bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒03‒20
sixteen papers selected by
Ceren Kimna
Technical University of Munich

  1. ACS Nano. 2022 Mar 16.
      Throughout the female menstrual cycle, physiological changes occur that affect the biodistribution of nanoparticles within the reproductive system. We demonstrate a 2-fold increase in nanoparticle accumulation in murine ovaries and uterus during ovulation, compared to the nonovulatory stage, following intravenous administration. This biodistribution pattern had positive or negative effects when drug-loaded nanoparticles, sized 100 nm or smaller, were used to treat different cancers. For example, treating ovarian cancer with nanomedicines during mouse ovulation resulted in higher drug accumulation in the ovaries, improving therapeutic efficacy. Conversely, treating breast cancer during ovulation, led to reduced therapeutic efficacy, due to enhanced nanoparticle accumulation in the reproductive system rather than at the tumor site. Moreover, chemotherapeutic nanoparticles administered during ovulation increased ovarian toxicity and decreased fertility compared to the free drug. The menstrual cycle should be accounted for when designing and implementing nanomedicines for females.
    Keywords:  breast cancer; fertility; gender medicine; gold nanoparticles; liposome; mRNA LNP; ovarian cancer
  2. Nano Lett. 2022 Mar 14.
      Uncontrolled growth of tumor cells is highly dependent on the energy metabolism. Fasting-mimicking diet (FMD) is a low-calorie, low-protein, low-sugar diet representing a promising strategy for cancer treatment. However, triglyceride stored in adipose tissue is hydrolyzed into free fatty acids and glycerol for energy supply during FMD treatment. Herein, we design a nutrient-sensing nanodrug, VFETX, which is self-assembled with vitamin B1 (VB1), ferrous ions, and etomoxir (ETX). FMD treatment upregulate the expression of VB1 transporters on tumor cells, thereby increasing cellular uptake and tumor accumulation of VFETX. Importantly, treatments of VFETX and FMD synergistically inhibit the energy metabolism in tumor cells and subsequently markedly enhance cytotoxicity of ETX. As a result, VFETX nanodrugs efficiently inhibit the growth of two tumor models in vivo without obvious side effects. This study demonstrates the potential of FMD-assisted nutrient-sensing nanodrugs for cancer therapy.
    Keywords:  Biomolecule; cancer therapy; fasting-mimicking diet; self-assembly
  3. Nat Biotechnol. 2022 Mar 17.
      Living bacteria therapies have been proposed as an alternative approach to treating a broad array of cancers. In this study, we developed a genetically encoded microbial encapsulation system with tunable and dynamic expression of surface capsular polysaccharides that enhances systemic delivery. Based on a small RNA screen of capsular biosynthesis pathways, we constructed inducible synthetic gene circuits that regulate bacterial encapsulation in Escherichia coli Nissle 1917. These bacteria are capable of temporarily evading immune attack, whereas subsequent loss of encapsulation results in effective clearance in vivo. This dynamic delivery strategy enabled a ten-fold increase in maximum tolerated dose of bacteria and improved anti-tumor efficacy in murine models of cancer. Furthermore, in situ encapsulation increased the fraction of microbial translocation among mouse tumors, leading to efficacy in distal tumors. The programmable encapsulation system promises to enhance the therapeutic utility of living engineered bacteria for cancer.
  4. Adv Mater. 2022 Mar 15. e2200449
      Various macro/microscopic biomaterials have been developed for controlled drug delivery in the combination therapy of malignancies. However, uncertain loading ratio, release sequence, and spatiotemporal distribution of drugs hinder their synergistic therapeutic effects and clinical applications. Herein, a tumor microenvironments-adapted composite consisting of thermo-sensitive hydrogel and reactive oxygen species (ROS)-responsive nanogel was developed for precisely sequential drug release to enhance molecular targeted therapy and amplify immune activation. LY3200882 (LY), a selective transforming growth factor-β (TGF-β) inhibitor, was encapsulated in the ROS-responsive nanogel and dispersed uniformly with regorafenib (REG) in a thermo-sensitive hydrogel (Gel/(REG+NG/LY)). After in situ administration, REG was preferentially released from the hydrogel to inhibit tumor growth and promote ROS generation, which triggered the subsequent on-demand release of LY from the nanogel. LY contributed to preventing the epithelial-mesenchymal transition and immune escape of tumor cells induced by elevated TGF-β. In subcutaneous and orthotopic colorectal tumor-bearing mouse models, Gel/(REG+NG/LY) effectively inhibited tumor growth and liver metastasis by increasing the tumor infiltration of CD8+ T cells, reducing the recruitment of tumor-associated macrophages and myeloid-derived suppressor cells, and promoting the polarization of macrophages from M2 to M1 type, indicating the significant potential in improving the prognosis of advanced cancer patients. This article is protected by copyright. All rights reserved.
