bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒10‒24
fourteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Adv Mater. 2021 Oct 17. e2104355
      Intracellular delivery of proteins is receiving considerable attention in biotherapeutics for various diseases by replacing dysfunctional proteins. Successful intracellular protein delivery highly relies on the development of efficient and safe polymeric carriers, which remains a grand challenge due to the lack of strong binding sites on proteins and their distinct molecular sizes and polarities. In this work, a strategy is proposed for efficient intracellular protein delivery by using dynamic polymer supra-amphiphiles, which are prepared by grafting boronated polylysine with a series of lipidated catechols via dynamic covalent catechol-boronate ester bonds. The prepared supra-amphiphiles can coassemble with proteins to form stable nanoparticles in water and also enable the release of bound proteins in cells due to their dynamic features, thereby strongly promoting the intracellular delivery process. The lead supra-amphiphiles screened in the library demonstrate high efficiency in the delivery of various proteins including bovine serum albumin, β-galactosidase, α-chymotrypsin, saporin, R-phycoerythrin, ovalbumin, catalase, and superoxide dismutase, and show great potency in delivering superoxide dismutase to treat ulcerative colitis in vivo. This work provides new opportunities for rational design and facile construction of robust intracellular protein delivery materials by the integration of polymer chemistry and supramolecular engineering strategies.
    Keywords:  amphiphiles; dynamic covalent bonds; intracellular protein delivery; polymers; ulcerative colitis
  2. Adv Mater. 2021 Oct 23. e2106669
      Methods capable of distributing antitumor therapeutics uniformly and durably throughout an entire tumor would be of great significance in maximizing their treatment efficacy, but they have proven to be extremely challenging. Here, bacteria-mediated spatiotemporally controllable distribution of combination therapeutics in solid tumors is reported to reprogram the immune microenvironment for optimizing antitumor efficacy. By combining synthetic biology and interfacial chemistry, bacteria are inside and outside concurrently modified to express photothermal melanin and to attach immune checkpoint inhibitors on their surface. Due to the nature of bacteria to colonize the hypoxia intratumoral environment, both therapeutic agents can be distributed homogenously and lastingly in tumors during ex vivo human and in vivo mouse studies. Spatiotemporally controllable localization of melanin can repeatedly generate a moderate yet uniform heating of the tumor upon light exposure in a broad treatment window. Combination with similarly localized inhibitors elicits a dual photothermally stimulated and checkpoint-blockade-mediated immune activation effect, synergistically reprogramming the immunosuppressive tumor microenvironment. Therapeutic values are demonstrated by significantly inhibited tumor growth and prolonged survival of mice in both subcutaneous and orthotopic murine models. Colonization of dually modified bacteria paves an avenue for spatiotemporally controllable distribution of therapeutic drugs in solid tumors.
    Keywords:  antitumor therapeutics; bacteria; combination therapy; immune microenvironment; intratumoral distribution
  3. Adv Mater. 2021 Oct 16. e2105738
      Helicobacter pylori (H. pylori) infection is the leading cause of chronic gastritis, peptic ulcer and gastric cancer. Antibiotics, as traditional method for eliminating H. pylori, have no targeting effect, which cause serious bacterial resistance and gut dysbacteriosis. Moreover, antibiotics can hardly address hyperactive inflammatory response or damaged gastric mucosal barrier caused by H. pylori infection. Here, we report a pH-responsive metal-organic framework hydrogen generation nanoparticle (Pd(H)@ZIF-8), which is encapsulated with ascorbate palmitate (AP) hydrogel. Both in vitro and in vivo experiments demonstrate that the outer AP hydrogel can target and adhere to the inflammatory site through electrostatic interaction, and is then hydrolyzed by matrix metalloproteinase (MMP) enriching in inflammatory sites. The released Pd(H)@ZIF-8 nanoparticles are further decomposed by gastric acid to generate zinc ions (Zn2+ ) and hydrogen, thus effectively killing H. pylori, alleviating inflammation and restoring impaired gastric mucosa simultaneously. Unexpectedly, this metal-organic framework hydrogen generation platform (Pd(H)@ZIF-8@AP) also has an inappreciable impact toward intestinal flora, which thus provides a more precise, effective and healthy strategy for the treatment of H. pylori infection. This article is protected by copyright. All rights reserved.
