bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒07‒03
thirteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Biomaterials. 2022 May 25. pii: S0142-9612(22)00239-3. [Epub ahead of print]287 121599
      The compact extracellular matrix (ECM) of pancreatic ductal adenocarcinoma (PDAC) is the major physical barrier that hinders the delivery of anti-tumor drugs, leading to strong inherent chemotherapy resistance as well as establishing an immunosuppressive tumor microenvironment (TME). However, forcibly destroying the stroma barrier would break the balance of delicate signal transduction and dependence between tumor cells and matrix components. Uncontrollable growth and metastasis would occur, making PDAC more difficult to control. Hence, we design and construct an aptamer-decorated hypoxia-responsive nanoparticle s(DGL)n@Apt co-loading gemcitabine monophosphate and STAT3 inhibitor HJC0152. This nanoparticle can reverse its surficial charge in the TME, and reduce the size triggered by hypoxia. The released ultra-small DGL particles loading gemcitabine monophosphate exhibit excellent deep-tumor penetration, chemotherapy drugs endocytosis promotion, and autophagy induction ability. Meanwhile, HJC0152 inhibits overactivated STAT3 in both tumor cells and tumor stroma, softens the stroma barrier, and reeducates the TME into an immune-activated state. This smart codelivery strategy provides an inspiring opportunity in PDAC treatment.
    Keywords:  Charge reversal; Deep penetration; Hypoxia-responsive; Size reduction; TME modulation
  2. ACS Nano. 2022 Jul 01.
      A soccer-ball-shaped three-dimensional DNA origami framework was assembled to serve as an exoskeleton and to direct liposome growth inside. With up to 90 available inner modification sites, cholesterol moieties were introduced as nucleation seeds, and the vesicle templating efficiency was systematically investigated with precisely regulated seed numbers and arrangements. We confirmed that a nonsaturated optimum number (n = 30) of nucleation seeds with relatively even spatial distribution was essential for achieving well-templated and highly uniform liposomes. The seed arrangement principles and effects and the liposome formation mechanisms are thoroughly discussed. The revealed key factors in the design and optimization of 3D DNA nanoframes for functional liposome production could benefit the fields of nanotechnology and molecular medicine.
    Keywords:  DNA origami framework; molecular medicine; nucleation seeds; spatial distribution; templated liposome
  3. ACS Nano. 2022 Jun 28.
      Asthma is an intractable disease involving the infiltration of inflammatory cells and mucus plugging. Despite small molecular mucolytics having the ability to break the disulfide bonds of mucins, offering a potential way to overcome the airflow obstruction and airway infection, these mucolytics have limited therapeutic effects in vivo. Therefore, in this work, arginine-grafted chitosan (CS-Arg) is ionically cross-linked with tris(2-carboxyethyl)phosphine (TCEP) to obtain nanogels as a mucolytic agent. The positively charged nanogels effectively inhibit the formation of large aggregates of mucin in vitro, probably thanks to the formation of an ionic interaction between CS-Arg and mucin, as well as the breakage of disulfide bonds in mucin by the reductive TCEP. Moreover, the nanogels show good cytocompatibility at concentrations up to 5 mg mL-1, exhibiting effective inhibitory effects against the proliferation of both Staphylococcus aureus and Escherichia coli at 5 mg mL-1. After the administration of the nanogels by nebulization into a Balb/c mouse model with allergic asthma, they can efficiently reduce the mucus obstruction in bronchioles and alveoli and relieve airway inflammation. Therefore, these CS-Arg/TCEP nanogels potentially represent a promising mucolytic agent for the efficient treatment of allergic asthma and other muco-obstructive diseases.
    Keywords:  airway mucus obstruction; mucoadhesive; mucolysis; nanogel; pulmonary inflammation
  4. Nat Nanotechnol. 2022 Jun 30.
      Cells that were previously described as homogeneous are composed of subsets with distinct transcriptional states. However, it remains unclear whether this cell heterogeneity influences the efficiency with which lipid nanoparticles (LNPs) deliver messenger RNA therapies in vivo. To test the hypothesis that cell heterogeneity influences LNP-mediated mRNA delivery, we report here a new multiomic nanoparticle delivery system called single-cell nanoparticle targeting-sequencing (SENT-seq). SENT-seq quantifies how dozens of LNPs deliver DNA barcodes and mRNA into cells, the subsequent protein production and the transcriptome, with single-cell resolution. Using SENT-seq, we have identified cell subtypes that exhibit particularly high or low LNP uptake as well as genes associated with those subtypes. The data suggest that cell subsets have distinct responses to LNPs that may affect mRNA therapies.
