bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒04‒03
fourteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Adv Mater. 2022 Mar 31. e2200839
      Lipid nanoparticles (LNPs) are versatile structures with tunable physicochemical properties that are ideally suited as a platform for vaccine delivery and RNA therapeutics. A key barrier to LNP rational design is the inability to relate composition and structure to intracellular processing and function. Here we combine Single Particle Automated Raman Trapping Analysis (SPARTA® ) with small angle scattering (SAXS / SANS) techniques to link LNP composition with internal structure and morphology and to monitor dynamic LNP - phospholipase D (PLD) interactions. Our analysis demonstrates that phospholipase D, a key intracellular trafficking mediator, can access the entire LNP lipid membrane to generate stable, anionic LNPs. PLD activity on vesicles with matched amounts of enzyme substrate was an order of magnitude lower, indicating that the LNP lipid membrane structure can be used to control enzyme interactions. This represents an opportunity to design enzyme-responsive LNP solutions for stimuli-responsive delivery and diseases where PLD is dysregulated.  This article is protected by copyright. All rights reserved.
    Keywords:  SANS; SAXS; nanoparticles; phospholipase D; raman spectroscopy
  2. Small Methods. 2022 Mar 28. e2101474
      Due to the heterogeneity of a tumor, the tumor vascular interruption-based therapy has become an ideal treatment strategy. Herein, artificial nanoplatelets are reported to induce selective thrombosis in tumor vessels, which can achieve rapid and large-scale necrosis of tumor cells. For one, the nanoplatelets are exploited to specially release thrombin into target regions without affecting the established coagulation factors system. For another, the thrombin elicits vascular infarction to provide tumor-ablation effects. More importantly, the size-dependent effect of nanoplatelets (with diameters of 200, 400, and 800 nm) in vivo on blocking the tumor vessels is evaluated. The results show that the nanoplatelets from nanometer to submicron have achieved different biodistribution and therapeutic effects through the vascular transport. Notably, 400 nm scale nanoplatelets can induce thrombosis in tumor vessels and achieve 83% of the tumor elimination rate, thus manifesting the effectiveness of anti-tumor strategy compared with the other two scales of nanoplatelets (200 and 800 nm). These findings highlight the need of concern about nanoparticle size, providing a promising strategy for the future design of advanced vascular targeting reagents and the clinical translation of tumor vascular interruption-based therapy.
    Keywords:  artificial nanoplatelets; blocking tumor vessels; size-dependent effects; thrombin; tumor vascular interruption-based therapy
  3. Small. 2022 Mar 28. e2200743
      Developing effective therapies to fight against biofilm-associated infection is extremely urgent. The complex environment of biofilm forces the bacteria to evade the elimination of antibiotics, resulting in recalcitrant chronic infections. To address this issue, a cationic antibacterial agent based on phosphindole oxide (β-PM-PIO) is designed and prepared. The unique molecular structure endows β-PM-PIO with aggregation-induced emission feature and efficient singlet oxygen generation ability. β-PM-PIO shows excellent visual diagnostic function to planktonic bacteria and biofilm. In addition, owing to the synergistic effect of phototoxicity and dark toxicity, β-PM-PIO can achieve superb antibacterial and antibiofilm performance against Gram-positive bacteria with less potential of developing drug resistance. Notably, β-PM-PIO also holds excellent anti-infection capacity against drug-resistant bacteria in vivo with negligible side effects. This work offers a promising platform to develop advanced antibacterial agents against multidrug-resistant bacterial infection.
    Keywords:  bacterial infection; biofilms; cationic photosensitizers; drug-resistance bacteria; phosphindole oxides
  4. Adv Sci (Weinh). 2022 Mar 27. e2200732
      Photothermal therapy based on conjugated polymers represents a promising antibacterial strategy but still possesses notable limitations. Herein, degradable pseudo conjugated polymers (PCPs) containing photothermal molecular backbones and reactive oxygen species (ROS)-sensitive thioketal bonds are designed. Triphenylphosphine (PPh3 ) is introduced into PCPs to generate phosphonium-based PCPs (pPCPs), which further assembled with hyaluronic acid into pPCP nanoparticles (pPCP-NPs). pPCP-NPs with quaternary phosphonium cations selectively anchor on and destroy bacterial cell membranes through electrostatic action. Under 1064 nm laser irradiation, pPCP-NPs (pPCP-NPs/+L) produce near-infrared-II (NIR-II) photothermal antibacterial effect, thereby killing bacteria in a sustained manner. pPCP-NPs are readily degraded upon ROS abundant at infection sites, therefore exhibiting enough biosafety. pPCP-NPs/+L display an almost 100% bacterial inhibition rate in vitro and resultin a nearly complete recovery of bacteria-induced mouse wounds. A further metabolomics analysis denotes that pPCP-NPs/+L work in a concerted way to induce bacterial DNA damage, inhibit bacterial carbon/nitrogen utilization and amino acid/nucleotide synthesis. Taken together, degradable pPCP-NPs with both NIR-II photothermal effect and cationic phosphonium structural bacteriostasis provide a new avenue for antibiotics-alternative anti-infection therapy.
