic acid self-assembly; tumor therapy
  7. Adv Sci (Weinh). 2021 Apr;8(8): 2004128
      Atherosclerotic plaque is the primary cause of cardiovascular disorders and remains a therapeutic hurdle for the early intervention of atherosclerosis. Traditional clinical strategies are often limited by surgery-related complications or unsatisfactory effects of long-term drug administration. Inspired by the plaque-binding ability of platelets, a biomimic photodynamic therapeutic system is designed to mitigate the progression of atherosclerotic plaques. This system is composed of photosensitizer-loaded upconversion nanoparticle cores entrapped in the platelet membrane. The platelet membrane coating facilitates specific targeting of the therapeutic system to macrophage-derived foam cells, the hallmark, and main component of early stage atherosclerotic plaques, which is firmly confirmed by in vivo fluorescent and single-photon emission computed tomography/computed tomography (SPECT/CT) radionuclide imaging. Importantly, in vivo phototherapy guided by SPECT/CT imaging alleviates plaque progression. Further immunofluorescence analysis reveals foam cell apoptosis and ameliorated inflammation. This biomimic system, which combines plaque-binding with radionuclide imaging guidance, is a novel, noninvasive, and potent strategy to mitigate the progression of atherosclerotic plaque.
    Keywords:  atherosclerotic plaques; photodynamics; platelet‐mimicking systems; radionuclide imaging
  8. Nat Biomed Eng. 2021 Apr 26.
      The immunosuppressive microenvironment of solid tumours reduces the antitumour activity of chimeric antigen receptor T cells (CAR-T cells). Here, we show that the release-through the implantation of a hyaluronic acid hydrogel-of CAR-T cells targeting the human chondroitin sulfate proteoglycan 4, polymer nanoparticles encapsulating the cytokine interleukin-15 and platelets conjugated with the checkpoint inhibitor programmed death-ligand 1 into the tumour cavity of mice with a resected subcutaneous melanoma tumour inhibits the local recurrence of the tumour as well as the growth of distant tumours, through the abscopal effect. The hydrogel, which functions as a reservoir, facilitates the enhanced distribution of the CAR-T cells within the surgical bed, and the inflammatory microenvironment triggers platelet activation and the subsequent release of platelet-derived microparticles. The post-surgery local delivery of combination immunotherapy through a biocompatible hydrogel reservoir could represent a translational route for preventing the recurrence of cancers with resectable tumours.
  9. Adv Mater. 2021 Apr 26. e2101158
      Multimodal therapy is attracting increasing attention to improve tumor treatment efficacy, but generally requires various complicated ingredients combined within one theranostic system to achieve multiple functions. Herein, a multifunctional theranostic nanoplatform based on a single aggregation-induced-emission luminogen (AIEgen), DDTB, is designed to integrate near-infrared (NIR) fluorescence, photothermal, photodynamic, and immunological effects. Intravenously injected AIEgen-based nanoparticles can efficiently accumulate in tumors with NIR fluorescence to provide preoperative diagnosis. Most of the tumors are excised under intraoperative fluorescence navigation, whereafter, some microscopic residual tumors are completely ablated by photodynamic and photothermal therapies for maximally killing the tumor cells and tissues. Up to 90% of the survival rate can be achieved by this synergistic image-guided surgery and photodynamic and photothermal therapies. Importantly, the nanoparticles-mediated photothermal/photodynamic therapy plus programmed death-ligand 1 antibody significantly induce tumor elimination by enhancing the effect of immunotherapy. This theranostic strategy on the basis of a single AIEgen significantly improves the survival of cancer mice with maximized therapeutic outcomes, and holds great promise for clinical cancer treatment.
