bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒06‒05
ten papers selected by
Ceren Kimna
Technical University of Munich

  1. Adv Mater. 2022 May 31. e2203993
      Cancer-targeting ligands used for nanomedicines have been limited to mostly antibodies, peptides, aptamers, and small molecules thus far. Here we report a library of glycocalyx-mimicking nanoparticles as a platform enabling screening and identification of cancer-targeting nanomedicines. Specifically, a library of 31 artificial glycopolymers composed of either homogeneous or heterogeneous display of five different sugar moieties (β-Glc, β-Gal, α-Man, β-GlcNAc, and β-GalNAc) was converted to a library of glyconanoparticles (GlyNPs). We systematically screened and identified GlyNPs optimal for targeting CT26, DU145, A549, and PC3 tumors. The cypate-conjugated GlyNP displaying α-Man and β-GlcNAc showed selective targeting and potent photothermal therapeutic efficacy against A549 human lung tumors. The docetaxel-contained GlyNP displaying β-Glc, β-Gal, and α-Man demonstrated targeted chemotherapy against DU145 human prostate tumors. The results presented herein collectively demonstrated that the GlyNP library is a versatile platform enabling the identification of cancer-targeting glyconanoparticles and suggested its potential applicability for targeting various diseased cells beyond cancer. This article is protected by copyright. All rights reserved.
    Keywords:  cancer; chemotherapy; glyconanoparticle; glycopolymer; photothermal therapy
  2. Nucleic Acids Res. 2022 May 30. pii: gkac431. [Epub ahead of print]
      MicroRNA-dependent mRNA decay plays an important role in gene silencing by facilitating posttranscriptional and translational repression. Inspired by this intrinsic nature of microRNA-mediated mRNA cleavage, here, we describe a microRNA-targeting mRNA as a switch platform called mRNA bridge mimetics to regulate the translocation of proteins. We applied the mRNA bridge mimetics platform to Cas9 protein to confer it the ability to translocate into the nucleus via cleavage of the nuclear export signal. This system performed programmed gene editing in vitro and in vivo. Combinatorial treatment with cisplatin and miR-21-EZH2 axis-targeting CRISPR Self Check-In improved sensitivity to chemotherapeutic drugs in vivo. Using the endogenous microRNA-mediated mRNA decay mechanism, our platform is able to remodel a cell's natural biology to allow the entry of precise drugs into the nucleus, devoid of non-specific translocation. The mRNA bridge mimetics strategy is promising for applications in which the reaction must be controlled via intracellular stimuli and modulates Cas9 proteins to ensure safe genome modification in diseased conditions.
  3. Proc Natl Acad Sci U S A. 2022 Jun 07. 119(23): e2118697119
      Significance The blood-brain barrier represents a major therapeutic challenge for the treatment of glioblastoma, and there is an unmet need for in vitro models that recapitulate human biology and are predictive of in vivo response. Here, we present a microfluidic model of vascularized glioblastoma featuring a tumor spheroid in direct contact with self-assembled vascular networks comprising human endothelial cells, astrocytes, and pericytes. This model was designed to accelerate the development of targeted nanotherapeutics and enabled rigorous assessment of a panel of surface-functionalized nanoparticles designed to exploit a receptor overexpressed in tumor-associated vasculature. Trafficking and efficacy data in the in vitro model compared favorably to parallel in vivo data, highlighting the utility of the vascularized glioblastoma model for therapeutic development.
    Keywords:  blood–brain barrier; drug delivery; glioblastoma; microfluidic; nanoparticle
  4. Proc Natl Acad Sci U S A. 2022 Jun 07. 119(23): e2200363119
      SignificanceThis study analyzed the dynamic protein corona on the surface of nanoparticles as they traversed from blood to cell lysosomes and escaped from lysosomes to cytoplasm in the target cells. We found with proteomic analysis an abundance of chaperone and glycolysis coronal proteins (i.e., heat shock cognate protein 70, heat shock protein 90, and pyruvate kinase M2 [PKM2]) after escape of the nanoparticles from lysosomes to the cytosol. Alterations of the coronal proteins (e.g., PKM2 and chaperone binding) induced proteostasis collapse, which subsequently led to elevated chaperone-mediated autophagy (CMA) activity in cells. As PKM2 is a key molecule in cell metabolism, we also revealed that PKM2 depletion was causative to CMA-induced cell metabolism disruption from glycolysis to lipid metabolism.
