bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒07‒17
thirteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Nat Commun. 2022 Jul 12. 13(1): 4032
      Nanomedicine holds promise to enhance cancer immunotherapy; however, its potential to elicit highly specific anti-tumor immunity without compromising immune tolerance has yet to be fully unlocked. This study develops deep-tissue activatable cancer sono-immunotherapy based on the discovery of a semiconducting polymer that generates sonodynamic singlet oxygen (1O2) substantially higher than other sonosensitizers. Conjugation of two immunomodulators via 1O2-cleavable linkers onto this polymer affords semiconducting polymer immunomodulatory nanoparticles (SPINs) whose immunotherapeutic actions are largely inhibited. Under ultrasound irradiation, SPINs generate 1O2 not only to directly debulk tumors and reprogram tumor microenvironment to enhance tumor immunogenicity, but also to remotely release the immunomodulators specifically at tumor site. Such a precision sono-immunotherapy eliminates tumors and prevents relapse in pancreatic mouse tumor model. SPINs show effective antitumor efficacy even in a rabbit tumor model. Moreover, the sonodynamic activation of SPINs confines immunotherapeutic action primarily to tumors, reducing the sign of immune-related adverse events.
  2. Nanoscale. 2022 Jul 15.
      Although various nanomaterials have been designed as intracellular delivery tools, the following aspects have become obstacles to limit their development, like a complex and time-consuming synthesis process, as well as relatively limited application areas (i.e. biosensing or cell imaging). Here, we developed a novel nano-delivery system called "nano-sperm" with low cytotoxicity and high biocompatibility. In this system, we used DNA oligonucleotides as a backbone to synthesize a nanostructure with silver nanoclusters in the head and functional fragments in the tail, which is shaped like a sperm, to achieve dual functions of ultrafast delivery and imaging/therapy. As a model, we analyzed the possibility of the "nano-sperm" carrying DNA with different structures for imaging or survivin-asDNA for tumor therapy. Therefore, this work reports a novel bifunctional high-speed delivery vehicle, which successfully fills the gap in the field of tumor therapy using DNA-templated nanoclusters as a delivery vehicle.
  3. J Control Release. 2022 Jul 09. pii: S0168-3659(22)00419-9. [Epub ahead of print]
      Breast-to-brain metastatic cells can interact with the surrounding cells, including astrocytes and microglia, to generate a pro-tumorigenic niche. Breast-to-brain metastasis can be treated using a dual strategy of eliminating metastatic tumor cells and normalizing their localized microenvironment. The effective accumulation of drugs at the action site of metastasis is crucial to realizing the above strategy, especially when dealing with the blood-brain barrier (BBB)-penetrating and tumor-targeting tactics. Here, we establish an in-situ microenvironment-tailored micelle (T-M/siRNA) to co-deliver therapeutic siRNA and paclitaxel (PTX) into the breast-to-brain metastasis. Anchored with a D-type cyclic peptide, T-M/siRNA can penetrate the BBB and subsequently target the brain metastases. Upon internalization by metastatic tumor cells, T-M/siRNA can release PTX in the high-level glutathione (GSH), resulting in killing cancer cells. Meanwhile, the micellar structure is dissociated, resulting in lowering the charge density to release the loaded siRNA that can targeted downregulate the expression of protocadherin 7 (PCDH7). Treatment of model mice revealed that T-M/siRNA can inhibit the abnormal activation of astrocytes and immunosuppressive activation of microglia, resulting in significantly enhanced synergistic anti-tumor efficacy. This study indicates that the micelle system can serve as a hopeful strategy to treat breast-to-brain metastasis.
    Keywords:  Breast-to-brain metastasis; Micelle; Microenvironment; Paclitaxel; Protocadherin 7
  4. ACS Nano. 2022 Jul 10.
      Both DNA- and RNA-based nanotechnologies are remarkably useful for the engineering of molecular devices in vitro and are applied in a vast collection of applications. Yet, the ability to integrate functional nucleic acid nanostructures in applications outside of the lab requires overcoming their inherent degradation sensitivity and subsequent loss of function. Viruses are minimalistic yet sophisticated supramolecular assemblies, capable of shielding their nucleic acid content in nuclease-rich environments. Inspired by this natural ability, we engineered RNA-virus-like particles (VLPs) nanocarriers (NCs). We showed that the VLPs can function as an exceptional protective shell against nuclease-mediated degradation. We then harnessed biological recognition elements and demonstrated how engineered riboswitch NCs can act as a possible disease-modifying treatment for genetic metabolic disorders. The functional riboswitch is capable of selectively and specifically binding metabolites and preventing their self-assembly process and its downstream effects. When applying the riboswitch nanocarriers to an in vivo yeast model of adenine accumulation and self-assembly, significant inhibition of the sensitivity to adenine feeding was observed. In addition, using an amyloid-specific dye, we proved the riboswitch nanocarriers' ability to reduce the level of intracellular amyloid-like metabolite cytotoxic structures. The potential of this RNA therapeutic technology does not apply only to metabolic disorders, as it can be easily fine-tuned to be applied to other conditions and diseases.
