bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒07‒04
nine papers selected by
Ceren Kimna
Technical University of Munich

  1. Nat Med. 2021 Jun 28.
      Inflammatory bowel disease (IBD) is a complex chronic inflammatory disorder of the gastrointestinal tract. Extracellular adenosine triphosphate (eATP) produced by the commensal microbiota and host cells activates purinergic signaling, promoting intestinal inflammation and pathology. Based on the role of eATP in intestinal inflammation, we developed yeast-based engineered probiotics that express a human P2Y2 purinergic receptor with up to a 1,000-fold increase in eATP sensitivity. We linked the activation of this engineered P2Y2 receptor to the secretion of the ATP-degrading enzyme apyrase, thus creating engineered yeast probiotics capable of sensing a pro-inflammatory molecule and generating a proportional self-regulated response aimed at its neutralization. These self-tunable yeast probiotics suppressed intestinal inflammation in mouse models of IBD, reducing intestinal fibrosis and dysbiosis with an efficacy similar to or higher than that of standard-of-care therapies usually associated with notable adverse events. By combining directed evolution and synthetic gene circuits, we developed a unique self-modulatory platform for the treatment of IBD and potentially other inflammation-driven pathologies.
  2. ACS Nano. 2021 Jun 30.
      MicroRNAs (miRNAs), a recently discovered class of noncoding RNAs, play pivotal roles in regulating fundamental biological processes by suppressing the expression of target genes. Aberrant miRNA expression is commonly correlated with human diseases, including cancers. Anti-miRNA oligonucleotides provide an innovative therapeutic strategy for silencing disease-associated miRNAs. However, the clinical application of anti-miRNA therapy has been limited by formulation challenges and physiological delivery barriers. Here, to provide the safe and effective tumor-targeted delivery of anti-miRNAs, we designed carrier-free maleimide-functionalized anti-miRNAs (MI-Anti-miRNAs) that enable "piggybacking" onto albumin in vivo. These functionalized MI-Anti-miRNAs covalently bind to cysteine-34 of endogenous albumin within minutes. In addition to resulting in a markedly extended blood circulation lifetime, this strategy allows MI-Anti-miRNAs to "hitchhike" to the tumor site. Importantly, in situ-generated albumin-Anti-miRNAs are capable of intracellularly internalizing highly negatively charged anti-miRNA molecules and knocking down target miRNAs. In particular, MI-Anti-miRNAs that targeted miRNA-21, which is involved in tumor initiation, progression, invasion, and metastasis in several types of cancer, successfully repressed miRNA-21 activity, resulting in a superior antitumor activity in both solid and metastatic tumor models without causing systemic toxicity. This endogenous albumin-piggybacking approach using MI-Anti-miRNAs provides a simple and broadly applicable platform strategy for the systemic delivery of anti-miRNA therapeutics.
    Keywords:  albumin; anti-miRNA delivery; in situ piggybacking; maleimide modification; tumor targeting
  3. Adv Mater. 2021 Jul 03. e2102044
      Oral peptide or protein delivery is considered a revolutionary alternative to daily subcutaneous injection; however, major challenges remain in terms of impediments of the gastrointestinal environment and the intestinal epithelium consisting of mucus and the epithelial cell layer, leading to low bioavailability. To protect against gastrointestinal degradation and promote penetration across the intestinal mucosa, a pH-triggered self-unpacking capsule encapsulating zwitterionic hydrogel-coated metal-organic framework (MOF) nanoparticles is engineered. The MOF nanoparticles possess a high exendin-4 loading capacity, and the zwitterionic hydrogel layer imparts unique capability of permeation across the mucus layer and effective internalization by epithelial cells to the nano-vehicles. In addition to the gastro-resistant feature, the pH-responsive capsules are dissociated drastically in the intestinal environment due to the rapid generation of abundant CO2 bubbles, which triggers a sudden release of the nanoparticles. After oral administration of the capsules containing exendin-4-loaded nanoparticles into a diabetes rat model, markedly enhanced plasma exendin-4 levels are achieved for over 8 h, leading to significantly increased endogenous insulin secretion and a remarkable hypoglycemic effect with a relative pharmacological availability of 17.3%. Owing to the low risk of hypoglycemia, this oral exendin-4 strategy will provide a vast potential for daily and facile diabetes treatment.