    Keywords:  cell metabolism; chaperone-mediated autophagy; protein corona; proteostasis
  5. ACS Nano. 2022 Jun 02.
      Developing effective intelligent nanotheranostics is highly desirable for cancer treatment but remains challenging. In this study, an acidic tumor microenvironment-activated organosilica nanosystem, namely AD-Cu-DOX-HA, is straightforwardly constructed, which is composed of aggregation-induced emission (AIE)-active photosensitizer, copper ion-engineered aminosilica, direct coordination polymer of doxorubicin (DOX), and targeting component hyaluronic acid (HA). AD-Cu-DOX-HA is able to accurately distinguish cancer cells over normal cells; meanwhile, it simultaneously exhibits selective accumulation and copper ion-mediated rapid disassembly and turn-on fluorescence in tumor tissue, consequently achieving efficient tumor diagnosis and tumor-growth inhibition through fluorescence imaging-navigated synergetic photodynamic therapy, copper ion-mediated chemodynamic therapy, and DOX-enabled chemotherapy. This work thus brings fresh insight into the exploration of versatile theranostics and presents a momentous advance for potential clinical cancer treatment.
    Keywords:  aggregation-induced emission; coordination polymer; intelligent nanotheranostics; ion engineering; organosilica nanoparticles
  6. J Control Release. 2022 May 26. pii: S0168-3659(22)00311-X. [Epub ahead of print]
      Many protein immunotherapeutics are hindered by transport barriers that prevent the obtainment of minimum effective concentrations (MECs) in solid tumors. Local delivery vehicles with tunable release (infusion) rates for immunotherapeutics are being developed to achieve local and sustained release. To expedite their discovery and translation, in vitro models can identify promising delivery vehicles and immunotherapies that benefit from sustained release by evaluating cancer spheroid killing in real-time. Using displacement affinity release (DAR) within a hydrogel, we tuned the release of a CD133 targeting dual antigen T cell engager (DATE) without the need for further DATE or hydrogel modifications, yielding an injectable vehicle that acts as a tunable infusion pump. To quantify bioactivity benefits, a 3D embedded cancer spheroid model was developed for the evaluation of sustained protein release and combination therapies on T cell mediated spheroid killing. Using automated brightfield and fluorescent microscopy, the size of red fluorescent protein (iRFP670) expressing spheroids were tracked to quantify spheroid growth or killing over time as a function of controlled delivery. We demonstrate that sustained DATE release enhanced T cell mediated killing of embedded glioblastoma spheroids at longer timepoints, killing was further enhanced with the addition of anti-PD1 antibody (αPD1). The multi-cellular embedded spheroid model with automated microscopy demonstrated the benefit of extended bispecific release on T cell mediated killing, which will expedite the identification and translation of delivery vehicles such as DAR for immunotherapeutics.
    Keywords:  Affinity release; Bispecific T cell engagers; Displacement affinity release; Spheroid killing; Three-dimensional cell culture
  7. Nat Commun. 2022 May 31. 13(1): 3019
      For the practical use of synthetic hydrogels as artificial biological tissues, flexible electronics, and conductive membranes, achieving requirements for specific mechanical properties is one of the most prominent issues. Here, we demonstrate superstrong, superstiff, and conductive alginate hydrogels with densely interconnecting networks implemented via simple reconstructing processes, consisting of anisotropic densification of pre-gel and a subsequent ionic crosslinking with rehydration. The reconstructed hydrogel exhibits broad ranges of exceptional tensile strengths (8-57 MPa) and elastic moduli (94-1,290 MPa) depending on crosslinking ions. This hydrogel can hold sufficient cations (e.g., Li+) within its gel matrix without compromising the mechanical performance and exhibits high ionic conductivity enough to be utilized as a gel electrolyte membrane. Further, this strategy can be applied to prepare mechanically outstanding, ionic-/electrical-conductive hydrogels by incorporating conducting polymer within the hydrogel matrix. Such hydrogels are easily laminated with strong interfacial adhesion by superficial de- and re-crosslinking processes, and the resulting layered hydrogel can act as a stable gel electrolyte membrane for an aqueous supercapacitor.
