bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒09‒19
seventeen papers selected by
Ceren Kimna
Technical University of Munich

  1. Nat Mater. 2021 Sep 13.
      Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin-integrin α3/α6 signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness-a hallmark of pancreatic cancer-was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro.
  2. Adv Mater. 2021 Sep 17. e2104729
      Nanobottles refer to colloidal particles featuring a hollow body connected to a single opening on the surface. This unique feature makes them ideal carriers for the encapsulation and controlled release of various types of cargos. Here a facile route to the fabrication of uniform nanobottles made of polydopamine by leveraging swelling-induced pressure is reported. When polystyrene spheres are coated with polydopamine and then incubated with a toluene/water emulsion, the polystyrene will be swollen to automatically poke a single hole in the shell because of the pressure inside the shell. After quenching the swelling with ethanol and then removing all the polystyrene with tetrahydrofuran, polydopamine nanobottles are obtained. The dimensions of the hollow body are determined by the polystyrene template, while the size of the opening can be tuned by varying the shell thickness. Through the opening, different types of cargos, including small molecules and biomacromolecules, can be easily loaded with a thermoresponsive material into the cavity. The cargos can be released in a controllable manner through direct heating or polydopamine-enabled photothermal heating. In a proof-of-concept experiment, the polydopamine nanobottles are used for temperature-controlled release of thrombin to trigger the formation of fibrin gels in situ.
    Keywords:  controlled release; nanobottle; phase-change material; polydopamine; swelling
  3. Nat Commun. 2021 Sep 16. 12(1): 5473
      Implant related infections are the most common cause of joint arthroplasty failure, requiring revision surgeries and a new implant, resulting in a cost of $8.6 billion annually. To address this problem, we created a class of coating technology that is applied in the operating room, in a procedure that takes less than 10 min, and can incorporate any desired antibiotic. Our coating technology uses an in situ coupling reaction of branched poly(ethylene glycol) and poly(allyl mercaptan) (PEG-PAM) polymers to generate an amphiphilic polymeric coating. We show in vivo efficacy in preventing implant infection in both post-arthroplasty infection and post-spinal surgery infection mouse models. Our technology displays efficacy with or without systemic antibiotics, the standard of care. Our coating technology is applied in a clinically relevant time frame, does not require modification of implant manufacturing process, and does not change the implant shelf life.
  4. Nat Biomed Eng. 2021 Sep 13.
      Site-1 sodium channel blockers (S1SCBs) act as potent local anaesthetics, but they can cause severe systemic toxicity. Delivery systems can be used to reduce the toxicity, but the hydrophilicity of S1SCBs makes their encapsulation challenging. Here, we report a self-assembling delivery system for S1SCBs whose design is inspired by the specific interactions of S1SCBs with two peptide sequences on the sodium channel. Specifically, the peptides were modified with hydrophobic domains so that they could assemble into nanofibres that facilitated specific binding with the S1SCBs tetrodotoxin, saxitoxin and dicarbamoyl saxitoxin. Injection of S1SCB-carrying nanofibres at the sciatic nerves of rats led to prolonged nerve blockade and to reduced systemic toxicity, with benign local-tissue reaction. The strategy of mimicking a molecular binding site via supramolecular interactions may be applicable more broadly to the design of drug delivery systems for receptor-mediated drugs.