    Keywords:  diabetes therapy; intestinal environment responsive; metal-organic frameworks; oral exendin-4 delivery; zwitterionic nanoparticles
  4. Adv Sci (Weinh). 2021 Jun;8(12): 2100166
      Success in anticancer immune therapy relies on stimulation of tumor antigen-specific T lymphocytes and effective infiltration of the T cells into tumor tissue. Here, a therapeutic vaccine that promotes proliferation and tumor infiltration of antigen-specific T cells in both inflamed and noninflamed tumor types is described. The vaccine consists of STING agonist 2'3'-cGAMP, TLR9 ligand CpG, and tumor antigen peptides that are loaded into nanoporous microparticles (μGCVax). μGCVax is effective in inhibiting lung metastatic melanoma, primary breast cancer, and subcutaneous colorectal cancer in their respective murine models, including functional cure of HER2-positive breast cancer. Mechanistically, μGCVax potently stimulates type I interferon expression in dendritic cells, and promotes CD8+ and CD103+ dendritic cell maturation and migration to lymph nodes and other lymphatic tissues. Antitumor responses are dependent on TLR9 and interferon α/β receptor signaling, and to a less extent on STING signaling. These results demonstrate a high potential for μGCVax in mediating antitumor immunity in personalized cancer therapy.
    Keywords:  antigen peptides; cancer; innate immunity; microparticles; nanoparticles; therapeutic vaccines
  5. J Control Release. 2021 Jun 23. pii: S0168-3659(21)00317-5. [Epub ahead of print]336 296-309
      The rapid development of gene therapy and genome editing techniques brings up an urgent need to develop safe and efficient nanoplatforms for nucleic acids and CRISPR genome editors. Herein we report a stimulus-responsive silica nanoparticle (SNP) capable of encapsulating biomacromolecules in their active forms with a high loading content and loading efficiency as well as a well-controlled nanoparticle size (~50 nm). A disulfide crosslinker was integrated into the silica network, endowing SNP with glutathione (GSH)-responsive cargo release capability when internalized by target cells. An imidazole-containing component was incorporated into the SNP to enhance the endosomal escape capability. The SNP can deliver various cargos, including nucleic acids (e.g., DNA and mRNA) and CRISPR genome editors (e.g., Cas9/sgRNA ribonucleoprotein (RNP), and RNP with donor DNA) with excellent efficiency and biocompatibility. The SNP surface can be PEGylated and functionalized with different targeting ligands. In vivo studies showed that subretinally injected SNP conjugated with all-trans-retinoic acid (ATRA) and intravenously injected SNP conjugated with GalNAc can effectively deliver mRNA and RNP to murine retinal pigment epithelium (RPE) cells and liver cells, respectively, leading to efficient genome editing. Overall, the SNP is a promising nanoplatform for various applications including gene therapy and genome editing.
    Keywords:  CRISPR-Cas9 genome editing; Gene delivery; Silica nanoparticle
  6. ACS Appl Mater Interfaces. 2021 Jul 01.
      Pathogenic bacterial infection has become a serious medical threat to global public health. Once the skin has serious defects, bacterial invasion and the following chain reactions will be a thorny clinical conundrum, which takes a long time to heal. Although various strategies have been used to eradicate bacteria, the treatment which can simultaneously disinfect and regulate the infection-related host responses is rarely reported. Herein, inspired by the host microenvironment, a photoenhanced dual-functional nanomedicine is constructed (Hemin@Phmg-TA-MSN) for localized bacterial ablation and host microenvironment modulation. The "NIR-triggered local microthermal therapy" and positively charged surface endow the nanomedicine with excellent bacterial capture and killing activities. Meanwhile, the nanomedicine exhibits broad-spectrum reactive oxygen species (ROS) scavenging activity via the synergistic effect of hemin and tannic acid with photoenhanced electron and hydrogen transfers. Furthermore, the in vivo experiments demonstrate that the dual-functional nanomedicine not only presents robust bacterial eradication capability, but also triggers the oxidative stress and inflammatory microenvironment regulation. The work not only shows a facile and effective way for infected wound management but also provides a new horizon for designing novel and efficient anti-infection therapy shifting focus from bacteria treatment to host microenvironment modulation.