    Keywords:  RNA nanotechnology; VLPs; metabolic disorders; nanocarriers; riboswitch
  5. ACS Nano. 2022 Jul 13.
      M13 bacteriophage (phage) are versatile, genetically tunable nanocarriers that have been recently adapted for use as diagnostic and therapeutic platforms. Applying p3 capsid chlorotoxin fusion with the "inho" circular single-stranded DNA (cssDNA) gene packaging system, we produced miniature chlorotoxin inho (CTX-inho) phage particles with a minimum length of 50 nm that can target intracranial orthotopic patient-derived GBM22 glioblastoma tumors in the brains of mice. Systemically administered indocyanine green conjugated CTX-inho phage accumulated in brain tumors, facilitating shortwave infrared detection. Furthermore, we show that our inho phage can carry cssDNA that are transcriptionally active when delivered to GBM22 glioma cells in vitro. The ability to modulate the capsid display, surface loading, phage length, and cssDNA gene content makes the recombinant M13 phage particle an ideal delivery platform.
    Keywords:  engineered m13 bacteriophage; glioblastoma targeting; materials and gene delivery; nanotheranostic particle; short-wavelength infrared imaging
  6. Acta Biomater. 2022 Jul 12. pii: S1742-7061(22)00410-X. [Epub ahead of print]
      There are many problems and challenges related to the treatment of highly prevalent oral mucosal diseases and oral drug delivery because of a large amount of saliva present in the oral cavity, the accompanying oral movements, and unconscious swallowing in the mouth. Therefore, an ideal oral dressing should possess stable adhesion and superior tough strength in the oral cavity. However, this fundamental requirement greatly limits the use of synthetic adhesive dressings for oral dressings. Here, we developed a mussel-inspired Janus gelatin-polydopamine-nano-clay (GPC) hydrogel with controlled adhesion and toughness through the synergistic physical and chemical interaction of gelatin (Gel), nano-clay, and dopamine (DA). The hydrogel not only exhibits strong wet adhesion force (63 kPa) but also has high toughness (1026 ± 100 J m-3). Interfacial adhesion of hydrogels is achieved by modulating the interaction of catechol groups of the hydrogel with specific functional groups (e.g., NH2, SH, OH, and COOH) on the tissue surface. The matrix dissipation of the hydrogel is regulated by physical crosslinking of gelatin, chemical crosslinking of gelatin with polydopamine (Michael addition and Schiff base formation), and nano-clay-induced constraint of the molecular chain. In addition, the GPC hydrogel shows high cell affinity and favors cell adhesion and proliferation. The hydrogel's instant and strong mucoadhesive properties provide a long-lasting therapeutic effect of the drug, thereby enhancing the healing of oral ulcers. Therefore, mussel-inspired wet-adhesion Janus GPC hydrogels can be used as a platform for mucosal dressing and drug delivery systems. STATEMENT OF SIGNIFICANCE: : It is a great challenge to treat oral mucosal diseases due to the large amount of saliva present in the oral cavity, the accompanying oral movements, unconscious swallowing, and flushing of drugs in the mouth. To overcome the significant limitations of clinical bioadhesives, such as weakness, toxicity, and poor usage, in the present study, we developed a simple method through the synergistic effects of gelatin, polydopamine, and nano-clay to prepare an optimal mucosal dressing (Janus GPC) that integrates Janus, adhesion, toughness, and drug release property. It fits effectively in the mouth, resists saliva flushing and oral movements, provides oral drug delivery, and reduces patient discomfort. The Janus GPC adhesive hydrogels have great commercial potential to support further the development of innovative therapies for oral mucosal diseases.
