bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒09‒05
fourteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Nat Biotechnol. 2021 Aug 30.
      Oral administration provides a simple and non-invasive approach for drug delivery. However, due to poor absorption and swift enzymatic degradation in the gastrointestinal tract, a wide range of molecules must be parenterally injected to attain required doses and pharmacokinetics. Here we present an orally dosed liquid auto-injector capable of delivering up to 4-mg doses of a bioavailable drug with the rapid pharmacokinetics of an injection, reaching an absolute bioavailability of up to 80% and a maximum plasma drug concentration within 30 min after dosing. This approach improves dosing efficiencies and pharmacokinetics an order of magnitude over our previously designed injector capsules and up to two orders of magnitude over clinically available and preclinical chemical permeation enhancement technologies. We administered the capsules to swine for delivery of clinically relevant doses of four commonly injected medications, including adalimumab, a GLP-1 analog, recombinant human insulin and epinephrine. These multi-day dosing experiments and oral administration in awake animal models support the translational potential of the system.
  2. ACS Nano. 2021 Sep 03.
      Pancreatic ductal adenocarcinoma (PDAC) cells are surrounded by a dense extracellular matrix (ECM), which greatly restricts the access of therapeutic agents, resulting in poor clinical response to chemotherapy. Transforming growth factor-β1 (TGF-β1) signaling plays a crucial role in construction of the desmoplastic stroma and provides potential targets for PDAC therapy. To surmount the pathological obstacle, we developed a size switchable nanosystem based on PEG-PLGA nanospheres encapsulated within liposomes for the combined delivery of vactosertib (VAC), a TGF-β1 receptor kinase inhibitor, and the cytotoxic drug paclitaxel (TAX). By surface modification of the liposomes with a peptide, APTEDB, the nanosystem can be anchored to abundant tumor-associated fibronectin in PDAC stroma and decreases its size by releasing encapsulated TAX-loaded nanospheres, as well as VAC after collapse of the liposomes. The inhibition of ECM hyperplasia by VAC allows TAX more ready access to the cancer cells in addition to its small size, thereby shrinking pancreatic tumor xenografts more effectively than a combination of the free drugs. This size switchable nanosystem enables sequential delivery of drugs at a fixed dose combination with simplified administration and provides an encouraging cascade approach of drug penetration for enhanced chemotherapy in cancers with a dense desmoplastic stroma.
    Keywords:  TGF-β1 inhibitor; combination therapy; drug penetration; pancreatic cancer; size switchable nanosystem
  3. Adv Mater. 2021 Sep 02. e2103490
      The globally high prevalence of peripheral artery diseases poses a pressing need for biomaterials grafts to rebuild vasculature. When implanted, they should promote endothelial cells (ECs) adhesion both profoundly and selectively-but the latter expectation remains unfulfilled. Here, this work is inspired by fungi that invade blood vessels via the "bridge" of galectins that, secreted by ECs, can simultaneously bind carbohydrates on fungal surface and integrin receptors on ECs. A glucomannan decanoate (GMDE) substrate mimicking fungal carbohydrates that highly and preferentially supports ECs adhesion while rejecting several other cell types is designed. Electrospun GMDE scaffolds efficiently sequester endogenous galectin-1-which bridges ECs to the scaffolds as it functions in fungal invasions-and promote blood perfusion in a murine limb ischemic model. Meanwhile, the application of GMDE requires no exogenous pro-angiogenic agents and causes no organ toxicity or adverse inflammation in mice, highlighting its high safety of potential translation. This glycan material, uniquely mimicking a microbial action and harnessing a secreted protein as a "bridge," represents an effective, safe, and different strategy for ischemic vascular therapy.