    Keywords:  chemo-photothermal disinfection; dual-functional nanomedicine; host microenvironment regulation; photoenhanced ROS scavenging activity; wound healing
  7. J Control Release. 2021 Jun 29. pii: S0168-3659(21)00341-2. [Epub ahead of print]
      Thrombus related diseases seriously threaten human's health and life. The drawbacks of thrombolytic drugs, such as poor targeting ability and unexpected bleeding complications limit their clinical application. Thus, targeted delivery and controlled release of drugs at local thrombus sites to achieve efficient thrombolysis is an urgent event to be resolved. Herein, we developed an intelligent system MnO2/uPA@pep-Fuco for precise thrombolysis and thrombus inflammatory microenvironment remodeling. MnO2/uPA@pep-Fuco exhibited an excellent thrombus targeting ability via the high affinity of fucoidan (Fuco) for P-selectin overexpressed by activated platelets. And then pep-Fuco modified onto the surface of mesopore could be removed to release urokinase (uPA) locally under the high level of thrombin microenvironment in thrombus site. Meanwhile, due to the catalase-like activity of MnO2 nanoplatform, MnO2/uPA@pep-Fuco could regulate the inflammatory thrombus microenvironment by eliminating hydrogen peroxide (H2O2), so as to achieve a collaborative thrombolysis therapy. In ferric chloride (FeCl3)-induced carotid thrombus models, MnO2/uPA@pep-Fuco specifically targeted to the obstructive artery (3.43 times that of the normal artery) and significantly decreased the percentage of thrombus closure (5.99 ± 5.07%), demonstrating the superior thrombolysis ability. In addition, the significantly reduced tail bleeding time suggested MnO2/uPA@pep-Fuco might possess a low risk of bleeding complications.
    Keywords:  Collaborative thrombolysis therapy; MnO(2); Thrombin-responsive; Thrombus targeting
  8. Adv Funct Mater. 2021 Jun 09. pii: 2100478. [Epub ahead of print]31(24):
      Nucleotide-based drugs, such as antisense oligonucleotides (ASOs), have unique advantages in treating human diseases as they provide virtually unlimited ability to target any gene. However, their clinical translation faces many challenges, one of which is poor delivery to the target tissue in vivo. This problem is particularly evident in solid tumors. Here, we functionalized liposomes with a tumor-homing and -penetrating peptide, iRGD, as a carrier of an ASO against androgen receptor (AR) for prostate cancer treatment. The iRGD-liposomes exhibited a high loading efficiency of AR-ASO, and an efficient knockdown of AR gene products was achieved in vitro, including AR splice variants. In vivo, iRGD-liposomes significantly increased AR-ASO accumulation in the tumor tissue and decreased AR expression relative to free ASOs in prostate tumors established as subcutaneous xenografts. Similar results were obtained with intra-tibial xenografts modeling metastasis to bones, the predominant site of metastasis for prostate cancer. In treatment studies, iRGD-liposomes markedly improved the AR-ASO efficacy in suppressing the growth of both subcutaneous xenografts and intra-tibial xenografts. The inhibitory effect on tumor growth was also significantly prolonged by the delivery of the AR-ASO in the iRGD-liposomes. Meanwhile, iRGD-liposomes did not increase ASO accumulation or toxicity in healthy organs. Overall, we provide here a delivery system that can significantly increase ASO accumulation and efficacy in solid tumors. These benefits are achieved without significant side effects, providing a way to increase the antitumor efficacy of ASOs.
  9. Adv Sci (Weinh). 2021 Jun;8(12): 2100389
      Majority of drugs are administered orally, yet their efficient absorption is often difficult to achieve, with a low dose fraction reaching the blood compartment. Here, a microstirring pill technology is reported with built-in mixing capability for oral drug delivery that greatly enhances bioavailability of its therapeutic payload. Embedding microscopic stirrers into a pill matrix enables faster disintegration and dissolution, leading to improved release profiles of three widely used model drugs, aspirin, levodopa, and acetaminophen, without compromising their loading. Unlike recently developed drug-carrying nanomotors, drug molecules are not associated with the microstirrers, and hence there is no limitation on the loading capacity. These embedded microstirrers are fabricated through the asymmetric coating of titanium dioxide thin film onto magnesium microparticles. In vitro tests illustrate that the embedded microstirrers lead to substantial enhancement of local fluid transport. In vivo studies using murine and porcine models demonstrate that the localized stirring capability of microstirrers leads to enhanced bioavailability of drug payloads. Such improvements are of considerable importance in clinical scenarios where fast absorption and high bioavailability of therapeutics are critical. The encouraging results obtained in porcine model suggest that the microstirring pill technology has translational potential and can be developed toward practical biomedical applications.
    Keywords:  active drug delivery; bioavailability; microstirring pills; porcine models; translational medicine