    Keywords:  anti-infectieon therapy; cationic quaternary phosphonium structural bacteriostasis; nanoparticle; photothermal antibacterial effect; pseudo conjugated polymer
  5. Adv Mater. 2022 Mar 31. e2202168
      Nanovaccines have emerged as promising alternatives or complements to conventional cancer treatments. Despite the progresses, specific co-delivery of antigen and adjuvant to their corresponding intracellular destinations for maximizing the activation of antitumor immune responses remains a challenge. Herein, we developed a lipid-coated iron oxide nanoparticle as nanovaccine (IONP-C/O@LP) that could co-deliver peptide antigen and adjuvant (CpG DNA) into cytosol and lysosomes of dendritic cells (DCs) through both membrane fusion and endosome-mediated endocytosis. Such two-pronged cellular uptake pattern enabled IONP-C/O@LP to synergistically activate immature DCs. Iron oxide nanoparticle also exhibited adjuvant effects by generating intracellular reactive oxygen species, which further promoted DC maturation. IONP-C/O@LP accumulated in the DCs of draining lymph nodes effectively increased the antigen-specific T cells in both tumor and spleen, inhibited tumor growth, and improved animal survival. Moreover, we have demonstrated that this nanovaccine is a general platform of delivering clinically relevant peptide antigens derived from human papilloma virus 16 to trigger antigen-specific immune responses in vivo. This article is protected by copyright. All rights reserved.
    Keywords:  CpG; cancer immunotherapy; iron oxide nanoparticle; membrane fusion; nanovaccine
  6. Adv Mater. 2022 Mar 30. e2200182
      Soft, elastically deformable composites with liquid metal (LM) droplets can enable new generations of soft electronics, robotics, and reconfigurable structures. However, techniques to control local composite microstructure, which ultimately governs material properties and performance, is lacking. Here we develop a direct ink writing technique to program LM microstructure (i.e., shape, orientation, and connectivity) on demand throughout elastomer composites. In contrast to inks with rigid particles that have fixed shape and size, we show that emulsion inks with LM fillers enable in-situ control of microstructure. This enables filaments, films, and 3D structures with unique LM microstructures that are generated on demand and locked in during printing. This includes smooth and discrete transitions from spherical to needle-like droplets, curvilinear microstructures, geometrically complex embedded inclusion patterns, and connected LM pathways. The printed materials are soft (modulus < 200 kPa), highly deformable (> 600% strain), and can be made locally insulating or electrically conductive using a single ink by controlling process conditions. We demonstrate these capabilities by embedding elongated LM droplets in a soft heat sink, which rapidly dissipates heat from high power LEDs. These programmable microstructures can enable new composite paradigms for emerging technologies that demand mechanical compliance with multifunctional response.  This article is protected by copyright. All rights reserved.
    Keywords:  3D printing; additive manufacturing; liquid metal; microstructure; soft robots
  7. Adv Sci (Weinh). 2022 Mar 31. e2105854
      The blood-brain barrier (BBB) severely blocks the intracranial accumulation of most systemic drugs. Inspired by the contribution of the bacterial outer membrane to Escherichia coli K1 (EC-K1) binding to and invasion of BBB endothelial cells in bacterial meningitis, utilization of the BBB invasion ability of the EC-K1 outer membrane for brain-targeted drug delivery and construction of a biomimetic self-assembled nanoparticle with a surface featuring a lipopolysaccharide-free EC-K1 outer membrane are proposed. BBB penetration of biomimetic nanoparticles is demonstrated to occur through the transcellular vesicle transport pathway, which is at least partially dependent on internalization, endosomal escape, and transcytosis mediated by the interactions between outer membrane protein A and gp96 on BBB endothelial cells. This biomimetic nanoengineering strategy endows the loaded drugs with prolonged circulation, intracranial interstitial distribution, and extremely high biocompatibility. Based on the critical roles of gp96 in cancer biology, this strategy reveals enormous potential for delivering therapeutics to treat gp96-overexpressing intracranial malignancies.