  5. Adv Mater. 2021 Sep 12. e2102661
      Engineering hierarchical vasculatures is critical for creating implantable functional thick tissues. Current approaches focus on fabricating mesoscale vessels for implantation or hierarchical microvascular in vitro models, but a combined approach is yet to be achieved to create engineered tissue flaps. Here, millimetric vessel-like scaffolds and 3D bioprinted vascularized tissues interconnect, creating fully engineered hierarchical vascular constructs for implantation. Endothelial and support cells spontaneously form microvascular networks in bioprinted tissues using a human collagen bioink. Sacrificial molds are used to create polymeric vessel-like scaffolds and endothelial cells seeded in their lumen form native-like endothelia. Assembling endothelialized scaffolds within vascularizing hydrogels incites the bioprinted vasculature and endothelium to cooperatively create vessels, enabling tissue perfusion through the scaffold lumen. Using a cuffing microsurgery approach, the engineered tissue is directly anastomosed with a rat femoral artery, promoting a rich host vasculature within the implanted tissue. After two weeks in vivo, contrast microcomputer tomography imaging and lectin perfusion of explanted engineered tissues verify the host ingrowth vasculature's functionality. Furthermore, the hierarchical vessel network (VesselNet) supports in vitro functionality of cardiomyocytes. Finally, the proposed approach is expanded to mimic complex structures with native-like millimetric vessels. This work presents a novel strategy aiming to create fully-engineered patient-specific thick tissue flaps.
    Keywords:  3D bioprinting; ECM bioink; engineered flap; personalized medicine; tissue engineering; vascularization
  6. Adv Healthc Mater. 2021 Sep 17. e2100683
      Ferritin internalized into tumor cells is degraded and releases iron ions via ferritinophagy. Iron ions participate in Fenton reaction to produce reactive oxygen species for lipid peroxidation and ferroptosis. Inhibition of indoleamine-2,3-dioxygenase (IDO) decreases tryptophan elimination to induce T cells activation for tumor immunosuppression relief. The active tumor targeting nanoparticles containing ferritin and a pH-sensitive molecular-switch (FPBC@SN) are developed to utilize ferritinophagy-cascade ferroptosis and tumor immunity activation for cancer therapy. FPBC@SN disintegrates in acidic cytoplasm and releases sorafenib (SRF) and IDO inhibitor (NLG919). SRF upregulates nuclear receptor coactivator 4 (NCOA4) to induce ferritin and endogenous iron pool degradation by ferritinophagy, then obtained iron ions participate in the Fenton reaction to produce lipid peroxide (LPO). Meanwhile, SRF blocks glutathione synthesis to downregulate glutathione peroxidase 4 (GPX4) which can scavenge LPO as a different pathway from ferritinophagy to promote ferroptosis in tumor cells. NLG919 inhibits IDO to reduce tryptophan metabolism, so immunity in tumors is aroused to anti-tumor. In vitro and in vivo experiments prove FPBC@SN inhibits tumor cell growth and metastasis, indicating the potential of FPBC@SN for breast cancer therapy based on the combination of ferritinophagy-cascade ferroptosis and tumor immunity activation.
    Keywords:  ferritin; ferritinophagy; ferroptosis; sorafenib; tumor immunity
  7. Adv Drug Deliv Rev. 2021 Sep 13. pii: S0169-409X(21)00367-7. [Epub ahead of print] 113974
      The translational success of liposomes in chemotherapeutics has already demonstrated the great potential of biomembrane-based nanostructure in effective drug delivery. Meanwhile, increasing efforts are being dedicated to the application of naturally derived lipid membranes, including cellular membranes and extracellular vesicles in anti-cancer therapies. While synthetic liposomes support superior multifunctional flexibility, natural biomembrane materials possess interesting biomimetic properties and can also be further engineered for intelligent design. Despite being remarkably different from each other in production and composition, the phospholipid bilayer structure in common allows liposomes, cell membrane-derived nanomaterials, and extracellular vesicles to be modified, functionalized, and exploited in many similar manners against challenges posed by tumor-targeted drug delivery. This review will summarize the recent advancements in engineering the membrane-derived nanostructures with "intelligent" modules to respond, regulate, and target tumor cells and the microenvironment to fight against malignancy. We will also discuss perspectives of combining engineered functionalities with naturally occurring activity for enhanced cancer therapy.