    Keywords:  Drug released; Janus; Oral mucosal; Toughness; Wet adhesion
  7. J Control Release. 2022 Jul 12. pii: S0168-3659(22)00416-3. [Epub ahead of print]349 354-366
      First-line treatments for mild to moderate psoriasis are typically topical formulations containing corticosteroids, however, the therapeutic efficacy of these formulations is compromised by limited penetration and skin retention. Even more challenging, off-target corticosteroids are known to adversely affect healthy skin, including induction of epidermal and dermal atrophy. Here, we report a nanoparticle-based topical formulation that cures psoriasis in a single dose, but leaves healthy skin intact. Specifically, we developed tris(hydroxymethyl)aminomethane-modified bioadhesive nanoparticles (Tris-BNPs) that exploit the high permeability characteristic of psoriasis to penetrate only psoriatic skin but not the healthy skin. Furthermore, as Tris-BNPs diffuse and penetrate into the epidermis, the Tris molecules slowly diffuse away, exposing the aldehyde groups of BNPs, which can bind to amine groups present within lesional skin, leading to long local retention of BNPs in lesions of psoriatic skin. The accumulated BNPs within lesions release corticosteroids over a ~ 3 day period to maintain local drug concentration above the therapeutic level. In addition to deeper penetration and longer retention compared with commercial psoriasis treatments, the topical applied Tris-BNPs were not affected by sweating, humidity, or active wiping due to their preferential accumulation between the stratum corneum and the basal cells of the epidermis. Overall, Tris-BNP as a topical formulation hold promise to overcome the limitations of current psoriasis treatment.
    Keywords:  Disease-specific treatment; Formulation optimization; Local drug delivery; Psoriasis; Single-dose cure; Surface-modified nanoparticles
  8. Nat Commun. 2022 Jul 16. 13(1): 4135
      Spatial control of gene expression is critical to modulate cellular functions and deconstruct the function of individual genes in biological processes. Light-responsive gene-editing formulations have been recently developed; however, they have shown limited applicability in vivo due to poor tissue penetration, limited cellular transfection and the difficulty in evaluating the activity of the edited cells. Here, we report a formulation composed of upconversion nanoparticles conjugated with Cre recombinase enzyme through a photocleavable linker, and a lysosomotropic agent that facilitates endolysosomal escape. This formulation allows in vitro spatial control in gene editing after activation with near-infrared light. We further demonstrate the potential of this formulation in vivo through three different paradigms: (i) gene editing in neurogenic niches, (ii) gene editing in the ventral tegmental area to facilitate monitoring of edited cells by precise optogenetic control of reward and reinforcement, and (iii) gene editing in a localized brain region via a noninvasive administration route (i.e., intranasal).
  9. Adv Healthc Mater. 2022 Jul 11. e2201049
      Incomplete contact between a pre-formed hydrogel and irregular wound limits the therapeutic effect of the dressing and increases the risk of infection; while great concerns have remained regarding the potential toxicity of the residual additives of chemical crosslinking for in-situ forming hydrogels. Therefore, it is desirable to develop a self-adaptive hydrogel in response to skin temperature with shape adaptability and efficient antibacterial property to prevent microbial invasion. Herein, a dually-thermoresponsive hydrogel composed of poly(N-isopropylacrylamide) (PNIPAm) and methacrylated κ-carrageenan (MA-κ-CA) is designed with compliance at physiological temperature to realize shape adaptability for completely covering irregular wounds. Furthermore, the hydrogel with near-infrared (NIR)-responsive polypyrrole-polydopamine nanoparticles (PPy-PDA NPs) and Zn2+ -derived zeolitic imidazolate framework (ZIF-8) can generate localized heat and gradually release Zn2+ to realize safe, effective synergetic photothermal-chemical bactericidal capability. In addition, the release rate of Zn2+ can be accelerated by NIR-induced heating, and thus a more efficient sterilization can be provided to severely infected wounds. Therefore, the proposed hydrogel would serve as a promising wound dressing for the full course of wound healing, with the abilities of perfectly covering the wound and adapting to regenerating tissue, and controllable photothermal-chemical antibacterial capability to reach high bactericidal efficiency and long-term release of antibacterial agents. This article is protected by copyright. All rights reserved.
    Keywords:  Dually-thermoresponsive hydrogel; shape adaptability; synergetic antibacterial; wound healing
  10. Adv Drug Deliv Rev. 2022 Jul 08. pii: S0169-409X(22)00334-9. [Epub ahead of print] 114444
      The components and hospitable properties of tumor microenvironment (TME) are associated with tumor progression. Recently, TME modulating vectors and strategies have garnished significant attention in cancer therapy. Although a pilot work has reviewed TME regulation via nanoparticle-based delivery systems, there is no systematical review that summarizes the natural bacteria-based anti-tumor system to modulate TME. In this review, we conclude the strategies of bacterial carriers (including whole bacteria, bacterial skeleton and bacterial components) to regulate TME from the perspective of TME components and hospitable properties, and the clinical trials of bacteria-mediated cancer therapy. Current challenges and future prospects for the design of bacteria-based carriers are also proposed that provide critical insights into this natural delivery system and related translation from the bench to the clinic.
