bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒11‒14
fourteen papers selected by
Ceren Kimna
Technical University of Munich

  1. J Control Release. 2021 Nov 03. pii: S0168-3659(21)00584-8. [Epub ahead of print]
      Congenital disorders resulting in pathological protein deficiencies are most often treated postnatally with protein or enzyme replacement therapies. However, treatment of these disorders in utero before irreversible disease onset could significantly minimize disease burden, morbidity, and mortality. One possible strategy for the prenatal treatment of congenital disorders is the in utero delivery of messenger RNA (mRNA). mRNA is a gene therapeutic that has previously been investigated for protein replacement therapies and gene editing technologies. While viral vectors have been explored to induce intracellular expression of mRNA, they are limited in their clinical application due to concerns of immunogenicity and genomic integration. As an alternative to viral vectors, safe and efficient in utero mRNA delivery can be achieved using ionizable lipid nanoparticles (LNPs). While LNPs have demonstrated potent in vivo mRNA delivery to the liver following intravenous administration, intra-amniotic delivery has the potential to deliver mRNA to cells and tissues beyond those in the liver, such as in the skin, lung, and digestive tract. However, LNP stability in fetal amniotic fluid and how this stability affects mRNA delivery has not been previously investigated. Here, we engineered a library of LNPs using orthogonal design of experiments (DOE) to evaluate how LNP structure affects ex utero stability in amniotic fluid, and whether a lead candidate identified from these stability measurements enables intra-amniotic mRNA delivery in utero. We used a combination of techniques including dynamic light scattering (DLS), transmission electron microscopy (TEM), and chromatography followed by protein content quantification to screen ex vivo LNP stability in amniotic fluids. These results identified multiple lead LNP formulations that are highly stable in amniotic fluids ranging from small animals to humans, including mouse, sheep, pig, and human amniotic fluid samples. We then demonstrate that stable LNPs from the ex utero screen in mouse amniotic fluid enabled potent mRNA delivery in vitro in fetal lung fibroblasts and in utero following intra-amniotic injection in a murine model. This exploration of ex utero stability in amniotic fluids demonstrates a means by which to identify novel LNP formulations for prenatal treatment of congenital disorders via in utero mRNA delivery.
    Keywords:  Gene therapy; In utero; Nucleic acid therapeutics; lipid nanoparticles; mRNA
  2. Adv Mater. 2021 Nov 12. e2106520
      Radiotherapy is widely exploited for the treatment of a large range of cancers in clinic, but its therapeutic effectiveness is seriously crippled by the tumor immunosuppression, mainly driven by the altered metabolism of cancer cells. Here, we prepare a pH-responsive nanomedicine by coating calcium carbonate (CaCO3 ) nanoparticles with 4-phenylimidazole (4PI), an inhibitor against indoleamine 2,3-dioxygenase 1 (IDO-1), together with zinc ions via the coordination reaction, aiming at reinforcing the treatment outcome of radiotherapy. The obtained pH-responsive nanomedicine, coined as acidity-IDO1-modulation nanoparticles (AIM NPs), is able to instantly neutralize protons, and release 4PI to suppress the IDO1 mediated production of kynurenine (Kyn) upon tumor accumulation. As the result, treatment with AIM NPs can remarkably enhance the therapeutic efficacy of radiotherapy against both murine CT26 and 4T1 tumors by eliciting potent anti-tumor immunity. Furthermore, it is shown that such combination treatment can effectively suppress the growth of untreated distant tumors via the abscopal effect, and result in immune memory responses to reject re-challenged tumors. This work highlights a novel strategy of simultaneous tumor acidity neutralization and IDO1 inhibition to potentiate radiotherapy, with great promises to suppress tumor metastasis and recurrence by eliciting robust antitumor immunity. This article is protected by copyright. All rights reserved.