  5. Adv Mater. 2022 Jun 27. e2205462
      Lung metastasis is challenging in patients with triple-negative breast cancer (TNBC). Surgery is always not available due to the dissemination of metastatic foci and most of drugs are powerless because of poor retention at metastatic sites. TNBC cells generate inflamed microenvironment and overexpress adhesive molecules to promote the invasion and colonization. Herein, we develop walking dead TNBC cells through conjugating anti-PD-1 (programmed death protein 1 inhibitor) and doxorubicin (DOX)-loaded liposomes onto cell corpses for temporal chemo-immunotherapy against lung metastasis. The walking dead TNBC cells maintain plenary tumor antigens to conduct vaccination effects. Anti-PD-1 antibodies are conjugated to cell corpses via reduction-activated linker, and DOX-loaded liposomes are attached by maleimide-thiol coupling. This anchor strategy enables rapid release of anti-PD-1 upon reduction conditions while long-lasting release of DOX at inflamed metastatic sites. The walking dead TNBC cells improve pulmonary accumulation and local retention of drugs, reprogram lung microenvironment through damage associated molecular patterns (DAMPs) and PD-1 blockade, and prolong overall survival of lung metastatic 4T1 and EMT6-bearing mice. Taking advantage of the walking dead TNBC cells for pulmonary preferred delivery of chemotherapeutics and checkpoint inhibitors, this study suggests an alternative treatment option of chemo-immunotherapy to augment the efficacy against lung metastasis. This article is protected by copyright. All rights reserved.
    Keywords:  PD-1 blockade; chemo-immunotherapy; drug delivery; metastasis; triple-negative breast cancer
  6. Proc Natl Acad Sci U S A. 2022 Jul 12. 119(28): e2200183119
      The term "molecular ZIP (or area) codes" refers to an originally hypothetical system of cell adhesion molecules that would control cell trafficking in the body. Subsequent discovery of the integrins, cadherins, and other cell adhesion molecules confirmed this hypothesis. The recognition system encompassing integrins and their ligands came particularly close to fulfilling the original ZIP code hypothesis, as multiple integrins with closely related specificities mediate cell adhesion by binding to an RGD or related sequence in various extracellular matrix proteins. Diseased tissues have their own molecular addresses that, although not necessarily involved in cell trafficking, can be made use of in targeted drug delivery. This article discusses the molecular basis of ZIP codes and the extensive effort under way to harness them for drug delivery purposes.
    Keywords:  bacteriophage; cancer drugs; integrins; neuropilin; tumor vessels
  7. ACS Nano. 2022 Jun 27.
      Sonodynamic therapy (SDT) and photothermal therapy (PTT) are two effective strategies for the treatment of atherosclerotic plaques. However, the low yield of reactive oxygen species (ROS) of conventional organic sonosensitizers and the low biosafety of hyperthermia limit the therapeutic efficacy of SDT and PTT. Herein, we report copper sulfide/titanium oxide heterostructure nanosheets modified with hyaluronic acid (HA) and PEG (HA-HNSs) for low-intensity sonodynamic and mild-photothermal synergistic therapy for early atherosclerotic plaques. CuS/TiO2 heterostructure nanosheets (HNSs) show high electron-hole separation efficiency and superior sonodynamic performance, because it has high surface energy crystal facets as well as a narrow band. Moreover, HNSs exhibit intense absorbance in the NIR-II region, which endows the nanosheets with excellent photothermal performance. With a further modification of HA, HA-HNSs can selectively target intraplaque proinflammatory macrophages through CD44-HA interaction. Because SDT reduces the expression of heat shock protein 90 and PTT facilitates the sonocatalytic process, the combination of SDT and PTT based on HA-HNSs could synergistically induce proinflammatory macrophage apoptosis. More importantly, the synergistic therapy prevents the progression of early atherosclerotic plaque by removing lesional macrophages and mitigating inflammation. Taken together, this work provides a macrophage-targeting sonodynamic/photothermal synergistic therapy, which is an effective translational clinical intervention for early atherosclerotic plaques.