    Keywords:  aggregation-induced emission; immunotherapy; intraoperative fluorescence navigation; multimodal therapy; phototheranostics
  10. J Control Release. 2021 Apr 22. pii: S0168-3659(21)00183-8. [Epub ahead of print]
      Peritendinous adhesion, secondary to the repair surgery of tendon rupture or injury, is one of the most common causes of reoperation, owing to the proliferation of fibrous tissue and excessive collagen synthesis caused by the residing inflammatory cells. In this study, a smart oxidative stress-responsive electrospun polyester membrane (EPM) was fabricated as both physical barrier and reservoir of curcumin/celecoxib (CUR/CEL) to prevent peritendinous adhesion. The multicomponent EPM was designed to release the encapsulated drugs in response to oxidative stress of the local microenvironment induced by inflammation. Specifically, sulfides in the EPM were able to react with reactive oxygen species (ROS) and become hydrophilic sulfoxide or sulfone to accelerate the release rate of drugs and regulate oxidative stress level in the inflammatory site intelligently. The oxidation-sensitive multicomponent EPM loaded with CUR and CEL was tested for anti-adhesion capacity in vitro and in vivo. An excellent ROS-sensitive degradation behavior and good cytocompatibility with cell viability of above 85% were presented with the fabricated EPM. The CUR- or CEL-loaded EPM possessed a better anti-adhesion ability compared with EPM without the drugs. Nevertheless, they were inferior to the EPM simultaneously loaded with both drugs, where the adhesion rate and fibrous adhesion number in the EPM + CUR/CEL group were close to extremely low values of about zero, demonstrating that CUR and CEL could synergistically prevent peritendinous adhesion. More interestingly, the multicomponent EPM was able to react with the local oxidative stress, leading to a smart and sustained behavior of releasing approximately 80% of the drug within 20 days. Overall, the smart multicomponent EPM offers a promising barrier strategy to prevent peritendinous adhesion.
    Keywords:  Anti-adhesion; Anti-bacterium; Anti-inflammation; Electrospun polyester membrane; Oxidative stress-responsiveness
  11. Adv Sci (Weinh). 2021 Apr;8(8): 2004379
      Nuclei and mitochondria are the only cellular organelles containing genes, which are specific targets for efficient cancer therapy. So far, several photosensitizers have been reported for mitochondria targeting, and another few have been reported for nuclei targeting. However, none have been reported for photosensitization in both mitochondria and nucleus, especially in cascade mode, which can significantly reduce the photosensitizers needed for maximal treatment effect. Herein, a light-driven, mitochondria-to-nucleus cascade dual organelle cancer cell ablation strategy is reported. A functionalized iridium complex, named BT-Ir, is designed as a photosensitizer, which targets mitochondria first for photosensitization and subsequently is translocated to a cell nucleus for continuous photodynamic cancer cell ablation. This strategy opens new opportunities for efficient photodynamic therapy.
    Keywords:  functional iridium complex; mitochondria‐to‐nucleus translocation; nucleic acid damage; photodynamic therapy
  12. Sci Adv. 2021 Apr;pii: eabd4742. [Epub ahead of print]7(18):
      m6A RNA modification is implicated in multiple cellular responses. However, its function in the innate immune cells is poorly understood. Here, we identified major m6A "writers" as the top candidate genes regulating macrophage activation by LPS in an RNA binding protein focused CRISPR screening. We have confirmed that Mettl3-deficient macrophages exhibited reduced TNF-α production upon LPS stimulation in vitro. Consistently, Mettl3 flox/flox;Lyzm-Cre mice displayed increased susceptibility to bacterial infection and showed faster tumor growth. Mechanistically, the transcripts of the Irakm gene encoding a negative regulator of TLR4 signaling were highly decorated by m6A modification. METTL3 deficiency led to the loss of m6A modification on Irakm mRNA and slowed down its degradation, resulting in a higher level of IRAKM, which ultimately suppressed TLR signaling-mediated macrophage activation. Our findings demonstrate a previously unknown role for METTL3-mediated m6A modification in innate immune responses and implicate the m6A machinery as a potential cancer immunotherapy target.
  13. ACS Biomater Sci Eng. 2021 Apr 28.
      Nanoparticulate formulations are being developed toward enhancing the bioavailability of orally administrated biologics. However, the processes mediating particulate carriers' intestinal uptake and transport remains to be fully elucidated. Herein, an optical clearing-based whole tissue mount/imaging strategy was developed to enable high quality microscopic imaging of intestinal specimens. It enabled the distribution of nanoparticles within intestinal villi to be quantitatively analyzed at a cellular level. Two-hundred and fifty nm fluorescent polystyrene nanoparticles were modified with polyethylene glycol (PEG), Concanavalin A (ConA), and pectin to yield mucopenetrating, enterocyte targeting, and mucoadhesive model nanocarriers, respectively. Introducing ConA on the PEGylated nanoparticles significantly increased their uptake in the intestinal epithelium (∼4.16 fold for 200 nm nanoparticle and ∼2.88 fold for 50 nm nanoparticles at 2 h). Moreover, enterocyte targeting mediated the trans-epithelial translocation of 50 nm nanoparticles more efficiently than that of the 200 nm nanoparticles. This new approach provides an efficient methodology to obtain detailed insight into the transcytotic activity of enterocytes as well as the barrier function of the constitutive intestinal mucus. It can be applied to guide the rational design of particulate formulations for more efficient oral biologics delivery.