    Keywords:  bacterial outer membrane; biomimetic; blood-brain barrier; drug delivery; nanoparticles
  8. Adv Sci (Weinh). 2022 Mar 28. e2105875
      Atherosclerosis with unstable plaques is the dominant pathological basis of lethal cardio-cerebrovascular diseases, which can cause acute death due to the rupture of plaques. Plaque-targeted drug delivery to achieve promoted treatment remains the main challenge because of the systemic occurrence of atheroma. Herein, a rapamycin (RAP) spherical nucleic acid (SNA) structure, capable of specifically accumulating in plaques for synergistic atherosclerosis treatment is constructed. By designing consecutive phosphorothioate (PS) at 3' terminus of the deoxyribonucleic acid (DNA) strand, multiple hydrophobic RAPs are covalently grafted onto the PS segment to form an amphiphilic drug-grafted DNA (RAP-DNA), which successively self-assembles into micellar SNA (RAP-SNA). Moreover, the phosphodiester-DNA segment constitutes the outer shell of RAP-SNA, enabling further hybridization with functional siRNA (targeting lectin-like oxidized low-density lipoprotein receptor-1, LOX-1) to obtain the drug codelivered SNA (LOX-1/RAP-SNA). With two active ingredients inside, LOX-1/RAP-SNA can not only induce robust autophagy and decrease the evil apoptosis of the pathological macrophages, but also simultaneously prohibit the LOX-1-mediated formation of damageable foam cells, realizing the effect of synergistic therapy. As a result, the LOX-1/RAP-SNA significantly reduces the progression of atheroma and stabilizes the plaques, providing a new strategy for synergistically targeted atherosclerosis treatment.
    Keywords:  LOX-1; atherosclerosis; plaque targeting; rapamycin; spherical nucleic acids
  9. J Control Release. 2022 Mar 23. pii: S0168-3659(22)00163-8. [Epub ahead of print]
      Complex in vitro models of human immune cells and intestinal mucosa may have a translation-assisting role in the assessment of anti-inflammatory compounds. Chronic inflammation of the gastrointestinal tract is a hallmark of inflammatory bowel diseases (IBD). In both IBD entities, Crohn's disease and ulcerative colitis, impaired immune cell activation and dysfunctional epithelial barrier are the common pathophysiology. Current therapeutic approaches are targeting single immune modulator molecules to stop disease progression and reduce adverse effects. Such molecular targets can be difficult to assess in experimental animal models of colitis, due to the disease complexity and species differences. Previously, a co-culture model based on human epithelial cells and monocytes arranged in a physiological microenvironment was used to mimic inflamed mucosa for toxicological and permeability studies. The leaky gut model described here, a co-culture of Caco-2, THP-1 and MUTZ-3 cells, was used to mimic IBD-related pathophysiology and for combined investigations of permeability and target engagement of two Janus kinase (JAK) inhibitors, tofacitinib (TOFA) and a JAK1-targeting siRNA nanomedicine. The co-culture just before reaching confluency of the epithelium was used to mimic the compromised intestinal barrier. Delivery efficacy and target engagement against JAK1 was quantified via downstream analysis of STAT1 protein phosphorylation after IFN-γ stimulation. Compared to a tight barrier, the leaky gut model showed 92 ± 5% confluence, a barrier function below 200 Ω*cm2, and enhanced immune response to bacteria-derived lipopolysaccharides. By confocal microscopy we observed an increased accumulation of siJAK1-nanoparticles within the sub-confluent regions leading to uptake into immune cells near the epithelium. A concentration-dependent downregulation of JAK/STAT pathway was observed for siJAK1-nanoparticles (10 ± 12% to 16 ± 12%), whereas TOFA inhibition was 86 ± 2%, compared to untreated cells. By mimicking the status of severely damaged epithelium, like in IBD, the leaky gut model holds promise as a human in vitro system to evaluate the efficacy of anti-inflammatory drugs and nanomedicines.
    Keywords:  IBD; In vitro model; JAK/STAT pathway; Lipid nanoparticles; Tofacitinib; siRNA
  10. ACS Nano. 2022 Mar 31.
      The slow mass transport of the target molecule essentially limits the biosensing performance. Here, we report a Janus mesoporous microsphere/Pt-based (meso-MS/Pt) nanostructure with greatly enhanced target transport and accelerated recognition process for microRNA (miRNA) amplified detection in complex biological samples. The mesoporous MS was synthesized via double emulsion interfacial polymerization, and Pt nanoparticles (PtNPs) were deposited on the half-MS surface to construct Janus meso-MS/Pt micromotor. The heterogeneous meso-MS/Pt with a large surface available was attached to an entropy-driven DNA recognition system, termed meso-MS/Pt/DNA, and the tremendous pores network was beneficial to enhanced receptor-target interaction. It enabled moving around complex biological samples to greatly enhance target miRNA mass transport and accelerate recognition procedure due to the self-diffusiophoretic propulsion. Coupling with the entropy-driven signal amplification, extremely sensitive miRNA detection in Dulbecco's modified Eagle medium (DMEM), and cell lysate without preparatory and washing steps was realized. Given the free preparatory and washing steps, fast mass transport, and amplified capability, the meso-MS/Pt/DNA micromotor provides a promising method for miRNAs analysis in real biological samples.
