bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒08‒15
sixteen papers selected by
Ceren Kimna
Technical University of Munich

  1. ACS Nano. 2021 Aug 12.
      Metabolic interactions between different cell types in the tumor microenvironment (TME) often result in reprogramming of the metabolism to be totally different from their normal physiological processes in order to support tumor growth. Many studies have attempted to inhibit tumor growth and activate tumor immunity by regulating the metabolism of tumors and other cells in TME. However, metabolic inhibitors often suffer from the heterogeneity of tumors, since the favorable metabolic regulation of malignant cells and other cells in TME is often inconsistent with each other. Therefore, we reported the design of a pH-sensitive drug delivery system that targets different cells in TME successively. Outer membrane vesicles (OMVs) derived from Gram-negative bacteria were applied to coload paclitaxel (PTX) and regulated in development and DNA damage response 1 (Redd1)-siRNA and regulate tumor metabolism microenvironment and suppress tumor growth. Our siRNA@M-/PTX-CA-OMVs could first release PTX triggered by the tumor pH (pH 6.8). Then the rest of it would be taken in by M2 macrophages to increase their level of glycolysis. Great potential was observed in TAM repolarization, tumor suppression, tumor immune activation, and TME remolding in the triple-negative breast cancer model. The application of the OMV provided an insight for establishing a codelivery platform for chemical drugs and genetic medicines.
    Keywords:  TAM polarization; bacterial OMVs; cancer treatment; immune therapy; pH sensitive
  2. Adv Funct Mater. 2020 Apr 14. pii: 1908743. [Epub ahead of print]30(15):
      Oligodeoxynucleotides (ODNs) with CpG motifs have potent immunostimulatory effects on many subsets of immune cells. For example, Class B CpG-ODNs, such as ODN1826 induce the phagocytic activity of macrophages by activating the Toll-like receptor 9 signaling pathway. Systemic ODN delivery results in unfavorable pharmacokinetic profiles and can trigger adverse effects. To address this issue, plant virus-like particles (VLPs) are developed for the targeted delivery of ODN1826 to tumor-associated macrophages (TAMs). ODN1826 is encapsulated by the in vitro disassembly and reassembly of Cowpea chlorotic mottle virus (CCMV), producing VLPs that are structurally analogous to the native virus. The encapsulation of ODN1826 in CCMV-derived VLPs promotes ODN uptake by TAMs ex vivo and significantly enhance their phagocytic activity. The antitumor activity of the VLPs in vivo is also evaluated, revealing that the direct injection of ODN1826 VLPs into established tumors induces a robust antitumor response by increasing the phagocytic activity of TAMs in the tumor microenvironment. CCMV encapsulation significantly enhances the efficacy of ODN1826 compared to the free drug, slowing tumor growth and prolonging survival in mouse models of colon cancer and melanoma.
    Keywords:  CpG; biomimetic particle; cancer immunotherapy; macrophages; nanomedicine; virus particles
  3. Adv Mater. 2021 Aug 13. e2103497
      Immunotherapy has shown encouraging results in various cancers, but the response rates are relatively low due to the complex tumor immunosuppressive microenvironment (TIME). The presence of tumor-associated macrophages (TAMs) and tumor hypoxia correlates significantly with potent immunosuppressive activity. Here, a hemoglobin-poly(ε-caprolactone) (Hb-PCL) conjugate self-assembled biomimetic nano red blood cell (nano-RBC) system (V(Hb)) is engineered to deliver chemotherapeutic doxorubicin (DOX) and oxygen for reprogramming TIME. The Hb moiety of V(Hb)@DOX can bind to endogenous plasma haptoglobin (Hp) and specifically target the M2-type TAMs via the CD163 surface receptor, and effectively kill the cells. In addition, the O2 released by the Hb alleviates tumor hypoxia, which further augments the antitumor immune response by recruiting fewer M2-type macrophages. TAM-targeting depletion and hypoxia alleviation synergistically reprogram the TIME, which concurrently downregulate PD-L1 expression of tumor cells, decrease the levels of immunosuppressive cytokines such as IL-10 and TGF-β, elevate the immunostimulatory IFN-γ, enhance cytotoxic T lymphocyte (CTL) response, and boost a strong memory response. The ensuing TAM-targeted chemo-immunotherapeutic effects markedly inhibit tumor metastasis and recurrence. Taken together, the engineered endogenous TAM-targeted biomimetic nano-RBC system is a highly promising tool to reprogram TIME for cancer chemo-immunotherapy.