    Keywords:  angiogenesis; blood vessels; carbohydrates; cell adhesion; natural biomaterials
  4. ACS Nano. 2021 Sep 01.
      The complete regression of residual tumors after photothermal therapy (PTT) depends on the activation and recognition of the immune system. However, the inevitable local inflammation after PTT in residual tumor recruits abundant abnormal immune cells, especially the tumor-associated macrophages (TAMs) which further promote immune escape and survival of the remaining tumor cells, resulting in the tumor recurrence and progression. To solve this problem, herein we explored biomimetic nanoparticles carrying repolarization agent of TAMs to remodel the post-PTT inflammatory microenvironment. The polydopamine nanoparticles were used simultaneously as photothermal transduction agents to ablate tumor cells and the delivery vehicles for TMP195 which can repolarize the M2-like TAMs into an antitumor phenotype. In addition, a biomimetic decoration of macrophage membrane coating was designed to endow nanoparticles the ability to actively target the tumor site after PTT mediated by inflammation-mediated chemotaxis. In the breast tumor model, these biomimetic nanoparticles with immune-modulating ability significantly elevated the levels of M1-like TAMs, ultimately resulting in a tumor-elimination rate of 60%, increased from 10% after PTT. This synergistic treatment strategy of PTT and TAMs repolarization provides a promising approach to address the deteriorated tumor microenvironment after PTT and proposes a more effective way for combinational treatment option in clinic.
    Keywords:  biomimetic nanoparticles; inflammatory microenvironment; macrophages membrane; photothermal therapy; repolarization; tumor-associated macrophages
  5. ACS Nano. 2021 Sep 02.
      The successful control of coronavirus disease 2019 (COVID-19) pandemic is not only relying on the development of vaccines, but also depending on the storage, transportation, and administration of vaccines. Ideally, nucleic acid vaccine should be directly delivered to proper immune cells or tissue (such as lymph nodes). However, current developed vaccines are normally treated through intramuscular injection, where immune cells do not normally reside. Meanwhile, current nucleic acid vaccines must be stored in a frozen state that may hinder their application in developing countries. Here, we report a separable microneedle (SMN) patch to deliver polymer encapsulated spike (or nucleocapsid) protein encoding DNA vaccines and immune adjuvant for efficient immunization. Compared with intramuscular injection, SMN patch can deliver nanovaccines into intradermal for inducing potent and durable adaptive immunity. IFN-γ+CD4/8+ and IL-2+CD4/8+ T cells or virus specific IgG are significantly increased after vaccination. Moreover, in vivo results show the SMN patches can be stored at room temperature for at least 30 days without decreases in immune responses. These features of nanovaccines-laden SMN patch are important for developing advanced COVID-19 vaccines with global accessibility.
    Keywords:  COVID-19; DNA vaccines; adaptive immunity; immune adjuvant; separable microneedle
  6. Adv Mater. 2021 Aug 31. e2102668
      Immune evasion is the major obstacle for T-cell-based cancer immunotherapy. The insufficient expression of the tumor-rejection antigen causes the intrinsic immune resistance and high expression of programmed death ligand 1 (PD-L1) induced by interferon gamma (IFN-γ), which accounts for the inducible immune resistance. To deal with both the intrinsic and inducible immune resistance of cancer, a multifunctional prodrug nanovesicle is sequentially developed. It is first sorted out that doxycycline (Doxy) efficiently inhibits autophagy of the tumor cells, and increases the surface level of major histocompatibility complex class I (MHC-I). Then, chameleon-inspired prodrug nanovesicles are engineered for tumor-targeted delivery of Doxy. The prodrug nanovesicles integrating a sheddable poly(ethylene glycol) shell and CRGDK ligand are kept stable during blood circulation, while exposing the targeting ligand in the tumor, which significantly inhibits autophagy, elicits MHC-I expression, increases tumor antigen presentation, recruits more tumor-infiltrating T lymphocytes, and suppresses FN-γ-induced intratumoral PD-L1 expression. After a proof of concept for overcoming intrinsic and inducible immune evasion, the prodrug nanovesicles are applied to validate the efficacy of cancer immunotherapy in two tumor-bearing mouse models. This research thus provides a novel targeting strategy for reducing tumor immune resistance and potentiating tumor immunotherapy.