    Keywords:  IDO1 inhibition; metabolic tumor microenvironment modulation; reinforced radiotherapy; tumor acidity neutralization
  3. Adv Mater. 2021 Nov;33(45): e2104779
      Nanoparticle-based small interfering RNA (siRNA) therapy shows great promise for glioblastoma (GBM). However, charge associated toxicity and limited blood-brain-barrier (BBB) penetration remain significant challenges for siRNA delivery for GBM therapy. Herein, novel cation-free siRNA micelles, prepared by the self-assembly of siRNA-disulfide-poly(N-isopropylacrylamide) (siRNA-SS-PNIPAM) diblock copolymers, are prepared. The siRNA micelles not only display enhanced blood circulation time, superior cell take-up, and effective at-site siRNA release, but also achieve potent BBB penetration. Moreover, due to being non-cationic, these siRNA micelles exert no charge-associated toxicity. Notably, these desirable properties of this novel RNA interfering (RNAi) nanomedicine result in outstanding growth inhibition of orthotopic U87MG xenografts without causing adverse effects, achieving remarkably improved survival benefits. Moreover, as a novel type of polymeric micelle, the siRNA micelle displays effective drug loading ability. When utilizing temozolomide (TMZ) as a model loading drug, the siRNA micelle realizes effective synergistic therapy effect via targeting the key gene (signal transducers and activators of transcription 3, STAT3) in TMZ drug resistant pathways. The authors' results show that this siRNA micelle nanoparticle can serve as a robust and versatile drug codelivery platform, and RNAi nanomedicine and for effective GBM treatment.
    Keywords:  cation-free; glioblastoma; micelle; siRNA; spherical nucleic acid
  4. Nat Cancer. 2021 Sep;2(9): 904-918
      Chimeric antigen receptor (CAR) T cells showed great activity in hematologic malignancies. However, heterogeneous antigen expression in tumor cells and suboptimal CAR-T cell persistence remain critical aspects to achieve clinical responses in patients with solid tumors. Here we show that CAR-T cells targeting simultaneously two tumor-associated antigens and providing transacting CD28 and 4-1BB costimulation, while sharing the sane CD3ζ-chain cause rapid antitumor effects in in vivo stress conditions, protection from tumor re-challenge and prevention of tumor escape due to low antigen density. Molecular and signaling studies indicate that T cells engineered with the proposed CAR design demonstrate sustained phosphorylation of T cell receptor-associated (TCR) signaling molecules and a molecular signature supporting CAR-T cell proliferation and long-term survival. Furthermore, metabolic profiling of CAR-T cells displayed induction of glycolysis that sustains rapid effector T cell function, but also preservation of oxidative functions, which are critical for T cell long-term persistence.
  5. Adv Drug Deliv Rev. 2021 Nov 09. pii: S0169-409X(21)00439-7. [Epub ahead of print] 114046
      The occurrence and development of tumors depend on the tumor microenvironment (TME), which is made up of various immune cells, activated fibroblasts, basement membrane, capillaries, and extracellular matrix. Tumor associated macrophages (TAMs) and microbes are important components in TME. Tumor cells can recruit and educate TAMs and microbes, and the hijacked TAMs and microbes can promote the progression of tumor reciprocally. Tumor vaccine delivery remodeling TME by targeting TAM and microbes can not only enhance the specificity and immunogenicity of antigens, but also contribute to the regulation of TME. Tumor vaccine design benefits from nanotechnology which is a suitable platform for antigen and adjuvant delivery to catalyze new candidate vaccines applying to clinical therapy at unparalleled speed. In view of the characteristics and mechanisms of TME development, vaccine delivery targeting and break the malignant interactions among tumor cells, TAMs, and microbes may serve as a novel strategy for tumor therapy.
    Keywords:  macrophage; microbiota; tumor microenvironment; tumor vaccine; vaccine delivery
  6. Proc Natl Acad Sci U S A. 2021 Nov 16. pii: e2112604118. [Epub ahead of print]118(46):
      Just like atoms combine into molecules, colloids can self-organize into predetermined structures according to a set of design principles. Controlling valence-the number of interparticle bonds-is a prerequisite for the assembly of complex architectures. The assembly can be directed via solid "patchy" particles with prescribed geometries to make, for example, a colloidal diamond. We demonstrate here that the nanoscale ordering of individual molecular linkers can combine to program the structure of microscale assemblies. Specifically, we experimentally show that covering initially isotropic microdroplets with N mobile DNA linkers results in spontaneous and reversible self-organization of the DNA into Z(N) binding patches, selecting a predictable valence. We understand this valence thermodynamically, deriving a free energy functional for droplet-droplet adhesion that accurately predicts the equilibrium size of and molecular organization within patches, as well as the observed valence transitions with N Thus, microscopic self-organization can be programmed by choosing the molecular properties and concentration of binders. These results are widely applicable to the assembly of any particle with mobile linkers, such as functionalized liposomes or protein interactions in cell-cell adhesion.