    Keywords:  Cancer immunotherapy; Cancer vaccine; Cell membrane camouflages; Extracellular vesicles; Gene therapy; Multifunctional liposomes; Tumor microenvironment
  8. Angew Chem Int Ed Engl. 2021 Sep 17.
      Incorporating multiple molecular interactions within a system to realize the metabolic reprogramming of cancer cells is prospected to be of great potential in cancer therapy. Herein, we report a supramolecular self-assembled DNA nanosystem, which reprogrammed the cellular antioxidant system via synergistic chemical and gene regulations. In the nanosystem, amphipathic telluroether was coordinated with Mn(II) to self-assemble into micelle, on which a siNrf2 integrated DNA network was assembled. The great electron-donating capability of telluroether was revealed to greatly promote Mn(II)-based Fenton-like reaction to generate subversive ·OH in cancer cells. In response to adenosine triphosphoric acid, the siNrf2 was specially released in cytoplasm for down-regulating expression of detoxification enzymes, which enhanced chemocatalysis-mediated oxidative stress in cancer cells, thus significantly suppressing tumor progression.
    Keywords:  DNA nanostructure; DNA nanotechnology; gene therapy; nanomedicine; supramolecular self-assembly
  9. Adv Mater. 2021 Sep 17. e2104932
      Oral administration is the most convenient and commonly used approach for drug delivery, while it is still a challenge to overcome the complicated gastrointestinal barriers and realize efficient macromolecular drug absorption. Here, novel magneto-responsive microneedle robots are presented for efficient oral delivery of versatile macromolecules. These microneedle robots with three components of the magnetic substrate, the separable connection, and tips are generated by a Lego-brick-stacking-inspired multistage 3D fabrication strategy. With the assistance of commercial enteric capsule encapsulation, they can be taken orally and be released when entering the small intestine. Benefitting from their polarized magnetic substrate, the tips of the microneedle robots can orient to the small intestinal wall, overcome the barriers, insert into the tissue, and deliver encapsulated actives under specific magnetic fields. Besides, after the separable connection degrades, the tips can be left inside the tissue for continuous actives release, and the magnetic substrate can be excreted safely. Based on these features, the practical values of the microneedle robots are demonstrated by using them to orally deliver insulin and efficiently regulate the blood glucose of pigs. It is believed that the proposed microneedle robots can orally deliver diverse macromolecules and thus open a new chapter for oral administration.
    Keywords:  insulin; magneto-responsive; microneedles; oral delivery; robotics
  10. Small. 2021 Sep 12. e2103986
      Injecting micro/nanorobots into the body to kill tumors is one of the ultimate ambitions for medical nanotechnology. However, injecting current micro/nanorobots based on 3D-printed biocompatible materials directly into blood vessels for targeted therapy is often difficult, and mistakes in targeting can cause serious side effects, such as blood clots, oxidative stress, or inflammation. The natural affinity of macrophages to tumors, and their natural phagocytosis and ability to invade tumors, make them outstanding drug delivery vehicles for targeted tumor therapy. Hence, a magnetically controlled cell robot (MCR) based on a macrophage drug carrier is proposed. Here, living macrophages are converted into MCRs through endocytosis of specially-designed magnetic nanoparticles loaded with doxorubicin and indocyanine green. Following this, the MCRs can be transported to tumors through the blood vessels using external magnetic fields, and penetrate the blood vessels into the interior of the tumor due to their deformability. With the MCR's cascaded drug release, targeted killing of tumors in mice is demonstrated, with minimal effects on the normal surrounding tissue. The ability to impart precise drug doses onto natural cells, such as macrophages, and load various functional components into the MCRs, offers an efficient method for precise targeted therapy.
    Keywords:  cell robots; magnetic actuation; minimal invasion; precise control; targeted therapy
  11. Nano Lett. 2021 Sep 13.
      The blood-brain barrier (BBB) is highly selective and acts as the interface between the central nervous system and circulation. While the BBB is critical for maintaining brain homeostasis, it represents a formidable challenge for drug delivery. Here we synthesized gold nanoparticles (AuNPs) for targeting the tight junction specifically and demonstrated that transcranial picosecond laser stimulation of these AuNPs post intravenous injection increases the BBB permeability. The BBB permeability change can be graded by laser intensity, is entirely reversible, and involves increased paracellular diffusion. BBB modulation does not lead to significant disruption in the spontaneous vasomotion or the structure of the neurovascular unit. This strategy allows the entry of immunoglobulins and viral gene therapy vectors, as well as cargo-laden liposomes. We anticipate this nanotechnology to be useful for tissue regions that are accessible to light or fiberoptic application and to open new avenues for drug screening and therapeutic interventions in the central nervous system.