    Keywords:  intestinal uptake and transport; optical tissue clearing; oral drug delivery; particulate nanocarriers; physicochemical properties
  14. ACS Appl Mater Interfaces. 2021 Apr 29.
      The generation of complex physicochemical signals on the surface of biomedical materials is still challenging despite the fact that a broad range of surface modification methods have been developed over the last few decades. Colloidal self-assembled patterns (cSAPs) are combinations of unique colloids differing in size and surface chemistry acting as building blocks that can be programmed to generate surface patterns with exquisite control of complexity. This study reports on producing a variety of pre-modified colloids for the fabrication of cSAPs as well as post-assembly modifications to yield complex surfaces. The surface of cSAPs presents hierarchical micro- and nanostructures, localized hydrophilic/hydrophobic characteristics, and tunable surface functionality imparted by the individual colloids. The selected cSAPs can control bacterial adhesion (S. aureus, P. aeruginosa, and E. coli) and affect the cell cycle of human bone marrow stem cells (hBMSCs). Moreover, in a mouse subcutaneous model, cSAPs with selective [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium (SBMA) modification can reduce the inflammatory response after being challenged with bacteria. This study reveals that functionalized cSAPs are versatile tools for controlling cellular responses at biointerfaces, which is instructive for biomaterials or biodevices.
    Keywords:  anti-inflammation; cell differentiation; colloidal self-assembly; patterned signals; topography
  15. Int J Mol Sci. 2021 Apr 12. pii: 3967. [Epub ahead of print]22(8):
      Colorectal cancer (CRC) is the third most deadly cancer worldwide, and inflammatory bowel disease (IBD) is one of the critical factors in CRC carcinogenesis. IBD is responsible for an unphysiological and sustained chronic inflammation environment favoring the transformation. MicroRNAs (miRNAs) belong to a class of highly conserved short single-stranded segments (18-25 nucleotides) non-coding RNA and have been extensively discussed in both CRC and IBD. However, the role of miRNAs in the development of colitis-associated CRC (CAC) is less clear. The aim of this review is to summarize the major upregulated (miR-18a, miR-19a, miR-21, miR-31, miR-155 and miR-214) and downregulated (miR-124, miR-193a-3p and miR-139-5p) miRNAs in CAC, and their roles in genes' expression modulation in chronic colonic-inflammation-induced carcinogenesis, including programmed cell-death pathways. These miRNAs dysregulation could be applied for early CAC diagnosis, to predict therapy efficacy and for precision treatment.
    Keywords:  biomarkers; colitis-associated colorectal cancer; colorectal cancer; inflammatory bowel disease; microRNA
  16. Adv Sci (Weinh). 2021 Apr;8(8): 2003627
      Treatment of wounds in special areas is challenging due to inevitable movements and difficult fixation. Common cotton gauze suffers from incomplete joint surface coverage, confinement of joint movement, lack of antibacterial function, and frequent replacements. Hydrogels have been considered as good candidates for wound dressing because of their good flexibility and biocompatibility. Nevertheless, the adhesive, mechanical, and antibacterial properties of conventional hydrogels are not satisfactory. Herein, cationic polyelectrolyte brushes grafted from bacterial cellulose (BC) nanofibers are introduced into polydopamine/polyacrylamide hydrogels. The 1D polymer brushes have rigid BC backbones to enhance mechanical property of hydrogels, realizing high tensile strength (21-51 kPa), large tensile strain (899-1047%), and ideal compressive property. Positively charged quaternary ammonium groups of tethered polymer brushes provide long-lasting antibacterial property to hydrogels and promote crawling and proliferation of negatively charged epidermis cells. Moreover, the hydrogels are rich in catechol groups and capable of adhering to various surfaces, meeting adhesive demand of large movement for special areas. With the above merits, the hydrogels demonstrate less inflammatory response and faster healing speed for in vivo wound healing on rats. Therefore, the multifunctional hydrogels show stable covering, little displacement, long-lasting antibacteria, and fast wound healing, demonstrating promise in wound dressing.