    Keywords:  colloids; self-assembly; self-organization
  7. Adv Funct Mater. 2021 Oct 26. pii: 2103359. [Epub ahead of print]31(44):
      Dissolvable microneedle patches (MNPs) enable simplified delivery of therapeutics via the skin. However, most dissolvable MNPs do not deliver their full drug loading to the skin because only some of the drug is localized in the microneedles (MNs), and the rest remains adhered to the patch backing after removal from the skin. In this work, biphasic dissolvable MNPs are developed by mounting water-soluble MNs on a water-insoluble backing layer. These MNPs enable the drug to be contained in the MNs without migrating into the patch backing due to the inability of the drugs to partition into the hydrophobic backing materials during MNP fabrication. In addition, the insoluble backing is poorly wetted upon MN dissolution in the skin, which significantly reduces drug residue on the MNP backing surface after application. These effects enable a drug delivery efficiency of >90% from the MNPs into the skin 5 min after application. This study shows that the biphasic dissolvable MNPs can facilitate efficient drug delivery to the skin, which can improve the accuracy of drug dosing and reduce drug wastage.
    Keywords:  dissolvable microneedle patch; drug diffusion; hydrophobic surfaces; skin delivery efficiency; transdermal drug delivery; water insoluble backing
  8. Nat Nanotechnol. 2021 Nov 11.
      Activating CD8+ T cells by antigen cross-presentation is remarkably effective at eliminating tumours. Although this function is traditionally attributed to dendritic cells, tumour-associated macrophages (TAMs) can also cross-present antigens. TAMs are the most abundant tumour-infiltrating leukocyte. Yet, TAMs have not been leveraged to activate CD8+ T cells because mechanisms that modulate their ability to cross-present antigens are incompletely understood. Here we show that TAMs harbour hyperactive cysteine protease activity in their lysosomes, which impedes antigen cross-presentation, thereby preventing CD8+ T cell activation. We developed a DNA nanodevice (E64-DNA) that targets the lysosomes of TAMs in mice. E64-DNA inhibits the population of cysteine proteases that is present specifically inside the lysosomes of TAMs, improves their ability to cross-present antigens and attenuates tumour growth via CD8+ T cells. When combined with cyclophosphamide, E64-DNA showed sustained tumour regression in a triple-negative-breast-cancer model. Our studies demonstrate that DNA nanodevices can be targeted with organelle-level precision to reprogram macrophages and achieve immunomodulation in vivo.
  9. Acta Biomater. 2021 Oct 30. pii: S1742-7061(21)00710-8. [Epub ahead of print]
      Antitumor vaccines are a promising strategy for preventing or treating cancers by eliciting antitumor immune responses and inducing protective immunity against specific antigens expressed on tumor cells. Vaccine formulations that enhance the humoral and cellular immune responses of vaccine candidates would be highly beneficial but are still limited. Here we developed an antitumor vaccine candidate by conjugating a MUC1 glycopeptide antigen to dendritic cell-derived exosomes (Dex). In vivo, the MUC1-Dex construct induced high MUC1-specific IgG antibody titers with strong binding affinities for MUC1-positive tumor cells and promoted cytokine secretion. Moreover, CD8+ T cells from immunized mice exhibited strong cytotoxicity against MUC1-positive tumor cells. Importantly, in both preventative and therapeutic tumor-bearing mouse models, the construct inhibited tumor growth and prolonged survival. Collectively, these results demonstrate that Dex is a promising vaccine carrier that can be used as adjuvant to enhance the immunological efficacy of tumor vaccines. STATEMENT OF SIGNIFICANCE.
    Keywords:  Dendritic cells-derived exosomes; MUC1 antigen; Vaccine adjuvant; Vaccine carrier
  10. Nanoscale. 2021 Nov 10.
      With over millions of years of evolution, viruses can infect cells efficiently by utilizing their unique structures. Similarly, the drug delivery process is designed to imitate the viral infection stages for maximizing the therapeutic effect. From drug administration to therapeutic effect, nanocarriers must evade the host's immune system, break through multiple barriers, enter the cell, and release their payload by endosomal escape or nuclear targeting. Inspired by the virus infection process, a number of virus-like nanosystems have been designed and constructed for drug delivery. This review aims to present a comprehensive summary of the current understanding of the drug delivery process inspired by the viral infection stages. The most recent construction of virus-inspired nanosystems (VINs) for drug delivery is sorted, emphasizing their novelty and design principles, as well as highlighting the mechanism of these nanosystems for overcoming each biological barrier during drug delivery. A perspective on the VINs for therapeutic applications is provided in the end.