    Keywords:  blood−brain barrier; gold nanoparticle; therapeutics delivery; tight junction targeting
  12. Adv Mater. 2021 Sep 12. e2103923
      T cell activation-induced cell death (AICD) during tumor pathogenesis is a tumor immune escape process dependent on dendritic cells (DCs). Proper immune-modulatory therapies effectively inhibit tumor-specific CD8+ T cell exhaustion and enhance antitumor immune responses. Here, high-pressure homogenization is utilized to drive immunomodulator IL10-modified bacteria to extrude through the gap and self-assemble into bacterial biomimetic vesicles exposing IL10 (IL10-BBVs) on the surface with high efficiency. IL10-BBVs efficiently target DCs in tumor-draining lymph nodes and thus increase the interaction between IL10 on BBVs and IL10R on DCs to suppress AICD and mitigate CD8+ T cell exhaustion specific to tumor antigens. Two subcutaneous peripheral injections of IL10-BBVs 1 week apart in tumor-bearing mice effectively increase systemic and intratumoral proportions of CD8+ T cells to suppress tumor growth and metastasis. Tumor-specific antigen E7 is enclosed into the periplasm of IL10-BBVs (IL10-E7-BBVs) to realize concurrent actions of the immunomodulator IL10 and the tumor antigen human papillomavirus (HPV) 16E7 in lymph nodes, further enhancing the antitumor effects mediated by CD8+ T cells. The development of this modified BBV delivery platform will expand the application of bacterial membranes and provide novel immunotherapeutic strategies for tumor treatment.
    Keywords:  activation-induced T cell death; antitumor immunity; bacterial vesicles; cytokines; immunomodulators
  13. Nanoscale. 2021 Sep 17. 13(35): 15010-15020
      For effective targeted therapy of cancer with chemotherapy-loaded nanoparticles (NPs), antigens that are selective for cancer cells should be targeted to minimise off-tumour toxicity. Human leukocyte antigens (HLAs) are attractive cancer targets as they can present peptides from tumour-selective proteins on the cell surface, which can be recognised by T cells via T cell receptors (TCRs). In this study, docetaxel-loaded polymeric NPs were conjugated to recombinant affinity-enhanced TCRs to target breast cancer cells presenting a tumour-selective peptide-HLA complex. The TCR-conjugated nanoparticles enabled enhanced delivery of docetaxel and induced cell death through tumour-specific peptide-HLA targeting. These in vitro data demonstrate the potential of targeting tumour-restricted peptide-HLA epitopes using high affinity TCR-conjugated nanoparticles, representing a novel treatment strategy to deliver therapeutic drugs specifically to cancer cells.
  14. Nat Commun. 2021 Sep 13. 12(1): 5416
      Hypoxia is the most prominent feature in human solid tumors and induces activation of hypoxia-inducible factors and their downstream genes to promote cancer progression. However, whether and how hypoxia regulates overall mRNA homeostasis is unclear. Here we show that hypoxia inhibits global-mRNA decay in cancer cells. Mechanistically, hypoxia induces the interaction of AGO2 with LUBAC, the linear ubiquitin chain assembly complex, which co-localizes with miRNA-induced silencing complex and in turn catalyzes AGO2 occurring Met1-linked linear ubiquitination (M1-Ubi). A series of biochemical experiments reveal that M1-Ubi of AGO2 restrains miRNA-mediated gene silencing. Moreover, combination analyses of the AGO2-associated mRNA transcriptome by RIP-Seq and the mRNA transcriptome by RNA-Seq confirm that AGO2 M1-Ubi interferes miRNA-targeted mRNA recruiting to AGO2, and thereby facilitates accumulation of global mRNAs. By this mechanism, short-term hypoxia may protect overall mRNAs and enhances stress tolerance, whereas long-term hypoxia in tumor cells results in seriously changing the entire gene expression profile to drive cell malignant evolution.