    Keywords:  adhesive; antibacterial dressings; hydrogel dressings; stretchable materials; wound healing
  17. Biochem Biophys Res Commun. 2021 Apr 24. pii: S0006-291X(21)00645-8. [Epub ahead of print]558 107-113
      MicroRNAs play an irreplaceable role in gene expression regulation. Upregulation of several miRNAs increases the risk of invasion and metastasis of breast cancer cells. An oncogenic miRNA, miR-21, is highly expressed in triple-negative breast cancer (TNBC) and is associated with tumor proliferation, invasion, carcinogenesis, prognosis, and therapeutic resistance. However, targeted delivery of therapeutic anti-miRNAs into cancer cells remains challenging, especially for TNBC. In this study, we report the application of an RNA nanotechnology-based platform for the targeted delivery of anti-miR-21 by epidermal growth factor receptor (EGFR) aptamer in vitro to TNBC and chemical-resistant breast cancer cells. RNA nanoparticles reduced cell viability and sensitized breast cancer cells to doxorubicin (DOX) treatment in vitro. Inhibition of miR-21 by RNA nanoparticles suppressed TNBC cell invasion, migration, and colony formation. The results indicate the potential application of nanotechnology-based delivery platforms in clinical anti-cancer therapeutics.
    Keywords:  RNA nanoparticles; Triple-negative breast cancer; miR-21
  18. J Control Release. 2021 Apr 24. pii: S0168-3659(21)00193-0. [Epub ahead of print]
      Facile engineering of β-cyclodextrin (β-CD)-based supramolecular nanocontainers with simultaneous enhanced extracellular stability and efficient intracellular biosignals-triggered destabilization generally suffers from multistep synthesis and tedious purification process, thus remains a significant challenge for the scale-up production and clinical translation of β-CD-based supramolecular nanomedicine. To address these issues, we reported in this study a one-pot preparation of dual-redox sensitive, stabilized supramolecular nanocontainers for potential programmable drug release by self-crosslinking of a multifunctional β-CD unit that integrates a host cavity for oxidation-mediated reversible complexation with ferrocence (Fc) guest molecule and lipoic acids (LAs)-decorated primary and secondary faces for reversible in-situ crosslinking by the reducible disulfide links. The resulting doxorubicin (DOX)-loaded nanoparticles showed, on one hand, enhanced colloidal stability and high DOX loading capacity with a drug loading content (DLC) of approximately 11.3% due to the crosslinked structure, and on the other hand, a programmable destruction of the supramolecular micelles triggered by a simultaneous adoption of intracellular glutathione (GSH) and reactive oxygen species (ROS) toward a complete structural destruction for promoted drug release with enhanced therapeutic efficiency. Notably, an optimized DOX-loaded micelle formation, DOX@CL P1 showed greater cytotoxicity with an IC50 of 2.94 ± 0.25 μg/mL than free DOX (6.00 ± 0.56 μg/mL) in Bel-7402 cancer liver cells, but a significantly reduced side effect relative to free DOX in L02 normal liver cells. In vivo animal study in Bel-7402 tumor-bearing BALB/c mice further confirmed prolonger elimination half-life time, efficient tumor accumulation, enhanced therapeutic efficiency and compromised systemic toxicity of this micelle construct. Therefore the multifunctional CD unit developed in this study offers an extremely straightforward and robust strategy with respect to dual-redox responsive, stabilized supramolecular nanocontainers with potential programmable controlled release properties for clinical translations.
    Keywords:  Controlled drug release; Cross-linking; Dual-redox sensitivity; Ferrocence; β-Cyclodextrin
  19. Front Pharmacol. 2021 ;12 653924
      During the last decades, a better understanding of the mechanisms sustaining the pathogenic process in inflammatory bowel diseases (IBD) has contributed to expand the therapeutic armamentarium for patients with these disorders. Alongside with traditional therapies, monoclonal antibodies against tumor necrosis factor-α, the interleukin (IL)-12/IL-23 p40 subunit and the α4β7 integrin, and tofacitinib, a small molecule inhibiting intracellular pathways downstream to cytokine receptors, have entered into the clinic. However, these drugs are not effective in all patients and some responders can lose response over time. Such a therapeutic failure is, at least in part, dependent on the fact that, in IBD, the tissue damage is driven by simultaneous activation of multiple and distinct immune-inflammatory signals and the detrimental mucosal immune response changes over time even in the same patient. Therefore, personalized approaches aimed at identifying which patient should be treated with a specific drug at a precise time point are worth pursuing. A such approach has the advantage to improve efficacy of the drug and limit adverse reactions, thereby improving quality of the life of the patients and reducing costs. In this review, we summarize all the available evidence about the possible role of precision medicine in IBD.
    Keywords:  IBD; anti-TNF; crohn’s disease; personalized medicine; ulcerative colitis