    Keywords:  atherosclerosis; macrophages; nanosheets; photothermal therapy; sonodynamic therapy
  8. Acta Biomater. 2022 Jun 25. pii: S1742-7061(22)00374-9. [Epub ahead of print]
      Circumventing immune resistance and boosting immune response is the ultimate goal of cancer immunotherapy. Herein, we reported a tumor-associated macrophage (TAM) membrane-camouflaged nanodecoy containing a self-amplifying reactive oxygen species (ROS)-sensitive prodrug nanoparticle for specifically inducing immunogenic cell death (ICD) in combination with TAM depletion. A versatile ROS-cleavable camptothecin (CPT) prodrug (DCC) was synthesized through a thioacetal linker between CPT and the ROS generator cinnamaldehyde (CA), which could self-assemble into a uniform prodrug nanoparticle to realize a positive feedback loop of "ROS-triggered CA/CPT release and CA/CPT-mediated ROS generation." This DCC was further modified with the TAM membrane (abbreviated as DCC@M2), which could not only target both primary tumors and lung metastasis nodules through VCAM-1/α4β1 integrin interaction but also absorb CSF-1 secreted by tumor cells to disturb the interaction between TAMs and cancer cells. Our nanodecoy could effectively induce ICD cascade and deplete TAMs for priming tumor-specific effector T cell infiltration for antitumor immune response activation, which represents a versatile approach for cancer immunotherapy. STATEMENT OF SIGNIFICANCE: A tumor-associated macrophage (TAM) membrane-camouflaged nanodecoy containing a self-amplifying reactive oxygen species (ROS)-sensitive prodrug nanoparticle was fabricated for the first time. This ROS-cleavable camptothecin (CPT)/cinnamaldehyde (CA) prodrug (DCC) could self-assemble into a uniform nanoparticle to realize the positive feedback loop of "ROS-triggered CA/CPT release and CA/CPT-mediated ROS generation." After TAM membrane coating, this system (DCC@M2) could not only target both primary tumors and lung metastatic nodules but also scavenge CSF-1 secreted by tumor cells for TAM depletion for sufficient chemotherapy-sensitized immunotherapy.
    Keywords:  cancer immunotherapy; colony-stimulating factor 1; prodrug nanoparticles; self-amplifying; tumor immunosuppressive microenvironment; tumor-associated macrophage
  9. J Control Release. 2022 Jun 28. pii: S0168-3659(22)00370-4. [Epub ahead of print]348 870-880
      Dental decay is a highly prevalent chronic disease affecting people from all ages. Clinically, fluoride supplementation is the primary strategy in the prevention of dental decay. However, the current existing self-application formulations such as gels or mouthwashes are rapidly cleared after administration, resulting in modest efficacy even after repeated applications. Therefore, a user-friendly formulation that can provide sustained fluoride release in the oral cavity is of great interest for dental decay prevention. Herein, we report the utilization of fused deposition modelling to fabricate personalised mouthguards, which allow local and prolonged fluoride elution. Composite filaments comprising sodium fluoride and polymers with tuneable hydrophobicity were produced using blends of poly(ε-caprolactone) (PCL) and poly(vinyl alcohol) or poly(ethylene glycol) (PEG). The materials exhibited suitable mechanical properties for dental devices as well as different release kinetics depending on their composition. Ex vivo studies were performed on decayed human teeth using the 3D printed tooth caps that precisely fit the complex geometries of each specimen. A significant elevation of fluoride content in the lesion mineral in contact with the PCL/PEG tooth caps was achieved compared to the ones in contact with solutions mimicking dental care products. In conclusion, this study suggested that a sustained localized drug release of fluoride from personalised 3D printed mouthguards at the device-enamel interface can improve the incorporation of fluoride in the tooth matrix and prevent lesion progression.