    Keywords:  biomimetic nano-RBC; chemo-immunotherapy; tumor hypoxia; tumor immunosuppressive microenvironment; tumor-associated macrophages
  4. Adv Healthc Mater. 2021 Aug 12. e2101190
      Brachytherapy, as an effective setting for precise cancer therapy in clinic, can lead to serious DNA damage. However, its therapeutic efficacy is always limited by the DNA self-repair property, tumor hypoxia-associated radiation resistance as well as inhomogeneous distribution of the radioactive material. Herein, a multifunctional hybrid hydrogel (131 I-hydrogel/DOX/GNPs aggregates) is developed by loading gold nanoparticle aggregates (GNPs aggregates) and DOX into a radionuclide iodine-131 (131 I) labelled polymeric hydrogels (131 I-PEG-P(Tyr)8 ) for tumor destruction by completely damaging DNA self-repair functions. This hybrid hydrogel exhibits excellent photothermal/radiolabel stability, biocompatibility, and fluorescence/photothermal /SPECT imaging properties. After local injection, the sustained releasing DOX within tumor greatly inhibits the DNA replication. Meanwhile, GNPs aggregates as a radiosensitizer and photosensitizer show a significant improvement of brachytherapeutic efficacy and cause serious DNA damage. Simultaneously, GNPs aggregates induce mild photothermal therapy under 808 nm laser irradiation, which not only inhibits self-repair of the damaged DNA but also effectively relieves tumor hypoxic condition to enhance the therapeutic effects of brachytherapy, leading to a triple-synergistic destruction of DNA functions. Therefore, this study provides a highly efficient tumor synergistic therapy platform and insight into the synergistic antitumor mechanism in DNA level.
    Keywords:  DNA damage; brachytherapy; gold nanoparticle aggregates; hydrogels; synergistic anti-tumor therapies
  5. Nano Lett. 2021 Aug 12.
      Gut bacteria and their metabolites influence the immune microenvironment of liver through the gut-liver axis, thus representing emerging therapeutic targets for liver cancer therapy. However, directly manipulating gut microbiota or their metabolites is not practical in clinic since the safety concerns and the complicated mechanism of action. Considering the dysregulated bile acid profiles associated with liver cancer, here we propose a strategy that directly manipulates the primary and secondary bile acid receptors through nanoapproach as an alternative and more precise way for liver cancer therapy. We show that nanodelivery of bile acid receptor modulators elicited robust antitumor immune responses and significantly changed the immune microenvironment in the murine hepatic tumor. In addition, ex vivo stimulation on both murine and patient hepatic tumor tissues suggests the observation here may be meaningful for clinical practice. This study elucidates a novel and precise strategy for liver cancer immunotherapy.
    Keywords:  Bile acid; cancer immunotherapy; gut-liver axis; liver cancer; microbiome
  6. ACS Nano. 2021 Aug 12.
      The successful delivery of nanoparticles to solid tumors depends on their ability to pass through blood vessels and into the tumor microenvironment. Here, we discovered a subset of tumor endothelial cells that facilitate nanoparticle transport into solid tumors. We named these cells nanoparticle transport endothelial cells (N-TECs). We show that only 21% of tumor endothelial cells located on a small number of vessels are involved in transporting nanoparticles into the tumor microenvironment. N-TECs have an increased expression of genes related to nanoparticle transport and vessel permeability compared to other tumor endothelial cells. The N-TECs act as gatekeepers that determine the entry point, distribution, cell accessibility, and number of nanoparticles that enter the tumor microenvironment.