    Keywords:  polypeptide; reactive oxygen species-responsive nanogel; sequential drug delivery; synergistic cancer therapy; thermo-sensitive hydrogel
  5. Nat Commun. 2022 Mar 18. 13(1): 1454
      Reinvigoration of antitumor immunity has recently become the central theme for the development of cancer therapies. Nevertheless, the precise delivery of immunotherapeutic activities to the tumors remains challenging. Here, we explore a synthetic gene circuit-based strategy for specific tumor identification, and for subsequently engaging immune activation. By design, these circuits are assembled from two interactive modules, i.e., an oncogenic TF-driven CRISPRa effector, and a corresponding p53-inducible off-switch (NOT gate), which jointly execute an AND-NOT logic for accurate tumor targeting. In particular, two forms of the NOT gate are developed, via the use of an inhibitory sgRNA or an anti-CRISPR protein, with the second form showing a superior performance in gating CRISPRa by p53 loss. Functionally, the optimized AND-NOT logic circuit can empower a highly specific and effective tumor recognition/immune rewiring axis, leading to therapeutic effects in vivo. Taken together, our work presents an adaptable strategy for the development of precisely delivered immunotherapy.
  6. Nat Commun. 2022 Mar 17. 13(1): 1413
      Protecting the whole small intestine from radiation-induced intestinal injury during the radiotherapy of abdominal or pelvic solid tumors remains an unmet clinical need. Amifostine is a promising selective radioprotector for normal tissues. However, its oral application in intestinal radioprotection remains challenging. Herein, we use microalga Spirulina platensis as a microcarrier of Amifostine to construct an oral delivery system. The system shows comprehensive drug accumulation and effective radioprotection in the whole small intestine that is significantly superior to free drug and its enteric capsule, preventing the radiation-induced intestine injury and prolonging the survival without influencing the tumor regression. It also shows benefits on the gut microbiota homeostasis and long-term safety. Based on a readily available natural microcarrier, this work presents a convenient oral delivery system to achieve effective radioprotection for the whole small intestine, providing a competitive strategy with great clinical translation potential.
  7. ACS Nano. 2022 Mar 16.
      The dynamic transient formation and depletion of G-quadruplexes regulate gene replication and transcription. This process was found to be related to various diseases such as cancer and premature aging. We report on the engineering of nucleic acid modules revealing dynamic, transient assembly and disassembly of G-quadruplex structures and G-quadruplex-based DNAzymes, gated transient processes, and cascaded dynamic transient reactions that involve G-quadruplex and DNAzyme structures. The dynamic transient processes are driven by functional DNA reaction modules activated by a fuel strand and guided toward dissipative operation by a nicking enzyme (Nt.BbvCI). The dynamic networks were further characterized by computational simulation of the experiments using kinetic models, allowing us to predict the dynamic performance of the networks under different auxiliary conditions applied to the systems. The systems reported herein could provide functional DNA machineries for the spatiotemporal control of G-quadruplex structures perturbing gene expression and thus provide a therapeutic means for related emergent diseases.
    Keywords:  DNA nanotechnology; DNA network; G-quadruplex; dissipative; machinery; nicking enzyme; out-of-equilibrium
  8. Nat Commun. 2022 Mar 18. 13(1): 1459
      As one of the typical bioorthogonal reactions, copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction holds great potential in organic synthesis, bioconjugation, and surface functionalization. However, the toxicity of Cu(I), inefficient catalytic activity, and the lack of cell specific targeting of the existing catalysts hampered their practical applications in living systems. Herein, we design and construct a DNA-based platform as a biocompatible, highly efficient, and precisely targeted bioorthogonal nanocatalyst. The nanocatalyst presents excellent catalytic efficiency in vitro, which is one order of magnitude higher than the commonly used catalyst CuSO4/sodium ascorbate. The theoretical calculation further supports the contribution of DNA structure and its interaction with substrates to the superior catalytic activity. More importantly, the system can achieve efficient prodrug activation in cancer cells through cell type-specific recognition and produce a 40-fold enhancement of transformation compared to the non-targeting nanocatalyst, resulting in enhanced antitumor efficacy and reduced adverse effects. In vivo tumor therapy demonstrates the safety and efficacy of the system in mammals.
