bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒07‒10
thirteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Nat Biomed Eng. 2022 Jul 04.
      The first two mRNA vaccines against infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that were approved by regulators require a cold chain and were designed to elicit systemic immunity via intramuscular injection. Here we report the design and preclinical testing of an inhalable virus-like-particle as a COVID-19 vaccine that, after lyophilisation, is stable at room temperature for over three months. The vaccine consists of a recombinant SARS-CoV-2 receptor-binding domain (RBD) conjugated to lung-derived exosomes which, with respect to liposomes, enhance the retention of the RBD in both the mucus-lined respiratory airway and in lung parenchyma. In mice, the vaccine elicited RBD-specific IgG antibodies, mucosal IgA responses and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile in the animals' lungs, and cleared them of SARS-CoV-2 pseudovirus after a challenge. In hamsters, two doses of the vaccine attenuated severe pneumonia and reduced inflammatory infiltrates after a challenge with live SARS-CoV-2. Inhalable and room-temperature-stable virus-like particles may become promising vaccine candidates.
  2. J Control Release. 2022 Jul 02. pii: S0168-3659(22)00388-1. [Epub ahead of print]348 1004-1015
      Hypoxia-induced intratumoral heterogeneity poses a major challenge in tumor therapy due to the varying susceptibility to chemotherapy. Moreover, the spatial distribution patterns of hypoxic and normoxic tissues makes conventional combination therapy less effective. In this study, a tumor-acidity and bioorthogonal chemistry mediated in situ size transformable nanocarrier (NP@DOXDBCO plus iCPPAN3) was developed to spatially deliver two combinational chemotherapeutic drugs (doxorubicin (DOX) and PR104A) to combat hypoxia-induced intratumoral heterogeneity. DOX is highly toxic to tumor cells in normoxia state but less toxic in hypoxia state due to the hypoxia-induced chemoresistance. Meanwhile, PR104A is a hypoxia-activated prodrug has less toxic in normoxia state. Two nanocarriers, NP@DOXDBCO and iCPPAN3, can cross-link near the blood vessel extravasation sites through tumor acidity responsive bioorthogonal click chemistry to enhance the retention of DOX in tumor normoxia. Moreover, PR104A conjugated to the small-sized dendritic polyamidoamine (PAMAM) released under tumor acidity can penetrate deep tumor tissues for hypoxic tumor cell killing. Our study has demonstrated that this site-specific combination chemotherapy is better than the traditional combination chemotherapy. Therefore, spatial specific delivery of combinational therapeutics via in situ size transformable nanocarrier addresses the challenges of hypoxia induced intratumoral heterogeneity and provides insights into the combination therapy.
    Keywords:  Bioorthogonal chemistry; Combination chemotherapy; Intratumoral heterogeneity; Size transformable nanocarrier; Tumor hypoxia
  3. Nat Biomed Eng. 2022 Jul 07.
      Orally delivered antibiotics can reach the caecum and colon, and induce gut dysbiosis. Here we show that the encapsulation of antibiotics in orally administered positively charged polymeric nanoparticles with a glucosylated surface enhances absorption by the proximal small intestine through specific interactions of glucose and the abundantly expressed sodium-dependent glucose transporter 1. This improves bioavailability of the antibiotics, and limits their exposure to flora in the large intestine and their accumulation in caecal and faecal contents. Compared with the standard administration of the same antibiotics, the oral administration of nanoparticle-encapsulated ampicillin, chloramphenicol or vancomycin in mice with bacterial infections in the lungs effectively eliminated the infections, decreased adverse effects on the intestinal microbiota by protecting the animals from dysbiosis-associated metabolic syndromes and from opportunistic pathogen infections, and reduced the accumulation of known antibiotic-resistance genes in commensal bacteria. Glucosylated nanocarriers may be suitable for the oral delivery of other drugs causing gut dysbiosis.
  4. Small. 2022 Jul 09. e2202834
      Chemoradiotherapy (CRT) is the most accepted treatment for locally advanced pancreatic ductal adenocarcinoma (PDAC) and can significantly improve the R0 resection rate. However, there are few long-term survivors after CRT. Although some polymer nanoparticles have shown potential in alleviating the dose-limiting toxicity and assisting the chemotherapy of PDAC, there are few efficient nanosensitizers (NS) available for CRT of this malignancy, especially in the context of its hypoxic nature. Herein, based on the biological features of PDAC, a γ-glutamyl transpeptidase (GGT)/glutathione (GSH)/hypoxia triple-responsive prodrug NS to overcome the biological barrier and microenvironmental limitations confronted by CRT in PDAC is developed. Due to triple-responsiveness, deep tumor penetration, GSH/hypoxia-responsive drug release/activation, and hypoxia-induced chemoradio-sensitization can be simultaneously achieved with this NS. As a result, tumor shrinkage after CRT with this NS can be observed in both subcutaneous and orthotopic PDAC models, foreshadowing its potential in clinical neoadjuvant CRT.