  11. Biomech Model Mechanobiol. 2021 Nov 08.
      The human aorta is a high-risk area for vascular diseases, which are commonly restored by thoracic endovascular aortic repair. In this paper, we report a promising shear-activated targeted nanoparticle drug delivery strategy to assist in the treatment of coarctation of the aorta and aortic aneurysm. Idealized three-dimensional geometric models of coarctation of the aorta and aortic aneurysm are designed, respectively. The unique hemodynamic environment of the diseased aorta is used to improve nanoparticle drug delivery. Micro-carriers with nanoparticle drugs would be targeting activated to release nanoparticle drugs by local abnormal shear stress rate (SSR). Coarctation of the aorta provides a high SSR hemodynamic environment, while the aortic aneurysm is exposed to low SSR. We propose a method to calculate the SSR thresholds for the diseased aorta. Results show that the upstream near-wall area of the diseased location is an ideal injection location for the micro-carriers, which could be activated by the abnormal SSR. Released nanoparticle drugs would be successfully targeted delivered to the aortic diseased wall. Besides, the high diffusivity of the micro-carriers and nanoparticle drugs has a significant impact on the surface drug concentrations of the diseased aortic walls, especially for aortic aneurysms. This study preliminary demonstrates the feasibility of shear-activated targeted nanoparticle drug delivery in the treatment of aortic diseases and provides a theoretical basis for developing the drug delivery system and novel therapy.
    Keywords:  Aortic aneurysm; Coarctation of the aorta; Computational fluid dynamics; Hemodynamics; Nanoparticles
  12. Nat Commun. 2021 Nov 11. 12(1): 6520
      Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focus on the function of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a mouse model of muco-obstructive lung disease (Scnn1b-transgenic), we identify epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Functionally, AMs from Scnn1b-transgenic mice have reduced efferocytosis and phagocytosis, and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 function and expression. Ex vivo stimulation of wild-type AMs with native mucus impairs efferocytosis and phagocytosis capacities. In addition, mucus induces gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.
  13. J Control Release. 2021 Nov 06. pii: S0168-3659(21)00595-2. [Epub ahead of print]340 243-258
      Immunotherapies based on immune checkpoint-blocking antibodies have been considered the most attractive cancer treatments in recent years. However, the systemic administration of immune checkpoint-blocking antibodies is limited by low response rates and high risk of inducing immune-related adverse events (irAEs), which might be overcome by the tumor-targeted delivery of these antibodies. To achieve tumor-targeted delivery, immune checkpoint-blocking antibodies are usually modified with tumor-homing ligands through difficult genetic fusion or chemical conjugation. As most immune checkpoint-blocking antibodies are immunoglobin G (IgG) antibodies, we hypothesize that these IgG antibodies might be noncovalently modified with a tumor-homing ligand fused to an IgG-binding domain (IgBD). To test this hypothesis, the tumor-homing ZPDGFRβ affibody, which targets platelet-derived growth factor receptor β (PDGFRβ), was fused to the Fab-selective IgBD in a trimeric format. After mixing ZPDGFRβ fused to the IgBD with immune checkpoint-blocking IgG against programmed death-ligand 1 (αPD-L1), a novel homogenous complex was formed, indicating that αPD-L1 had been successfully modified with ZPDGFRβ fused to the IgBD. ZPDGFRβ-modified αPD-L1 bound to both PDGFRβ and PD-L1, thus leading to greater tumor uptake and antitumor effects in mice bearing PDGFRβ+PD-L1+ tumor grafts. In addition, due to the broad spectrum of IgBD for IgG, immune checkpoint-blocking IgG antibodies against cytotoxic T-lymphocyte-associated protein 4 (αCTLA-4) and signal regulatory protein alpha (αSIRPα) were also modified with ZPDGFRβ fused to the IgBD. These results demonstrated that a tumor-homing ligand fused to the IgBD might be developed as a versatile platform for the modification of immune checkpoint-blocking IgG antibodies to achieve tumor-targeted delivery.
    Keywords:  Affibody; Immune checkpoint inhibitor; Immunoglobin G-binding domain; Immunotherapy; Tumor-targeted delivery