    Keywords:  antigen presentation; autophagy inhibition; immune resistance; immunotherapy; prodrug nanovesicles
  7. ACS Biomater Sci Eng. 2021 Sep 01.
      Peptide nucleic acids (PNAs) are a class of artificial oligonucleotide mimics that have garnered much attention as precision biotherapeutics for their efficient hybridization properties and their exceptional biological and chemical stability. However, the poor cellular uptake of PNA is a limiting factor to its more extensive use in biomedicine; encapsulation in nanoparticle carriers has therefore emerged as a strategy for internalization and delivery of PNA in cells. In this study, we demonstrate that PNA can be readily loaded into porous silicon nanoparticles (pSiNPs) following a simple salt-based trapping procedure thus far employed only for negatively charged synthetic oligonucleotides. We show that the ease and versatility of PNA chemistry also allows for producing PNAs with different net charge, from positive to negative, and that the use of differently charged PNAs enables optimization of loading into pSiNPs. Differently charged PNA payloads determine different release kinetics and allow modulation of the temporal profile of the delivery process. In vitro silencing of a set of specific microRNAs using a pSiNP-PNA delivery platform demonstrates the potential for biomedical applications.
    Keywords:  anti-microRNA therapeutics; drug delivery; nanomaterials; oligonucleotide mimics; release kinetics
  8. Adv Mater. 2021 Sep 03. e2102586
      Anticounterfeiting labels based on physical unclonable functions (PUFs) exhibit high security with unreplicable code outputs, making them an ideal platform to realize unbreakable anticounterfeiting. Although various schemes are proposed for PUF labels, the utilization of natural randomness suffers from unpredictable signal extraction sites, which poses a challenge to efficient and convenient authentication for practical anticounterfeiting applications. Here, a covert optical PUF-based cryptographic protocol from silk protein-based microlaser (SML) arrays that possess hidden randomness of lasers for unclonable lasing signals as well as a defined location for efficient identification is proposed. The initial SMLs are patterned by casting laser dye-doped regenerated silk fibroin solution, resulting in a uniform microlaser array with regulated positions. With the SML array as substrate, random methanol microdroplets are stochastically sprayed on the SML array, which eventually induces uneven lasing signal changes of the patterned microlasers. The treated SML array possesses the deterministic readout sites of laser signals and unrepeatable signal distribution characteristics, which can guarantee efficient authentication and high security when serving as an anticounterfeiting label.
    Keywords:  anticounterfeiting; biocompatible laser; laser array; organic microlaser; physical unclonable functions
  9. Anal Chem. 2021 Sep 01.
      Synthetic DNA walkers are artificially designed DNA self-assemblies with the capability of performing quasi-mechanical movement at the micro/nanoscale and have shown extensive promise in biosensing, intracellular imaging, and drug delivery. However, DNA walkers are usually constructed by covalently or coordinately binding DNA strands specifically to hard surfaces, thereby greatly limiting their movement efficiency. Herein, we report an intraparticle and interparticle transferable DNA walker (dynamic micelle-supported DNA walker, DM-walker) constructed by immobilizing walking tracks and walking arms onto the corona of DNA micelles according to the principle of Watson-Crick base pairing. The DNAzyme-powered walking arm can drive the intraparticle and interparticle movements of the DM-walker due to the fact that the dynamic structure of the DNA micelle helps overcome the spatial barrier between the arms and tracks in the system, resulting in high walking efficiency. Moreover, the whole DM-walker can be constructed by self-assembly, getting rid of the tedious process and low efficiency of fixing DNA strands on hard surfaces. Taking miRNA-10b as a model target, the DM-walker demonstrates high walking efficiency (reaction duration of 20 min) and high sensitivity (LOD of 87 pM). The proposed DM-walker provides an avenue to develop novel DNA walkers on dynamic interfaces and holds great potential in clinical diagnosis.