    Keywords:  concurrent chemoradiotherapy; pancreatic ductal adenocarcinoma; prodrug nanomedicine; tumor penetration; γ-glutamyl transpeptidase responsive
  5. Adv Mater. 2022 Jul 05. e2202612
      With the advent of increasingly complex combination strategies of biologics, independent control over their delivery is key to their efficacy; however, current approaches are hindered by limited and independent tunability of their release rates. To overcome these limitations, we used directed evolution to engineer highly specific, low affinity affibody binding partners to multiple therapeutic proteins to independently control protein release rates. As a proof-of-concept, we identified specific affibody binding partners for two proteins with broad therapeutic utility: insulin-like growth factor-1 (IGF-1) and pigment epithelium-derived factor (PEDF). We discovered protein-affibody binding interactions specific to these target proteins with equilibrium dissociation constants (KD ) between 10-7 M and 10-8 M. The affibodies were covalently bound to the backbone of crosslinked hydrogels using click chemistry, enabling the sustained, independent, and simultaneous release of bioactive IGF-1 and PEDF over 7 days. The system was tested with C57BL/6J mice in vivo, and the affibody-controlled release of IGF-1 resulted in sustained activity when compared to bolus IGF-1 delivery. We demonstrate a new, broadly applicable approach to tune the release of therapeutic proteins simultaneously and independently and thus pave the way for precise control over the delivery of multicomponent therapies. This article is protected by copyright. All rights reserved.
    Keywords:  affibodies; controlled release; directed evolution; yeast display
  6. J Control Release. 2022 Jul 04. pii: S0168-3659(22)00395-9. [Epub ahead of print]349 2-15
      Current pharmacological treatments of atherosclerosis often target either cholesterol control or inflammation management, to inhibit atherosclerotic progression, but cannot lead to direct plaque lysis and atherosclerotic regression, partly due to the poor accumulation of medicine in the atherosclerotic plaques. Due to enhanced macrophage recruitment during atheromatous plaque progression, a macrophage-liposome conjugate was facilely constructed for targeted anti-atherosclerosis therapy via synergistic plaque lysis and inflammation alleviation. Endogenous macrophage is utilized as drug-transporting cell, upon membrane-modification with a β-cyclodextrin (β-CD) derivative to form β-CD decorated macrophage (CD-MP). Adamantane (ADA) modified quercetin (QT)-loaded liposome (QT-NP), can be conjugated to CD-MP via host-guest interactions between β-CD and ADA to form macrophage-liposome conjugate (MP-QT-NP). Thus, macrophage carries liposome "hand-in-hand" to significantly increase the accumulation of anchored QT-NP in the aorta plaque in response to the plaque inflammation. In addition to anti-inflammation effects of QT, MP-QT-NP efficiently regresses atherosclerotic plaques from both murine aorta and human carotid arteries via CD-MP mediated cholesterol efflux, due to the binding of cholesterol by excess membrane β-CD. Transcriptome analysis of atherosclerotic murine aorta and human carotid tissues reveal that MP-QT-NP may activate NRF2 pathway to inhibit plaque inflammation, and simultaneously upregulate liver X receptor to promote cholesterol efflux.
    Keywords:  Atherosclerosis; Cell-based carriers; Drug delivery; Host-guest interaction; β-Cyclodextrin
  7. Adv Mater. 2022 Jul 07. e2205567
      Tissue adhesives capable of achieving strong and tough adhesion in permeable wet environments are useful in many biomedical applications. However, adhesion generated through covalent bond formation directly with the functional groups of tissues (i.e., -COOH and -NH2 groups in collagen), or using non-covalent interactions can both be limited by weak, unstable, or slow adhesion. Here, we show that by combining pH-responsive bridging chitosan polymer chains and a tough hydrogel dissipative matrix one can achieve unprecedented ultra-tough adhesion to tissues (>2000J/m2 ) in 5-10mins without covalent bond formation. The strong non-covalent adhesion was shown to be stable under physiologically relevant conditions and strongly influenced by chitosan molecular weight, molecular weight of polymers in the matrix, and pH. The adhesion mechanism relies primarily on the topological entanglement between the chitosan chains and the permeable adherends. To further expand the applicability of the adhesives, adhesion time can be decreased by dehydrating the hydrogel matrix to facilitate rapid chitosan interpenetration and entanglement (>1000J/m2 in ≤1 min). The unprecedented adhesive properties presented in this study open opportunities for new strategies in the development of non-covalent tissue adhesives and numerous bio-applications. This article is protected by copyright. All rights reserved.