    Keywords:  Antibacterial; H. pylori infection; Hydrogen therapy; Inflammation targeting; ZIF-8
  4. Biomaterials. 2021 Oct 09. pii: S0142-9612(21)00533-0. [Epub ahead of print]278 121176
      Accumulating evidence suggests that stromal modifications improve chemotherapeutic outcomes in pancreatic ductal adenocarcinoma (PDAC). However, combination regimens of stroma-modifying agents and small-molecule cytotoxic drugs have achieved only limited improvements in the clinic, probably due to unsatisfactory pharmacokinetic profiles and restricted drug distribution in tumors. Here, we developed self-assembled prodrug nanoparticles integrating a stromal reprogramming inducer, calcipotriol (CAL), and a potent chemotherapeutic agent, 7-Ethyl-10-hydroxycamptothecin (SN38), to treat PDAC. While SN38 is conjugated to the block polymer backbone, CAL is loaded into the inner hydrophobic space during polymer self-assembly into nanoparticles. To achieve an efficient drug co-package, a planar and hydrophobic cholesterol domain was introduced to stabilize the hydrophobic CAL. Notably, the blood circulation time of CAL significantly improved as CAL|SN38 nanoparticle (CAL|SN38 NP). In addition, CAL|SN38 NP treatment significantly decreased the expression of N-cadherin, collagen, and fibronectin in tumors, which play critical roles in PDAC metastasis. Potent inhibition of primary tumor growth and vigorous anti-metastasis effects were observed after systemic administration of CAL|SN38 NP to stroma-rich PDAC orthotopic tumor-bearing mice. These findings provide a promising paradigm for developing tailor-made nanoparticles with potent stroma-modification capability to combat metastatic cancer.
    Keywords:  Calcipotriol; Cancer-associated fibroblast; Metastasis; Pancreatic cancer; Polymeric prodrug
  5. Adv Sci (Weinh). 2021 Oct 23. e2101562
      Cell membrane vesicles (CMVs) are composed of natural cell membranes which makes them effective drug delivery systems with low immunogenicity and prolonged circulation time. However, targeting delivery of CMVs in vivo for clinical applications is still a major challenge. In this study, CXCR4 recombinant lentivirus is transfected into MC-3T3 cells and membrane CXCR4-enriched MC-3T3 cells are obtained. CMVs with enriched membrane CXCR4 display (CXCR4-CMVs) are obtained from the transfected MC-3T3 cells. Curcumin, an effective natural anti-inflammatory compound, is encapsulated into CXCR4-CMVs through physical entrapment (CXCR4/Cur-CMVs), with the membrane integrity of CXCR4/Cur-CMVs being well-preserved. CXCR4/Cur-CMVs induce enhanced M2 macrophage polarization, exhibit anti-inflammatory effects, and significantly improve homing via the CXCR4/CXCL12 axis in vitro. Utilizing ulcerative colitis and apical periodontitis as inflammatory disease models, it is found that CXCR4/Cur-CMVs are obviously aggregated within inflammatory areas after intravenous administration, which results in significant amelioration of ulcerative colitis and apical periodontitis. Therefore, this research may provide a feasible and innovative approach for fabricating an inflammatory site-targeting delivery system, by engineering CMVs to increase membrane-presenting CXCR4 receptor.
    Keywords:  CXCR4; apical periodontitis; cell membrane vesicles; curcumin; inflammatory bowel disease
  6. Biomater Sci. 2021 Oct 21.
      Osteoarthritis (OA), a chronic and degenerative joint disease, remains a challenge in treatment due to the lack of disease-modifying therapies. As a promising therapeutic agent, adipose-derived stem cells (ADSCs) have an effective anti-inflammatory and chondroprotective paracrine effect that can be enhanced by genetic modification. Unfortunately, direct cell delivery without matrix support often results in poor viability of therapeutic cells. Herein, a hydrogel implant approach that enabled intra-articular delivery of gene-engineered ADSCs was developed for improved therapeutic outcomes in a surgically induced rat OA model. An injectable extracellular matrix (ECM)-mimicking hydrogel was prepared as the carrier for cell delivery, providing a favorable microenvironment for ADSC spreading and proliferation. The ECM-mimicking hydrogel could reduce cell death during and post injection. Additionally, ADSCs were genetically modified to overexpress transforming growth factor-β1 (TGF-β1), one of the paracrine factors that exert an anti-inflammatory and pro-anabolic effect. The gene-engineered ADSCs overexpressing TGF-β1 (T-ADSCs) had an enhanced paracrine effect on OA-like chondrocytes, which effectively decreased the expression of tumor necrosis factor-alpha and increased the expression of collagen II and aggrecan. In a surgically induced rat OA model, intra-articular injection of the T-ADSC-loaded hydrogel markedly reduced cartilage degeneration, joint inflammation, and the loss of the subchondral bone. Taken together, this study provides a potential biomaterial strategy for enhanced OA treatment by delivering the gene-engineered ADSCs within an ECM-mimicking hydrogel.