  9. Nat Commun. 2022 Mar 17. 13(1): 1435
      MicroRNAs (miRNAs) are small non-coding RNAs, which regulate the expression of thousands of genes; miRNAs silence gene expression from complementary mRNAs through translational repression and mRNA decay. For decades, the function of miRNAs has been studied primarily by ensemble methods, where a bulk collection of molecules is measured outside cells. Thus, the behavior of individual molecules during miRNA-mediated gene silencing, as well as their spatiotemporal regulation inside cells, remains mostly unknown. Here we report single-molecule methods to visualize each step of miRNA-mediated gene silencing in situ inside cells. Simultaneous visualization of single mRNAs, translation, and miRNA-binding revealed that miRNAs preferentially bind to translated mRNAs rather than untranslated mRNAs. Spatiotemporal analysis based on our methods uncovered that miRNAs bind to mRNAs immediately after nuclear export. Subsequently, miRNAs induced translational repression and mRNA decay within 30 and 60 min, respectively, after the binding to mRNAs. This methodology provides a framework for studying miRNA function at the single-molecule level with spatiotemporal information inside cells.
  10. ACS Biomater Sci Eng. 2022 Mar 17.
      Intestinal organoids are self-organized tissue constructs, grown in vitro, that resemble the structure and function of the intestine and are often considered promising as a prospective platform for drug testing and disease modeling. Organoid development in vitro is typically instructed by exogenous cues delivered from the media, but cellular responses also depend on properties of the surrounding microenvironmental niche, such as mechanical stiffness and extracellular matrix (ECM) ligands. In recent years, synthetic hydrogel platforms have been engineered to resemble the in vivo niche, with the goal of generating physiologically relevant environments that can promote mature and reproducible organoid development. However, a few of these approaches consider the importance of intestinal organoid morphology or how morphology changes during development, as cues that may dictate organoid functionality. For example, intestinal organoids grown in vitro often lack the physical boundary conditions found in vivo that are responsible for shaping a collection of cells into developmentally relevant morphologies, resulting in organoids that often differ in structure and cellular organization from the parent organ. This disconnect relates, in part, to a lack of appropriate adaptable and programmable materials for cell culture, especially those that enable control over colony growth and differentiation in space and time (i.e., 4D materials). We posit that the future of organoid culture platforms may benefit from advances in photoadaptable chemistries and integration into biomaterials scaffolds, thereby allowing greater user-directed control over both the macro- and microscale material properties. In this way, synthetic materials can begin to better replicate changes in the ECM during development or regeneration in vivo. Recapitulation of cellular and tissue morphological changes, along with an appreciation for the appropriate developmental time scales, should help instruct the next generation of organoid models to facilitate predictable outcomes.
    Keywords:  biomaterials; intestinal organoids; photochemistry; tissue geometry
  11. ACS Biomater Sci Eng. 2022 Mar 16.
      Mucus is a complex viscoelastic gel and acts as a barrier covering much of the soft tissue in the human body. High vascularization and accessibility have motivated drug delivery to various mucosal surfaces; however, these benefits are hindered by the mucus layer. To overcome the mucus barrier, many nanomedicines have been developed, with the goal of improving the efficacy and bioavailability of drug payloads. Two major nanoparticle-based strategies have emerged to facilitate mucosal drug delivery, namely, mucoadhesion and mucopenetration. Generally, mucoadhesive nanoparticles promote interactions with mucus for immobilization and sustained drug release, whereas mucopenetrating nanoparticles diffuse through the mucus and enhance drug uptake. The choice of strategy depends on many factors pertaining to the structural and compositional characteristics of the target mucus and mucosa. While there have been promising results in preclinical studies, mucus-nanoparticle interactions remain poorly understood, thus limiting effective clinical translation. This article reviews nanomedicines designed with mucoadhesive or mucopenetrating properties for mucosal delivery, explores the influence of site-dependent physiological variation among mucosal surfaces on efficacy, transport, and bioavailability, and discusses the techniques and models used to investigate mucus-nanoparticle interactions. The effects of non-homeostatic perturbations on protein corona formation, mucus composition, and nanoparticle performance are discussed in the context of mucosal delivery. The complexity of the mucosal barrier necessitates consideration of the interplay between nanoparticle design, tissue-specific differences in mucus structure and composition, and homeostatic or disease-related changes to the mucus barrier to develop effective nanomedicines for mucosal delivery.