    Keywords:  blood vessels; cancer; drug delivery; endothelial cells; image analysis; nanoparticles
  7. Sci Adv. 2021 Aug;pii: eabh0638. [Epub ahead of print]7(33):
      The delivery of small particles into porous environments remains highly challenging because of the low permeability to the fluids that carry these colloids. Even more challenging is that the specific location of targets in the porous environment usually is not known and cannot be determined from the outside. Here, we demonstrate a two-step strategy to deliver suspended colloids to targets that are "hidden" within closed porous media. The first step serves to automatically convert any hidden targets into soluto-inertial "beacons," capable of sustaining long-lived solute outfluxes. The second step introduces the deliverable objects, which are designed to autonomously migrate against the solute fluxes emitted by the targets, thereby following chemical trails that lead to the target. Experimental and theoretical demonstrations of the strategy lay out the design elements required for the solute and the deliverable objects, suggesting routes to delivering colloidal objects to hidden targets in various environments and technologies.
  8. Small. 2021 Aug 08. e2101810
      Disorders in the gut microbiota have been implicated in various diseases, such as inflammatory bowel diseases, diabetes, and cancers. Oral microecologics are of great importance due to their ability to directly intervene the gut microbiome as well as their noninvasiveness and low side effects, while have suffered from low bioavailability and a single therapeutic effect. Here, probiotics are coated with a therapeutic nanocoating for synergistically enhanced biotherapy, a method inspired by the robust protective and therapeutic effectiveness of silkworm cocoon. With its transition from a random coil to β-sheet conformation, silk fibroin can self-assemble onto the surface of bacteria. By a simple layer-by-layer procedure, an entire nanocoating can be formed along with a near quantitative coating ratio and almost uninfluenced bacterial viability. Thanks to its protective barrier role and innate pharmaceutical activity, silk fibroin nanocoating endows the coated bacteria with a markedly improved survival against gastric insults and a synergistically enhanced therapeutic effect in a murine model of intestinal mucositis. This work demonstrates how therapeutic elements can be combined with probiotics via a simple coating strategy and proposes an alternative to enhance bioavailability and treatment efficacy of oral microecologics.
    Keywords:  biotherapy; oral delivery; probiotic; silk fibroin; synergistic, therapeutic nanocoating
  9. Nat Biomed Eng. 2021 Aug 12.
      Treating solid malignancies with chimeric antigen receptor (CAR) T cells typically results in poor responses. Immunomodulatory biologics delivered systemically can augment the cells' activity, but off-target toxicity narrows the therapeutic window. Here we show that the activity of intratumoural CAR T cells can be controlled photothermally via synthetic gene switches that trigger the expression of transgenes in response to mild temperature elevations (to 40-42 °C). In vitro, heating engineered primary human T cells for 15-30 min led to over 60-fold-higher expression of a reporter transgene without affecting the cells' proliferation, migration and cytotoxicity. In mice, CAR T cells photothermally heated via gold nanorods produced a transgene only within the tumours. In mouse models of adoptive transfer, the systemic delivery of CAR T cells followed by intratumoural production, under photothermal control, of an interleukin-15 superagonist or a bispecific T cell engager bearing an NKG2D receptor redirecting T cells against NKG2D ligands enhanced antitumour activity and mitigated antigen escape. Localized photothermal control of the activity of engineered T cells may enhance their safety and efficacy.
  10. Nat Commun. 2021 08 09. 12(1): 4791
      Classical dendritic cells (cDC) are professional antigen-presenting cells (APC) that regulate immunity and tolerance. Neutrophil-derived cells with properties of DCs (nAPC) are observed in human diseases and after culture of neutrophils with cytokines. Here we show that FcγR-mediated endocytosis of antibody-antigen complexes or an anti-FcγRIIIB-antigen conjugate converts neutrophils into nAPCs that, in contrast to those generated with cytokines alone, activate T cells to levels observed with cDCs and elicit CD8+ T cell-dependent anti-tumor immunity in mice. Single cell transcript analyses and validation studies implicate the transcription factor PU.1 in neutrophil to nAPC conversion. In humans, blood nAPC frequency in lupus patients correlates with disease. Moreover, anti-FcγRIIIB-antigen conjugate treatment induces nAPCs that can activate autologous T cells when using neutrophils from individuals with myeloid neoplasms that harbor neoantigens or those vaccinated against bacterial toxins. Thus, anti-FcγRIIIB-antigen conjugate-induced conversion of neutrophils to immunogenic nAPCs may represent a possible immunotherapy for cancer and infectious diseases.