  7. Nat Commun. 2021 Oct 21. 12(1): 6116
      Critical cancer pathways often cannot be targeted because of limited efficiency crossing cell membranes. Here we report the development of a Salmonella-based intracellular delivery system to address this challenge. We engineer genetic circuits that (1) activate the regulator flhDC to drive invasion and (2) induce lysis to release proteins into tumor cells. Released protein drugs diffuse from Salmonella containing vacuoles into the cellular cytoplasm where they interact with their therapeutic targets. Control of invasion with flhDC increases delivery over 500 times. The autonomous triggering of lysis after invasion makes the platform self-limiting and prevents drug release in healthy organs. Bacterial delivery of constitutively active caspase-3 blocks the growth of hepatocellular carcinoma and lung metastases, and increases survival in mice. This success in targeted killing of cancer cells provides critical evidence that this approach will be applicable to a wide range of protein drugs for the treatment of solid tumors.
  8. Nano Lett. 2021 Oct 20.
      Viral engineered chimeric antigen receptor (CAR) T cell therapies are potent, targeted cancer immunotherapies, but their permanent CAR expression can lead to severe adverse effects. Nonviral messenger RNA (mRNA) CAR T cells are being explored to overcome these drawbacks, but electroporation, the most common T cell transfection method, is limited by cytotoxicity. As a potentially safer nonviral delivery strategy, here, sequential libraries of ionizable lipid nanoparticle (LNP) formulations with varied excipient compositions were screened in comparison to a standard formulation for improved mRNA delivery to T cells with low cytotoxicity, revealing B10 as the top formulation with a 3-fold increase in mRNA delivery. When compared to electroporation in primary human T cells, B10 LNPs induced comparable CAR expression with reduced cytotoxicity while demonstrating potent cancer cell killing. These results demonstrate the impact of excipient optimization on LNP performance and support B10 LNPs as a potent mRNA delivery platform for T cell engineering.
    Keywords:  CAR T; T cell engineering; lipid nanoparticles; mRNA delivery
  9. Nat Commun. 2021 Oct 22. 12(1): 6143
      Pathogenic drug-resistant bacteria represent a threat to human health, for instance, the methicillin-resistant Staphylococcus aureus (MRSA). There is an ever-growing need to develop non-antibiotic strategies to fight bacteria without triggering drug resistance. Here, we design a hedgehog artificial macrophage with atomic-catalytic centers to combat MRSA by mimicking the "capture and killing" process of macrophages. The experimental studies and theoretical calculations reveal that the synthesized materials can efficiently capture and kill MRSA by the hedgehog topography and substantial generation of •O2- and HClO with its Fe2N6O catalytic centers. The synthesized artificial macrophage exhibits a low minimal inhibition concentration (8 μg/mL Fe-Art M with H2O2 (100 μM)) to combat MRSA and rapidly promote the healing of bacteria-infected wounds on rabbit skin. We suggest that the application of this hedgehog artificial macrophage with "capture and killing" capability and high ROS-catalytic activity will open up a promising pathway to develop antibacterial materials for bionic and non-antibiotic disinfection strategies.
  10. Adv Mater. 2021 Oct 20. e2104962
      Supramolecular self-assembly in biological systems holds promise to convert and amplify disease-specific signals to physical or mechanical signals that can direct cell fate. However, it remains challenging to design physiologically stable self-assembling systems that demonstrate tunable and predictable behavior. Here, the use of zwitterionic tetrapeptide modalities to direct nanoparticle assembly under physiological conditions is reported. The self-assembly of gold nanoparticles can be activated by enzymatic unveiling of surface-bound zwitterionic tetrapeptides through matrix metalloprotease-9 (MMP-9), which is overexpressed by cancer cells. This robust nanoparticle assembly is achieved by multivalent, self-complementary interactions of the zwitterionic tetrapeptides. In cancer cells that overexpress MMP-9, the nanoparticle assembly process occurs near the cell membrane and causes size-induced selection of cellular uptake mechanism, resulting in diminished cell growth. The enzyme responsiveness, and therefore, indirectly, the uptake route of the system can be programmed by customizing the peptide sequence: a simple inversion of the two amino acids at the cleavage site completely inactivates the enzyme responsiveness, self-assembly, and consequently changes the endocytic pathway. This robust self-complementary, zwitterionic peptide design demonstrates the use of enzyme-activated electrostatic side-chain patterns as powerful and customizable peptide modalities to program nanoparticle self-assembly and alter cellular response in biological context.