  10. Adv Healthc Mater. 2021 Aug 31. e2101239
      Various lipid-based nanocarriers have been developed for the co-delivery of protein antigens with immunological adjuvants. However, their in vivo potency in vaccine delivery is limited by structural instability, which causes off-target delivery and low cross-presentation efficacies. Recent works employ covalent cross-linking to stabilize the lipid nanostructures, though the immunogenicity and side effects of chemically modified protein antigens and lipids can cause a long-lasting safety issue. Here robust "conjugation-free" multilamellar protein antigen-lipid hybrid nanovesicles (MPLVs) are introduced through the antigen-mediated self-assembly of unilamellar lipid vesicles for the co-delivery of protein antigens and immunologic adjuvants. The nanocarriers coated with monophosphoryl lipid A and hyaluronic acids elicit highly increase antigen-specific immune responses in vitro and in vivo. The MPLVs increase the generation of immunological surface markers and cytokines in mouse-derived bone-marrow dendritic cells compared to soluble antigens with adjuvants. Besides, the vaccination of mice with the MPLVs significantly increase the production of anti-antigen antibody and interferon-gamma via the activation of CD4+ and CD8+ T cells, respectively. These findings suggest that MPLVs can serve as a promising nanovaccine delivery platform for efficient antigen cross-presentation through the efficient co-delivery of protein antigens with adjuvants.
    Keywords:  antigen encapsulation; monophosphoryl lipid A; multilamellar self-assembly; ovalbumin; vaccine delivery
  11. Nat Commun. 2021 08 31. 12(1): 5195
      Functional tumor-specific cytotoxic T cells elicited by therapeutic cancer vaccination in combination with oncolytic viruses offer opportunities to address resistance to checkpoint blockade therapy. Two cancer vaccines, the self-adjuvanting protein vaccine KISIMA, and the recombinant oncolytic vesicular stomatitis virus pseudotyped with LCMV-GP expressing tumor-associated antigens, termed VSV-GP-TAA, both show promise as a single agent. Here we find that, when given in a heterologous prime-boost regimen with an optimized schedule and route of administration, combining KISIMA and VSV-GP-TAA vaccinations induces better cancer immunity than individually. Using several mouse tumor models with varying degrees of susceptibility for viral replication, we find that priming with KISIMA-TAA followed by VSV-GP-TAA boost causes profound changes in the tumor microenvironment, and induces a large pool of poly-functional and persistent antigen-specific cytotoxic T cells in the periphery. Combining this heterologous vaccination with checkpoint blockade further improves therapeutic efficacy with long-term survival in the spectrum. Overall, heterologous vaccination with KISIMA and VSV-GP-TAA could sensitize non-inflamed tumors to checkpoint blockade therapy.
  12. Nucleic Acids Res. 2021 Sep 03. pii: gkab759. [Epub ahead of print]
      Architectural proteins alter the shape of DNA. Some distort the double helix by introducing sharp kinks. This can serve to relieve strain in tightly-bent DNA structures. Here, we design and test artificial architectural proteins based on a sequence-specific Transcription Activator-like Effector (TALE) protein, either alone or fused to a eukaryotic high mobility group B (HMGB) DNA-bending domain. We hypothesized that TALE protein binding would stiffen DNA to bending and twisting, acting as an architectural protein that antagonizes the formation of small DNA loops. In contrast, fusion to an HMGB domain was hypothesized to generate a targeted DNA-bending architectural protein that facilitates DNA looping. We provide evidence from Escherichia coli Lac repressor gene regulatory loops supporting these hypotheses in living bacteria. Both data fitting to a thermodynamic DNA looping model and sophisticated molecular modeling support the interpretation of these results. We find that TALE protein binding inhibits looping by stiffening DNA to bending and twisting, while the Nhp6A domain enhances looping by bending DNA without introducing twisting flexibility. Our work illustrates artificial approaches to sculpt DNA geometry with functional consequences. Similar approaches may be applicable to tune the stability of small DNA loops in eukaryotes.