  11. Adv Funct Mater. 2020 Jul 02. pii: 2002299. [Epub ahead of print]30(27):
      Immune checkpoint therapy (ICT) has the potential to treat cancer by removing the immunosuppressive brakes on T cell activity. However, ICT benefits only a subset of patients because most tumors are "cold", with limited pre-infiltration of effector T cells, poor immunogenicity, and low-level expression of checkpoint regulators. It has been previously reported that Cowpea mosaic virus (CPMV) promotes the activation of multiple innate immune cells and the secretion of pro-inflammatory cytokines to induce T cell cytotoxicity, suggesting that immunostimulatory CPMV could potentiate ICT. Here it is shown that in situ vaccination with CPMV increases the expression of checkpoint regulators on Foxp3-CD4+ effector T cells in the tumor microenvironment. It is shown that combined treatment with CPMV and selected checkpoint-targeting antibodies, specifically anti-PD-1 antibodies, or agonistic OX40-specific antibodies, reduced tumor burden, prolonged survival, and induced tumor antigen-specific immunologic memory to prevent relapse in three immunocompetent syngeneic mouse tumor models. This study therefore reveals new design principles for plant virus nanoparticles as novel immunotherapeutic adjuvants to elicit robust immune responses against cancer.
    Keywords:  Cowpea mosaic virus; immune checkpoint therapy; immunotherapy
  12. Cell Chem Biol. 2021 Aug 02. pii: S2451-9456(21)00353-6. [Epub ahead of print]
      Potent, specific ligands drive precision medicine and fundamental biology. Proteins, peptides, and small molecules constitute effective ligand classes. Yet greater molecular diversity would aid the pursuit of ligands to elicit precise biological activity against challenging targets. We demonstrate a platform to discover protein-small molecule (PriSM) hybrids to combine unique pharmacophore activities and shapes with constrained, efficiently engineerable proteins. In this platform, a fibronectin protein library is displayed on yeast with a single cysteine coupled to acetazolamide via a maleimide-poly(ethylene glycol) linker. Magnetic and flow cytometric sorts enrich specific binders to carbonic anhydrase isoforms. Isolated PriSMs exhibit potent, specific inhibition of carbonic anhydrase isoforms with efficacy superior to that of acetazolamide or protein alone, including an 80-fold specificity increase and 9-fold potency gain. PriSMs are engineered with multiple linker lengths, protein conjugation sites, and sequences against two different isoforms, which reveal platform flexibility and impacts of molecular designs. PriSMs advance the molecular diversity of efficiently engineerable ligands.
    Keywords:  hybrid; ligand; pharmacophore; protein engineering; protein scaffold; yeast display
  13. Adv Sci (Weinh). 2021 Aug 08. e2101501
      The balance between antioxidants and reactive oxygen species (ROS) critically regulates tumor initiation and progression. However, whether and how the tumor-favoring redox status is controlled by cytokine networks remain poorly defined. Here, it is shown that IL-36γ and IL-36Ra reciprocally regulate the progression of non-small cell lung cancer (NSCLC) by modulating glutathione metabolism and ROS resolution. Knockout, inhibition, or neutralization of IL-36γ significantly inhibits NSCLC progression and prolongs survival of the KrasLSL-G12D/+ Tp53fl/fl and KrasLSL-G12D/+ Lkb1fl/fl mice after tumor induction, whereas knockout of IL-36Ra exacerbates tumorigenesis in these NSCLC mouse models and accelerates death of mice. Mechanistically, IL-36γ directly upregulates an array of genes involved in glutathione homeostasis to reduce ROS and prevent oxidative stress-induced cell death, which is mitigated by IL-36Ra or IL-36γ neutralizing antibody. Consistently, IL-36γ staining is positively and negatively correlated with glutathione biosynthesis and ROS in human NSCLC tumor biopsies, respectively. These findings highlight essential roles of cytokine networks in redox for tumorigenesis and provide potential therapeutic strategy for NSCLC.