    Keywords:  adhesive; bioinspiration; biomaterial; hydrogel; slug
  8. J Control Release. 2022 Jun 30. pii: S0168-3659(22)00393-5. [Epub ahead of print]
      Advanced-stage prostate cancer remains an incurable disease with poor patient prognosis. There is an unmet clinical need to target androgen receptor (AR) splice variants, which are key drivers of the disease. Some AR splice variants are insensitive to conventional hormonal or androgen deprivation therapy due to loss of the androgen ligand binding domain at the C-terminus and are constitutively active. Here we explore the use of RNA interference (RNAi) to target a universally conserved region of all AR splice variants for cleavage and degradation, thereby eliminating protein level resistance mechanisms. To this end, we tested five siRNA sequences designed against exon 1 of the AR mRNA and identified several that induced potent knockdown of full-length and truncated variant ARs in the 22Rv1 human prostate cancer cell line. We then demonstrated that 2'O methyl modification of the top candidate siRNA (siARvm) enhanced AR and AR-V7 mRNA silencing potency in both 22Rv1 and LNCaP cells, which represent two different prostate cancer models. For downstream in vivo delivery, we formulated siARvm-LNPs and functionally validated these in vitro by demonstrating knockdown of AR and AR-V7 mRNA in prostate cancer cells and loss of AR-mediated transcriptional activation of the PSA gene in both cell lines following treatment. We also observed that siARvm-LNP induced cell viability inhibition was more potent compared to LNP containing siRNA targeting full-length AR mRNA (siARfl-LNP) in 22Rv1 cells as their proliferation is more dependent on AR splice variants than LNCaP and PC3 cells. The in vivo biodistribution of siARvm-LNPs was determined in 22Rv1 tumor-bearing mice by incorporating 14C-radiolabelled DSPC in LNP formulation, and we observed a 4.4% ID/g tumor accumulation following intravenous administration. Finally, treatment of 22Rv1 tumor bearing mice with siARvm-LNP resulted in significant tumor growth inhibition and survival benefit compared to siARfl-LNP or the siLUC-LNP control. To best of our knowledge, this is the first report demonstrating therapeutic effects of LNP-siRNA targeting AR splice variants in prostate cancer.
    Keywords:  Androgen receptor; Gene therapy; Lipid nanoparticle; Prostate cancer; Splice variant; siRNA
  9. J Control Release. 2022 Jul 01. pii: S0168-3659(22)00389-3. [Epub ahead of print]
      Here, we constructed 3D-printed multiunit implants to enable remote light-controlled protein drug delivery in a spatiotemporal manner. Multiunit implants were designed to be 3D printed using polycaprolactone, lauric acid, and melanin as a matrix, and a polycaprolactone scaffold as a multiunit divider. As a model drug, insulin was loaded to each unit of the implant. The 3D printing yielded a rectangular matrix with multiunit sectors segregated by polycaprolactone lanes. Irradiation with near infrared light (NIR) triggered controlled release of insulin from the irradiated locus: Upon NIR irradiation, heat generated from the melanin melted the polycaprolactone/lauric acid matrix to release insulin from the scaffold. In the absence of melanin in the matrix, the implant did not show NIR-responsive insulin release. When lauric acid was absent from the matrix, the NIR-irradiated unit did not undergo dismantling. When the insulin-loaded multiunit implant was applied to a mouse diabetic model and irradiated with NIR, repetitive insulin release resulted in an efficient decrease of the blood glucose level over multiple days. Together, these results suggest that 3D printing technology-based multi-dosing of insulin on demand can enable convenient treatment of diabetes through external NIR irradiation, potentially avoiding the pain and discomfort of repeated insulin injections.
    Keywords:  3D printing; On-demand delivery; Protein drug; Pulsatile multi-dose; Remotely controlled delivery
  10. Nat Commun. 2022 Jul 02. 13(1): 3821
      Metabolic reprogramming of the tumor microenvironment (TME) and poor immunogenicity are two of the challenges that cancer immunotherapies have to overcome for improved clinical benefits. Among various immunosuppressive metabolites that keep anti-tumor immunity in check, the tryptophan catabolite kynurenine (Kyn) is an attractive target for blockade given its role in mediating immunosuppression through multiple pathways. Here, we present a local chemo-immunometabolic therapy through injection of a supramolecular hydrogel concurrently releasing doxorubicin that induces immunogenic tumor cell death and kynureninase that disrupts Kyn-mediated immunosuppressive pathways in TME. The combination synergically enhances tumor immunogenicity and unleashes anti-tumor immunity. In mouse models of triple negative breast cancer and melanoma, a single low dose peritumoral injection of the therapeutic hydrogel promotes TME transformation toward more immunostimulatory, which leads to enhanced tumor suppression and extended mouse survival. In addition, the systemic anti-tumor surveillance induced by the local treatment exhibits an abscopal effect and prevents tumor relapse post-resection. This versatile approach for local chemo-immunometabolic therapy may serve as a general strategy for enhancing anti-tumor immunity and boosting the efficacy of cancer immunotherapies.