    Keywords:  Janus micromotor; complex biological samples; entropy-driven DNA probe; meso-MS/Pt/DNA; microRNA detection
  11. Soft Matter. 2022 Mar 31.
      The properties of stimuli-responsive hydrogels can be tailored under various external stimuli, but it is difficult to realize the customized adjustment of hydrogel properties since the crosslinking degree in the gelation process is intractable. Here, a visible light triggered thiol-disulfide exchange reaction was applied for constructing disulfide-crosslinked hydrogels from P(EMA-SS-PEG), a poly(ethylene glycol) grafted poly(ethyl methacrylate) derivative with a disulfide linkage as the grafting point. This photochemical method provides mild gelation conditions to handily regulate the morphology, mechanical properties, swelling ratio, and degradation rate of hydrogels by simply varying the irradiation time. Based on this strategy, these disulfide-crosslinked hydrogel coatings showed rapid self-healing in 10 min under ambient conditions, which was dependent on the width of the scratch, temperature, and humidity. Notably, spraying water on these coatings could significantly accelerate the self-healing process of large scratches (360 μm) at room temperature with a self-healing time of 1 hour, enabling the practical application of hydrogel coatings in a natural environment.
  12. ACS Nano. 2022 Mar 28.
      Microrobots driven by multiple propelling forces hold great potential for noninvasively targeted delivery in the physiologic environment. However, the remotely collective perception and precise propelling in a low Reynold's number bioenvironment remain the major challenges of microrobots to achieve desired therapeutic effects in vivo. Here, we reported a biohybrid microrobot that integrated with magnetic, thermal, and hypoxia sensitivities and an internal fluorescent protein as the dual reporter of thermal and positioning signals for targeted cancer treatment. There were three key elements in the microrobotic system, including the magnetic nanoparticle (MNP)-loaded probiotic Escherichia coli Nissle1917 (EcN@MNP) for spatially magnetic and hypoxia perception, a thermal-logic circuit engineered into the bacteria to control the biosynthesis of mCherry as the temperature and positioning reporter, and NDH-2 enzyme encoded in the EcN for enhanced anticancer therapy. According to the fluorescent-protein-based imaging feedback, the microrobot showed good thermal sensitivity and active targeting ability to the tumor area in a collective manner under the magnetic field. The cancer cell apoptosis was efficiently triggered in vitro and in vivo by the hybrid microrobot coupled with the effects of magnetothermal ablation and NDH-2-induced reactive oxygen species (ROS) damage. Our study demonstrates that the biohybrid EcN microrobot is an ideal platform to integrate the physical, biological, and chemical properties for collective perception and propelling in targeted cancer treatment.
    Keywords:  biohybrid microrobot; cancer treatment; collective perception; imaging-guided therapy; magnetothermal activation
  13. Nat Commun. 2022 Apr 01. 13(1): 1772
      Cooperative motion in biological microswimmers is crucial for their survival as it facilitates adhesion to surfaces, formation of hierarchical colonies, efficient motion, and enhanced access to nutrients. Here, we confine synthetic, catalytic microswimmers along one-dimensional paths and demonstrate that they too show a variety of cooperative behaviours. We find that their speed increases with the number of swimmers, and that the activity induces a preferred distance between swimmers. Using a minimal model, we ascribe this behavior to an effective activity-induced potential that stems from a competition between chemical and hydrodynamic coupling. These interactions further induce active self-assembly into trains where swimmers move at a well-separated, stable distance with respect to each other, as well as compact chains that can elongate, break-up, become immobilized and remobilized. We identify the crucial role that environment morphology and swimmer directionality play on these highly dynamic chain behaviors. These activity-induced interactions open the door toward exploiting cooperation for increasing the efficiency of microswimmer motion, with temporal and spatial control, thereby enabling them to perform intricate tasks inside complex environments.
  14. Nat Nanotechnol. 2022 Mar 28.
      DNA has become the biomolecule of choice for molecular computation that may one day complement conventional silicon-based processors. In general, DNA computation is conducted in individual tubes, is slow in generating chemical outputs in response to chemical inputs and requires fluorescence readout. Here, we introduce a new paradigm for DNA computation where the chemical input is processed and transduced into a mechanical output using dynamic DNA-based motors operating far from equilibrium. We show that DNA-based motors with onboard logic (DMOLs) can perform Boolean functions (NOT, YES, AND and OR) with 15 min readout times. Because DMOLs are micrometre-sized, massive arrays of DMOLs that are identical or uniquely encoded by size and refractive index can be multiplexed and perform motor-to-motor communication on the same chip. Finally, DMOL computational outputs can be detected using a conventional smartphone camera, thus transducing chemical information into the electronic domain in a facile manner, suggesting potential applications.