  15. Adv Healthc Mater. 2021 Sep 15. e2101181
      It is common to improve the relevant performance in the field of energy storage materials or catalytic materials by regulating the number of defects. However, there are few studies on the biomaterials containing defects for tissue engineering. Herein, a new type of defect-rich scaffolds, black akermanite (B-AKT) bioceramic scaffolds with micro/nanostructure, the thickness of which is from 0.14 to 1.94 µm, is fabricated through introducing defects on the surface of bioceramic scaffolds. The B-AKT scaffolds have advantages on the degradation rate and the osteogenic capacity over the AKT (Ca2 MgSi2 O7 ) scaffolds due to the surface defects which stimulate the osteogenic differentiation of rabbit bone mesenchymal stem cells via activating bone morphogenetic protein 2 (BMP2) signaling pathway and further promote bone formation in vivo. In addition, the prepared B-AKT scaffolds, the temperature of which can be over 100 °C under the near infrared (NIR) irradiation (0.66 W cm-2 ), possess excellent performance on photothermal and antitumor effects. The work develops an introducing-defect strategy for regulating the biological performance of bioceramic scaffolds, which is expected to be applied in the next generation of bioceramic scaffolds for regenerative medicine.
    Keywords:  bioceramic scaffolds; defects; micro/nanostructures; osteogenesis; tissue engineering
  16. Adv Mater. 2021 Sep 18. e2104849
      Tumor tissues/cells are the best sources of antigens to prepare cancer vaccines. However, due to the difficulty of solubilization and delivery of water-insoluble antigens in tumor tissues/cells, including water-insoluble antigens into cancer vaccines and delivering such vaccines efficiently to antigen-presenting cells (APCs) remain challenging. To solve these problems, herein, water-insoluble components of tumor tissues/cells are solubilized by 8 m urea and thus whole components of macrometer-sized tumor cells are reasssembled into nanosized nanovaccines. To induce maximized immunization efficacy, various antigens are loaded both inside and on the surface of nanovaccines. By encapsulating both water-insoluble and water-soluble components of tumor tissues/cells into nanovaccines, the nanovaccines are efficiently phagocytosed by APCs and showed better therapeutic efficacy than the nanovaccine loaded with only water-soluble components in melanoma and breast cancer. Anti-PD-1 antibody and metformin can improve the efficacy of nanovaccines. In addition, the nanovaccines can prevent lung cancer (100%) and melanoma (70%) efficiently in mice. T cell analysis and tumor microenvironment analysis indicate that tumor-specific T cells are induced by nanovaccines and both adaptive and innate immune responses against cancer cells are activated by nanovaccines. Overall, this study demonstrates a universal method to make tumor-cell-based nanovaccines for cancer immunotherapy and prevention.
    Keywords:  cancer immunotherapy; cancer prevention; cell lysate; drug delivery; nanovaccines; tumor tissues; whole cell components
  17. Nano Lett. 2021 Sep 13.
      Immunotherapy holds great promise for patients undergoing tumor treatment. However, the clinical effect of immunotherapy is limited because of tumor immunogenicity and its immunosuppressive microenvironment. Herein, the metal-organic framework (MIL-100) loaded with chemotherapeutic agent mitoxantrone (MTO) was combined with photothermal-chemotherapy for enhancing immunogenic cell death. MIL-100 loaded with MTO and hyaluronic acid as nanoparticles (MMH NPs) yielded an NP with two therapeutic properties (photothermal and chemotherapy) with dual imaging modes (photoacoustic and thermal). When MMH NPs were coinjected with an anti-OX40 antibody in colorectal cancer, the highest antitumor efficacy and a robust immune effect were achieved. This work provides a novel combined therapeutic strategy, which will hold great promise in future tumor therapy.
    Keywords:  chemotherapy; immunogenic cell death; immunotherapy; metal−organic framework; photothermal therapy