  11. Genes Dis. 2022 May;9(3): 682-696
      Ischemic stroke resulting from atherosclerosis (particularly in the carotid artery) is one of the major subtypes of stroke and has a high incidence of death. Disordered lipid homeostasis, lipid deposition, local macrophage infiltration, smooth muscle cell proliferation, and plaque rupture are the main pathological processes of atherosclerotic ischemic stroke. Hepatocytes, macrophages, endothelial cells and vascular smooth muscle cells are the main cell types participating in these processes. By inhibiting the expression of the target genes in these cells, microRNAs play a key role in regulating lipid disorders and atherosclerotic ischemic stroke. In this article, we listed the microRNAs implicated in the pathology of atherosclerotic ischemic stroke and aimed to explain their pro- or antiatherosclerotic roles. Our article provides an update on the potential diagnostic use of miRNAs for detecting growing plaques and impending clinical events. Finally, we provide a perspective on the therapeutic use of local microRNA delivery and discuss the challenges for this potential therapy.
    Keywords:  Atherosclerotic ischemic stroke; ECs; Macrophages; Plaque stability; VSMCs; miRNA
  12. J Pharmacol Exp Ther. 2022 Jul 02. pii: JPET-MR-2022-001152. [Epub ahead of print]
      Since their discovery in 1993, microRNAs (miRNAs, miRs) have emerged as important regulators of many crucial cellular processes and their dysregulation have been shown to contribute to multiple pathological conditions, including cardiovascular disease (CVD). miRNAs have been found to regulate the expression of various genes involved in cardiac development and function, and in the development and progression of CVD. Many miRNAs are master regulators fine-tuning the expression of multiple, often interrelated, genes involved in inflammation, apoptosis, fibrosis, senescence, and other processes crucial for the development of different forms of CVD. This article presents a review of recent developments in our understanding of the role of miRNAs in the development of CVD and surveys their potential applicability as therapeutic targets and biomarkers to facilitate CVD diagnosis, prognosis, and treatment. There are currently multiple potential miRNA-based therapeutic agents in different stages of development, which can be grouped into two classes: miRNA mimics (replicating the sequence and activity of their corresponding miRNAs) and antagomiRs (antisense inhibitors of specific miRNAs). However, in spite of promising preliminary data and our ever-increasing knowledge about the mechanisms of action of specific miRNAs, miRNA-based therapeutics and biomarkers have yet to be approved for clinical applications. Significance Statement Over the last few years microRNAs have emerged as crucial, specific regulators of cardiovascular system and in the development of cardiovascular disease, by posttranscriptional regulation of their target genes. The minireview presents the most recent developments in this area of research, including the progress in diagnostic and therapeutic applications of microRNAs. microRNAs seem very promising candidates for biomarkers and therapeutic agents, though some challenges, such as efficient delivery and unwanted effects, need to be resolved.
    Keywords:  MicroRNA; cardiovascular disease; heart/cardiac
  13. J Am Chem Soc. 2022 Jul 02.
      Molecular circuits capable of processing temporal information are essential for complex decision making in response to both the presence and history of a molecular environment. A particular type of temporal information that has been recognized to be important is the relative timing of signals. Here we demonstrate the strategy of temporal memory combined with logic computation in DNA strand-displacement circuits capable of making decisions based on specific combinations of inputs as well as their relative timing. The circuit encodes the timing information on inputs in a set of memory strands, which allows for the construction of logic gates that act on current and historical signals. We show that mismatches can be employed to reduce the complexity of circuit design and that shortening specific toeholds can be useful for improving the robustness of circuit behavior. We also show that a detailed model can provide critical insights for guiding certain aspects of experimental investigations that an abstract model cannot. We envision that the design principles explored in this study can be generalized to more complex temporal logic circuits and incorporated into other types of circuit architectures, including DNA-based neural networks, enabling the implementation of timing-dependent learning rules and opening up new opportunities for embedding intelligent behaviors into artificial molecular machines.