  8. J Control Release. 2022 May 28. pii: S0168-3659(22)00313-3. [Epub ahead of print]
      Messenger RNA (mRNA) medicine has become a new therapeutic approach owing to the progress in mRNA delivery technology, especially with lipid nanoparticles (LNP). However, mRNA encapsulated-LNP (mRNA-LNP) cannot spontaneously cross the blood-brain barrier (BBB) which prevents the expression of foreign proteins in the brain. Microbubble-assisted focused ultrasound (FUS) BBB opening is an emerging technology that can transiently enhance BBB permeability. In this study, FUS/microbubble-assisted BBB opening was investigated for the intravenous delivery of mRNA-LNP to the brain. The intensity of FUS irradiation was optimized to 1.5 kW/cm2, at which BBB opening occurred efficiently without hemorrhage or edema. Exogenous protein (luciferase) expression by mRNA-LNP, specifically at the FUS-irradiated side of the brain, occurred only when FUS and microbubbles were applied. This exogenous protein expression was faster but shorter than that of plasmid DNA delivery. Furthermore, foreign protein expression was observed in the microglia, along with CD31-positive endothelial cells, whereas no expression was observed in astrocytes or neurons. These results support the addition of mRNA-LNP to the lineup of nanoparticles delivered by BBB opening.
    Keywords:  Blood-brain barrier (BBB); Focused ultrasound (FUS); Lipid nanoparticles (LNP); Messenger RNA (mRNA); Microbubble
  9. ACS Appl Mater Interfaces. 2022 Jun 01.
      Chronic diabetic wound healing remains a challenge due to the existence of excessive danger molecules and bacteria in the inflammatory microenvironment. There is an urgent need for advanced wound dressings that target both inflammation and infection. Here, a bioactive hydrogel without loading any anti-inflammatory ingredients is rationally designed to achieve a "Pull-Push" approach for efficient and safe bacteria-infected diabetic wound healing by integrating danger molecule scavenging (Pull) with antibiotic delivery (Push) in the inflammatory microenvironment. The cationic hydrogel, termed the OCMC-Tob/PEI hydrogel, is fabricated by the conjugation of polyethylenimine (PEI) and tobramycin (Tob) on an oxidized carboxymethyl cellulose (OCMC) backbone via the Schiff base reaction with injectable, self-healing, and biocompatible properties. The OCMC-Tob/PEI hydrogel not only displays the remarkable capability of capturing multiple negatively charged danger molecules (e.g., cell-free DNA, lipopolysaccharides, and tumor necrosis factor-α) to ameliorate anti-inflammation effects but also achieves controllable long-term antibacterial activity by the pH-sensitive release of Tob. Consequently, this multifunctional hydrogel greatly expedites the wound closure rate with combined anti-inflammation and anti-infection effects on Pseudomonas aeruginosa-infected diabetic wounds. Our work provides a highly versatile treatment approach for chronic diabetic wounds and a promising dressing for regenerative medicine.
    Keywords:  bioactive; hydrogel; infection; inflammation; wound healing
  10. Adv Healthc Mater. 2022 Jun 03. e2200874
      Although tissue adhesives have potential advantages over traditional sutures, existing ones suffer from several limitations: slow adhesion kinetic, low mechanical strength, and poor interfacial bonding with wet biological tissues. Herein, a cooperative mussel/slug double-bioinspired hydrogel adhesive (DBHA) composed of a robust adhesive interface and a stretchable dissipative matrix is developed. The DBHA is formed by a cationic polysaccharide (chitosan), an anionic polysaccharide (carboxymethyl cellulose), and a barbell-like dendritic lysine grafted with catechol groups. Compared to various commercial bio-glues and traditional adhesives, the DBHA has significantly stronger tissue adhesion and enhanced toughness both ex vivo and in vivo. Meanwhile, the DBHA exhibits fast, strong, tough and durable adhesion to diverse ex vivo tissue surfaces with blood. The adhesion energy between the adhesive and porcine skin can reach 200-900 J m-2 . Additionally, in vivo studies prove that DBHA has good hemostasis of rabbit artery trauma and achieves better wound healing of tissue incision than commercial bio-glues. This study provides a novel strategy for fabricating fast and strong wet adhesives, which can be used in many applications, such as soft robots, tissue adhesives, and hemostats. This article is protected by copyright. All rights reserved.
    Keywords:  hemostasis; hydrogel; peptide dendrimer; tissue adhesive; wet adhesion