  13. JACS Au. 2021 Feb 22. 1(2): 221-232
      To image membrane tension in selected membranes of interest (MOI) inside living systems, the field of mechanobiology requires increasingly elaborated small-molecule chemical tools. We have recently introduced HaloFlipper, i.e., a mechanosensitive flipper probe that can localize in the MOI using HaloTag technology to report local membrane tension changes using fluorescence lifetime imaging microscopy. However, the linker tethering the probe to HaloTag hampers the lateral diffusion of the probe in all the lipid domains of the MOI. For a more global membrane tension measurement in any MOI, we present here a supramolecular chemistry strategy for selective localization and controlled release of flipper into the MOI, using a genetically encoded supramolecular tag. SupraFlippers, functionalized with a desthiobiotin ligand, can selectively accumulate in the organelle having expressed streptavidin. The addition of biotin as a biocompatible external stimulus with a higher affinity for Sav triggers the release of the probe, which spontaneously partitions into the MOI. Freed in the lumen of endoplasmic reticulum (ER), SupraFlippers report the membrane orders along the secretory pathway from the ER over the Golgi apparatus to the plasma membrane. Kinetics of the process are governed by both the probe release and the transport through lipid domains. The concentration of biotin can control the former, while the expression level of a transmembrane protein (Sec12) involved in the stimulation of the vesicular transport from ER to Golgi influences the latter. Finally, the generation of a cell-penetrating and fully functional Sav-flipper complex using cyclic oligochalcogenide (COC) transporters allows us to combine the SupraFlipper strategy and HaloTag technology.
  14. Mater Sci Eng C Mater Biol Appl. 2021 Sep;pii: S0928-4931(21)00498-7. [Epub ahead of print]128 112358
      Bioreducible polyethylenimines (SSPEIs) are promising non-viral carriers for cancer gene therapy. However, the availability of significant gene transfection activity by SSPEIs remains a challenge. Herein, an essential step was taken to ascertain whether or not the disulfide bonds of SSPEIs play a critical role in promoting significant gene transfection activity in different tissues. Initially, a disulfide-linked linear polyethylenimine (denoted as SSLPEI) consisting of one 5.0 kDa LPEI main chain and three disulfide-linked 5.7 kDa LPEI grafts was designed and prepared to possess similar molecular weight with commercialized 25 kDa LPEI as a positive control. The SSLPEI could induce superior in vitro transfection activity in different cells to the LPEI control as well as low cytotoxicity. Notably, such enhanced in vitro transfection effect by the SSLPEI was more marked in type-II alveolar epithelial cells compared to different cancer cells. In a Balb/c nude mouse model bearing SKOV-3 tumor, the SSLPEI caused parallel level of transgene expression with the LPEI control in the tumor but significantly higher level in the mouse lung. Furthermore, the SSLPEI and LPEI groups afforded an identical antitumor efficacy against the SKOV-3 tumor via intravenous delivery of a shRNA for silencing VEGF expression in the tumor. However, via intravenous delivery of an interleukin-12 (IL-12) gene into metastatic lung cancers in a C57BL/6 mouse model, the SSLPEI group exerted markedly higher IL-12 expression level in the mouse lung and peripheral blood as compared to the LPEI group, thereby boosting IL-12 immunotherapy against the lung metastasis with longer medium survival time. The results of this work elicit that the disulfide bonds of SSPEIs play a pivotal role in enhancing gene transfection activity selectively in the lung tissue rather than solid tumor, enabling high translational potential of SSPEIs for non-viral gene therapy against metastatic lung cancers.
    Keywords:  Disulfide; Interleukin-12; Metastatic lung cancer; Polyethylenimine; Transfection