    Keywords:  IL-36γ; IL-36Ra; glutathione metabolism; non-small cell lung cancer; oxidative stress; reactive oxygen species
  14. Adv Healthc Mater. 2021 Aug 08. e2100068
      Various magnetic microcarrier systems capable of transporting cells to target lesions are developed for therapeutic agent-based tissue regeneration. However, the need for bioactive molecules and cells, the potential toxicity of the microcarrier, and the large volume and limited workspace of the magnetic targeting device remain challenging issues associated with microcarrier systems. Here, a multifunctional magnetic implant system is presented for targeted delivery, secure fixation, and induced differentiation of stem cells. This magnetic implant system consists of a biomaterial-based microcarrier containing bioactive molecules, a portable magnet array device, and a biocompatible paramagnetic implant. Among biomedical applications, the magnetic implant system is developed for knee cartilage repair. The various functions of these components are verified through in vitro, phantom, and ex vivo tests. As a result, a single microcarrier can load ≈1.52 ng of transforming growth factor β (TGF-β1) and 3.3 × 103 of stem cells and stimulate chondrogenic differentiation without extra bioactive molecule administration. Additionally, the implant system demonstrates high targeting efficiency (over 90%) of the microcarriers in a knee phantom and ex vivo pig knee joint. The results show that this implant system, which overcomes the limitations of the existing magnetic targeting system, represents an important advancement in the field.
    Keywords:  bioactive molecules; biomedical applications; microcarriers; paramagnetic implants; stem cells
  15. Angew Chem Int Ed Engl. 2021 Aug 14.
      In nature, the folding and conformation of proteins can control the cell or organelle membrane permeability and regulate the life activities. Here we report the first example of synthetic polypeptide vesicles that regulate their permeability via ordered transition of secondary conformations, in a manner similar to biological systems.  The polymersomes undergo a β-sheet to α-helix transition in response to reactive oxygen species (ROS), leading to wall thinning without loss of vesicular integrity. The change  of membrane structure increases the vesicular permeability and enables specific transport of payloads with different molecular weights.The change of membrane structure increases the vesicular permeability.  As a proof-of-concept, the polymersomes encapsulating enzymes could serve as nanoreactors and carries for glucose-stimulated insulin secretion in vivo inspired by human glucokinase, resulting in safe and effective treatment of type 1 diabetes mellitus in mouse models. This study will help understand the biology of biomembranes and facilitate the engineering of nanoplatforms for biomimicry, biosensing, and controlled delivery applications.
    Keywords:  Biomimetic; conformation; permeability; polypeptides; vesicles
  16. Small. 2021 Aug 10. e2102624
      Targeting B7-H3 chimeric antigen receptor (CAR) T cells has antitumor potential for therapy of non-small cell lung cancer (NSCLC) in preclinical studies. However, CAR T cell therapy remains a formidable challenge for the treatment of solid tumors due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Nanozymes exhibit merits modulating the immunosuppression of the tumor milieu. Here, a synergetic strategy by combination of nanozymes and CAR T cells in solid tumors is described. This nanozyme with dual photothermal-nanocatalytic properties is endowed to remodel TME by destroying its compact structure. It is found that the B7-H3 CAR T cells infused in mice engrafted with the NSCLC cells have superior antitumor activity after nanozyme ablation of the tumor. Importantly, it is found that the changes altered immune-hostile cancer environment, resulting in enhanced activation and infiltration of B7-H3 CAR T cells. The first evidence that the process of combination nanozyme therapy effectively improves the therapeutic index of CAR T cells is presented. Thus, this study clearly supports that the TME-immunomodulated nanozyme is a promising tool to improve the therapeutic obstacles of CAR T cells against solid tumors.
    Keywords:  B7-H3 immune checkpoint; chimeric antigen receptor T cell; immunotherapy; nanozyme; photothermal-nanocatalytic effect