    Keywords:  Bacterial carriers; Hospitable properties; Hypoxia; Immune activation; Immune tolerance/suppression; TME components; TME modulation
  11. Oncogenesis. 2022 Jul 11. 11(1): 38
      MiR-21 was identified as a gene whose expression correlated with the extent of metastasis of murine mammary tumours. Since miR-21 is recognised as being associated with poor prognosis in cancer, we investigated its contribution to mammary tumour growth and metastasis in tumours with capacity for spontaneous metastasis. Unexpectedly, we found that suppression of miR-21 activity in highly metastatic tumours resulted in regression of primary tumour growth in immunocompetent mice but did not impede growth in immunocompromised mice. Analysis of the immune infiltrate of the primary tumours at the time when the tumours started to regress revealed an influx of both CD4+ and CD8+ activated T cells and a reduction in PD-L1+ infiltrating monocytes, providing an explanation for the observed tumour regression. Loss of anti-tumour immune suppression caused by decreased miR-21 activity was confirmed by transcriptomic analysis of primary tumours. This analysis also revealed reduced expression of genes associated with cell cycle progression upon loss of miR-21 activity. A second activity of miR-21 was the promotion of metastasis as shown by the loss of metastatic capacity of miR-21 knockdown tumours established in immunocompromised mice, despite no impact on primary tumour growth. A proteomic analysis of tumour cells with altered miR-21 activity revealed deregulation of proteins known to be associated with tumour progression. The development of therapies targeting miR-21, possibly via targeted delivery to tumour cells, could be an effective therapy to combat primary tumour growth and suppress the development of metastatic disease.
  12. ACS Nano. 2022 Jul 11.
      Polymer-grafted nanoparticle (GNP) membranes show unexpected gas transport enhancements relative to the neat polymer, with a maximum as a function of graft molecular weight (MWg ≈ 100 kDa) for sufficiently high grafting densities. The structural origins of this behavior are unclear. Simulations suggest that polymer segments are stretched near the nanoparticle (NP) surface and form a dry layer, while more distal chain fragments are in their undeformed Gaussian states and interpenetrate with segments from neighboring NPs. This theoretical basis is derived by considering the behavior of two adjacent NPs; how this behavior is modified by multi-NP effects relevant to gas separation membranes is unexplored. Here, we measure and interpret SAXS data for poly(methyl acrylate)-grafted silica NPs and find that for very low MWgs, contact between GNPs obeys the two-NP theory─namely that the NPs act like hard spheres, with radii that are linear combinations of the NP core sizes and the dry zone dimensions; thus, the interpenetration zones relax into the interstitial spaces. For chains with MWg > 100 kDa, the interpenetration zones are in the contact regions between two NPs. These results suggest that for MWgs below the transition, gas primarily moves through a series of dry zones with favorable transport, with the interpenetration zone with less favorable transport properties in parallel. For higher MWgs, the dry and interpenetration zones are in series, resulting in a decrease in transport enhancement. The MWg at the transport maximum then corresponds to the chain length with the largest, unfavorable stretching free energy.
    Keywords:  X-ray scattering; polymer brushes; polymer-grafted nanoparticles; structural transition; structure−property relationship
  13. Adv Healthc Mater. 2022 Jul 16. e2200678
      Lacrimal plug is an effective and widely therapeutic strategy to treat the dry eye. However, almost all commercialized plugs are fixed in a certain design and associated with many complications, such as spontaneous plug extrusion, epiphora, granuloma and can not be traced for long-term. Herein, we develop a simple in situ forming hydrogel as a tracer and degradable lacrimal plug to achieve the best match with the irregular lacrimal passages. In this strategy, methacrylate-modified silk fibroin (SFMA) is served as a network, and self-assembled indocyanine green fluorescence tracer nanoparticle (FTN) is embedded as an indicator to develop the hydrogel plug using visible photo-crosslinking. This SFMA/FTN hydrogel plug has excellent biocompatibility and biodegradability, which can be noninvasively monitored by near-infrared light. In vivo tests based on dry eye rabbits show that the SFMA/FTN hydrogel plug can completely block the lacrimal passages and greatly improve the various clinical indicators of dry eye. These results demonstrate that the SFMA/FTN hydrogel is suitable as an injectable and degradable lacrimal plug with a long-term tracking function. Our work offers a new approach for the development of absorbable plugs for the treatment of the dry eye. This article is protected by copyright. All rights reserved.
    Keywords:  absorbable; dry eye; in situ-forming; lacrimal plug; tracer