    Keywords:  3D printing; Enamel remineralization; Fluoride; Personalized medical device; Tooth decay; Tunable drug delivery
  10. Nat Commun. 2022 Jun 30. 13(1): 3453
      Universal CAR T-cell therapies are poised to revolutionize cancer treatment and to improve patient outcomes. However, realizing these advantages in an allogeneic setting requires universal CAR T-cells that can kill target tumor cells, avoid depletion by the host immune system, and proliferate without attacking host tissues. Here, we describe the development of a novel immune-evasive universal CAR T-cells scaffold using precise TALEN-mediated gene editing and DNA matrices vectorized by recombinant adeno-associated virus 6. We simultaneously disrupt and repurpose the endogenous TRAC and B2M loci to generate TCRαβ- and HLA-ABC-deficient T-cells expressing the CAR construct and the NK-inhibitor named HLA-E. This highly efficient gene editing process enables the engineered T-cells to evade NK cell and alloresponsive T-cell attacks and extend their persistence and antitumor activity in the presence of cytotoxic levels of NK cell in vivo and in vitro, respectively. This scaffold could enable the broad use of universal CAR T-cells in allogeneic settings and holds great promise for clinical applications.
  11. Nat Commun. 2022 Jun 25. 13(1): 3634
      Fungal infections cause more than 1.5 million deaths annually. With an increase in immune-deficient susceptible populations and the emergence of antifungal drug resistance, there is an urgent need for novel strategies to combat these life-threatening infections. Here, we use a combinatorial screening approach to identify an imidazopyrazoindole, NPD827, that synergizes with fluconazole against azole-sensitive and -resistant isolates of Candida albicans. NPD827 interacts with sterols, resulting in profound effects on fungal membrane homeostasis and induction of membrane-associated stress responses. The compound impairs virulence in a Caenorhabditis elegans model of candidiasis, blocks C. albicans filamentation in vitro, and prevents biofilm formation in a rat model of catheter infection by C. albicans. Collectively, this work identifies an imidazopyrazoindole scaffold with a non-protein-targeted mode of action that re-sensitizes the leading human fungal pathogen, C. albicans, to azole antifungals.
  12. Proc Natl Acad Sci U S A. 2022 Jul 05. 119(27): e2200845119
      Gated protein channels act as rapid, reversible, and fully-closeable nanoscale valves to gate chemical transport across the cell membrane. Replicating or outperforming such a high-performance gating and valving function in artificial solid-state nanopores is considered an important yet unsolved challenge. Here we report a bioinspired rapid and reversible nanopore gating strategy based on controlled nanoparticle blockage. By using rigid or soft nanoparticles, we respectively achieve a trapping blockage gating mode with volatile memory where gating is realized by electrokinetically trapped nanoparticles near the pore and contact blockage gating modes with nonvolatile memory where gating is realized by a nanoparticle physically blocking the pore. This gating strategy can respond to an external voltage stimulus (∼200 mV) or pressure stimulus (∼1 atm) with response time down to milliseconds. In particular, when 1,2-diphytanoyl-sn-glycero-3-phosphocholine liposomes are used as the nanoparticles, the gating efficiency, defined as the extent of nanopore closing compared to the opening state, can reach 100%. We investigate the mechanisms for this nanoparticle-blockage-enabled nanopore gating and use it to demonstrate repeatable controlled chemical releasing via single nanopores. Because of the exceptional spatial and temporal control offered by this nanopore gating strategy, we expect it to find applications for drug delivery, biotic-abiotic interfacing, and neuromorphic computing.
    Keywords:  electrokinetic; gated protein channels; liposome; nanoparticle blockage; nanopore gating
  13. Adv Healthc Mater. 2022 Jul 01. e2200939
      Bioadhesive performance will be compromised due to bleeding. Bleeding increases mortality. Adhesive with hemostatic function is of great significance. We report a sustainable and robust hemostatic bioadhesive from okra. The adhesive strength reaches around 3- and 6-fold higher than commercial fibrin on pigskin and glass, respectively. The okra gel presents high-pressure resistance and great underwater adhesive strength. In human blood experiments, the okra gel can activate platelets, enhance the adhesion of activated platelets, and release coagulation factors Ⅺ and Ⅻ. By forming a fast gel layer and closely adhering to the wound, it can quickly stop bleeding in the liver and heart of rabbits and dogs. Meanwhile, okra gel can cause platelet activation at the wound site and further strengthen its hemostatic performance. Okra gel is biocompatible, biodegradable, and can promote wound healing. Okra gel shows potential as a sustainable bioadhesive, especially in the scenario of significant hemorrhage. This article is protected by copyright. All rights reserved.
    Keywords:  Bioadhesive; Hemostatic; Human blood; Liver and heart; Plant-derived okra gel; Rabit and Dog model