    Keywords:  clinical translation; mucoadhesion; mucopenetration; mucus models; nanoparticle; protein corona
  12. Sci Adv. 2022 Mar 18. 8(11): eabl3888
      There is a lack in clinically-suitable vascular grafts. Biotubes, prepared using in vivo tissue engineering, show potential for vascular regeneration. However, their mechanical strength is typically poor. Inspired by architectural design of steel fiber reinforcement of concrete for tunnel construction, poly(ε-caprolactone) (PCL) fiber skeletons (PSs) were fabricated by melt-spinning and heat treatment. The PSs were subcutaneously embedded to induce the assembly of host cells and extracellular matrix to obtain PS-reinforced biotubes (PBs). Heat-treated medium-fiber-angle PB (hMPB) demonstrated superior performance when evaluated by in vitro mechanical testing and following implantation in rat abdominal artery replacement models. hMPBs were further evaluated in canine peripheral arterial replacement and sheep arteriovenous graft models. Overall, hMPB demonstrated appropriate mechanics, puncture resistance, rapid hemostasis, vascular regeneration, and long-term patency, without incidence of luminal expansion or intimal hyperplasia. These optimized hMPB properties show promise as an alternatives to autologous vessels in clinical applications.
  13. Adv Mater. 2022 Mar 15. e2110305
      Tumor-targeted antibody (mAb)/fragment-conjugated nanoparticles (NPs) represent an innovative strategy for improving the local delivery of small molecules. However, the physicochemical properties of full mAb-NPs and fragment-NPs-that is, NP material, size, charge, as well as the targeting antibody moiety, and the linker conjugation strategies-remain to be optimized to achieve an efficient tumor targeting. A meta-analysis of 161 peer-reviewed studies is presented, which describes the use of tumor-targeted mAb-NPs and fragment-NPs from 2009 to 2021. The use of these targeted NPs is confirmed to result in significantly greater tumor uptake of NPs than that of naked NPs (7.9 ± 1.9% ID g-1 versus 3.2 ± 0.6% ID g-1 , respectively). The study further demonstrates that for lipidic NPs, fragment-NPs provide a significantly higher tumor uptake than full mAb-NPs. In parallel, for both polymeric and organic/inorganic NPs, full mAb-NPs yield a significant higher tumor uptake than fragment-NPs. In addition, for both lipidic and polymeric NPs, the tumor uptake is improved with the smallest sizes of the conjugates. Finally, the pharmacokinetics of the conjugates are demonstrated to be driven by the NPs and not by the antibody moieties, independently of using full mAb-NPs or fragment-NPs, confirming the importance of optimizing the NP design to improve the tumor uptake.
    Keywords:  active targeting; antibodies; biodistribution; nanomedicine; pharmacokinetics
  14. Adv Healthc Mater. 2022 Mar 14. e2102581
      The tumor microenvironment (TME) is the environment around the tumor, including blood vessels, immune cells, fibroblasts, signaling molecules, and the extracellular matrix (ECM). Owing to its component interactions, the TME influences tumor growth and drug delivery in a highly complex manner. Although several vascularized cancer models have been developed to mimic the TME in vitro, these models cannot comprehensively reflect blood vessel-tumor spheroid interactions. Here, we present a method for inducing controlled tumor angiogenesis by engineering the microenvironment. The interstitial flow direction regulates the direction of capillary sprouting, showing that angiogenesis occurs in the opposite direction of flow, while the existence of lung fibroblasts affects the continuity and lumen formation of sprouted capillaries. The vascularized tumor model shows enhanced delivery of anticancer drugs and immune cells to the tumor spheroids because of the perfusable vascular networks. The possibility of capillary embolism using anticancer drug-conjugated liquid metal nanoparticles was investigated using the vascularized tumor model. This vascularized tumor platform can aid in the development of effective anticancer drugs and cancer immunotherapy. This article is protected by copyright. All rights reserved.
    Keywords:  angiogenesis; drug delivery; immune cell transport; tumor spheroid; vascularization
  15. Nat Commun. 2022 Mar 18. 13(1): 1466
      Patient-derived tumor organoids (PDOs) are a highly promising preclinical model that recapitulates the histology, gene expression, and drug response of the donor patient tumor. Currently, PDO culture relies on basement-membrane extract (BME), which suffers from batch-to-batch variability, the presence of xenogeneic compounds and residual growth factors, and poor control of mechanical properties. Additionally, for the development of new organoid lines from patient-derived xenografts, contamination of murine host cells poses a problem. We propose a nanofibrillar hydrogel (EKGel) for the initiation and growth of breast cancer PDOs. PDOs grown in EKGel have histopathologic features, gene expression, and drug response that are similar to those of their parental tumors and PDOs in BME. In addition, EKGel offers reduced batch-to-batch variability, a range of mechanical properties, and suppressed contamination from murine cells. These results show that EKGel is an improved alternative to BME matrices for the initiation, growth, and maintenance of breast cancer PDOs.
  16. J Control Release. 2022 Mar 10. pii: S0168-3659(22)00121-3. [Epub ahead of print]
      In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 μM. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs.
    Keywords:  Enzyme-instructed self-assembly; In vivo; Ocular drug delivery; Tear fluid