    Keywords:  cellular uptake; enzyme-responsive materials; matrix metalloproteinase; nanomedicine; peptides; self-assembly; zwitterionic nanoparticles
  11. Adv Mater. 2021 Oct 22. e2100096
      Following treatment with androgen receptor (AR) pathway inhibitors, ∼20% of prostate cancer patients progress by shedding their AR dependence. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). Currently, no targeted therapies are available for CRPC-NEPCs, and there are minimal organoid models to discover new therapeutic targets against these aggressive tumors. Here, using a combination of patient tumor proteomics, RNA sequencing, spatial omics, immunohistochemistry, and a synthetic hydrogel-based organoid, we define putative extracellular matrix (ECM) cues that regulate the phenotypic, transcriptomic, and epigenetic underpinnings of CRPC-NEPCs. Short-term culture in tumor-expressed ECM differentially regulated DNA methylation and mobilized genes in CRPC-NEPC tumors. The ECM type distinctly regulated the response to small molecule inhibitors of epigenetic repressor EZH2 and Dopamine Receptor D2 (DRD2), the latter being an understudied target in neuroendocrine tumors. In vivo patient-derived xenograft studies in immunocompromised mice showed a robust anti-tumor response when treated with a DRD2 inhibitor. Finally, we demonstrate that therapeutic response in CRPC-NEPCs under drug-resistant ECM conditions can be overcome by first cellular reprogramming with EZH2 inhibitors, followed by DRD2 treatment. The synthetic hydrogel-based organoids suggest the regulatory role ECM may play in therapeutic response to targeted therapies in CRPC-NEPCs and enable the discovery of single drugs and combination therapies to overcome resistance. This article is protected by copyright. All rights reserved.
    Keywords:  chemoresistance; dopamine receptor; epigenetic; neuroendocrine; tumor microenvironment
  12. Nat Nanotechnol. 2021 Oct 21.
      Nanoparticle-sensitized photoporation is an upcoming approach for the intracellular delivery of biologics, combining high efficiency and throughput with excellent cell viability. However, as it relies on close contact between nanoparticles and cells, its translation towards clinical applications is hampered by safety and regulatory concerns. Here we show that light-sensitive iron oxide nanoparticles embedded in biocompatible electrospun nanofibres induce membrane permeabilization by photothermal effects without direct cellular contact with the nanoparticles. The photothermal nanofibres have been successfully used to deliver effector molecules, including CRISPR-Cas9 ribonucleoprotein complexes and short interfering RNA, to adherent and suspension cells, including embryonic stem cells and hard-to-transfect T cells, without affecting cell proliferation or phenotype. In vivo experiments furthermore demonstrated successful tumour regression in mice treated with chimeric antibody receptor T cells in which the expression of programmed cell death protein 1 (PD1) is downregulated after nanofibre photoporation with short interfering RNA to PD1. In conclusion, cell membrane permeabilization with photothermal nanofibres is a promising concept towards the safe and more efficient production of engineered cells for therapeutic applications, including stem cell or adoptive T cell therapy.
  13. Exp Ther Med. 2021 Dec;22(6): 1373
      Inflammatory bowel diseases (IBD) are a group of chronic disorders occurring in the intestinal tract. Previous studies demonstrated that genetics and microbiota play critical roles in the pathogenesis of IBD. Discoveries of genes that may regulate the homeostasis of gut microbiota and pathogenesis of IBD have the potential to provide new therapeutic targets for IBD treatment. The results suggested that the expression level of microRNA (miR)-602 is negatively related to the development of IBD, and that miR-602 overexpression in mice may prevent inflammation and intestinal barrier injuries in dextran sulfate sodium (DSS)-induced IBD mice. It was also found that the microbiota is important for miR-602-mediated prevention of IBD, as the inhibitory effect of miR-602 was lost when the microbiota was depleted using antibiotics. Furthermore, co-housing or adoptive transfer of microbiota from miR-602 could attenuate the pathogenesis of IBD. In addition, it was demonstrated that miR-602 could target tumor necrosis factor receptor-associated factor 6 (TRAF6) in intestinal epithelial cells. Collectively, the present results suggest that miR-602 plays a protective role in DSS-induced IBD by targeting TRAF6 in a microbiota-dependent manner.
    Keywords:  inflammatory bowel diseases; microRNA-602; microbiota; tumor necrosis factor receptor-associated factor 6
  14. Biomedicines. 2021 Sep 26. pii: 1322. [Epub ahead of print]9(10):
      MicroRNAs (miRNAs) are small ribonucleic acid molecules that play a key role in regulating gene expression. The increasing number of studies undertaken on the functioning of microRNAs in the tumor formation clearly indicates their important potential in oncological therapy. Pancreatic cancer is one of the deadliest cancers. The expression of miRNAs released into the bloodstream appears to be a good indicator of progression and evaluation of the aggressiveness of pancreatic cancer, as indicated by studies. The work reviewed the latest literature on the importance of miRNAs for pancreatic cancer development.
    Keywords:  miRNA; pancreatic cancer; therapeutic potential