bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒01‒09
fourteen papers selected by
Ceren Kimna
Technical University of Munich

  1. ACS Nano. 2022 Jan 03.
      Hypoxia, a common feature of most solid tumors, causes severe tumor resistance to chemotherapy and immunotherapy. Herein, a tumor-acidity and bioorthogonal chemistry-mediated on-site size transformation clustered nanosystem is designed to overcome hypoxic resistance and enhance chemoimmunotherapy. The nanosystem utilized the tumor-acidity responsive group poly(2-azepane ethyl methacrylate) with a rapid response rate and highly efficient bioorthogonal click chemistry to form large-sized aggregates in tumor tissue to enhance accumulation and retention. Subsequently, another tumor-acidity responsive group of the maleic acid amide with a slow response rate was cleaved allowing the aggregates to slowly dissociate into ultrasmall nanoparticles with better tumor penetration ability for the delivery of doxorubicin (DOX) and nitric oxide (NO) to a hypoxic tumor tissue. NO can reverse a hypoxia-induced DOX resistance and boost the antitumor immune response through a reprogrammed tumor immune microenvironment. This tumor-acidity and bioorthogonal chemistry-mediated on-site size transformation clustered nanosystem not only helps to counteract a hypoxia-induced chemoresistance and enhance antitumor immune responses but also provides a general drug delivery strategy for enhanced tumor accumulation and penetration.
    Keywords:  bioorthogonal chemistry; chemoresistance; hypoxia; immunogenic cell death; nitric oxide; on-site size transformation
  2. ACS Nano. 2022 Jan 03.
      Immune checkpoint blockade (ICB) therapy has shown tremendous promises in the treatment of various types of tumors. However, ICB therapy with antibodies appears to be less effective for glioma, partly owing to the existence of the blood-brain barrier (BBB) that impedes the entrance of therapeutics including most proteins to the central nervous system (CNS). Herein, considering the widely existing nicotinic acetylcholine receptors (nAChRs) and choline transporters (ChTs) on the surface of BBB, a choline analogue 2-methacryloyloxyethyl phosphorylcholine (MPC) is employed to fabricate the BBB-crossing copolymer via free-radical polymerization, followed by conjugation with antiprogrammed death-ligand 1 (anti-PD-L1) via a pH-sensitive traceless linker. The obtained nanoparticles exhibit significantly improved BBB-crossing capability owing to the receptor-mediated transportation after intravenous injection in an orthotopic glioma tumor model. Within the acidic glioma microenvironment, anti-PD-L1 would be released from such pH-responsive nanoparticles, further triggering highly effective ICB therapy of glioma to significantly prolong animal survival. This work thus realizes glioma microenvironment responsive BBB-crossing delivery of ICB antibodies, promising for the next generation immunotherapy of glioma.
    Keywords:  blood−brain barrier; choline analogue; glioma; immunotherapy; pH-responsive modification
  3. Adv Mater. 2022 Jan 04. e2109254
      In recent years, significant evolutions have been made in applying nanotechnologies for prophylactic and therapeutic cancer vaccine design. However, the clinical translation of nanovaccines is still limited owing to their complicated compositions and difficulties in the spatiotemporal coordination of antigen-presenting cell (APC) activation and antigen cross-presentation. Herein, we designed a minimalist binary nanovaccine (BiVax) that integrates innate stimulating activity into the carrier to elicit robust antitumor immunity. We started by making a series of azole molecules end-capped polyethylenimine (PEI-M), and we were surprised to find that over 60% of the PEI-M polymers had innate stimulating activity via activation of the stimulator of interferon genes (STING) pathway. PEI-4BImi, a PEI-M obtained from a series of polymers, elicited robust antitumor immune responses when used as a subcutaneously injected nanovaccine by simply mixing with ovalbumin (OVA) antigens, and this BiVax system performed much better than the traditional "ternary" vaccine system as well as commercialized aluminum-containing adjuvants. This system also enabled the fast preparation of personalized BiVax by compositing PEI-4BImi with autologous tumor cell membrane protein antigens, and a 60% postoperative cure rate was observed when combined with immune checkpoint inhibitors. This article is protected by copyright. All rights reserved.
    Keywords:  cancer immunotherapy; cancer vaccine; nanovaccine; polymeric carriers; postoperative therapy
  4. Adv Mater. 2022 Jan 07. e2109213
      The major hurdle in glioblastoma therapy is the low efficacy of drugs crossing the blood brain barrier (BBB). Neisseria meningitidis is known to specifically enrich in the central nervous system through the guidance of an outer membrane invasion protein named Opca. Here, by loading a chemotherapeutic drug methotrexate (MTX) in the hollow manganese dioxide (MnO2 ) nanoparticles with surface modification of Opca protein of Neisseria meningitidis, a bionic nanotherapeutic system (MTX@MnO2 -Opca) is demonstrated to effectively overcome the BBB. The presence of Opca protein enables the drug to cross the BBB and penetrate into tumor tissues. After accumulating in glioblastoma, the nanotherapeutic system catalyzes the decomposition of excess H2 O2 in the tumor tissue and thereby generates O2 , which alleviates tumor hypoxia and enhances the effect of chemotherapy in the treatment of glioblastoma. This bionic nanotherapeutic system may exhibit great potential in the treatment of glioblastoma. This article is protected by copyright. All rights reserved.
    Keywords:  Glioblastoma; Neisseria meningitidis; blood-brain barrier; chemotherapy; manganese dioxide
  5. ACS Nano. 2022 Jan 04.
      Untethered small-scale robots offer great promise for medical applications in complex biological environments. However, challenges remain in the control and medical imaging of a robot for targeted delivery inside a living body, especially in flowing conditions (e.g., blood vessels). In this work, we report a strategy to autonomously navigate a miniature helical robot in dynamic blood flow under ultrasound Doppler imaging guidance. A magnetic torque and force-hybrid control approach is implemented, enabling the actuation of a millimeter-scale helical robot against blood flow under a rotating magnetic field with a controllable field gradient. Experimental results demonstrate that the robot (length 7.30 mm; diameter 2.15 mm) exhibits controlled navigation in vascular environments, including upstream and downstream navigation in flowing and pulsatile flowing blood with flow rates up to 24 mL/min (mean flow velocity: 14.15 mm/s). During navigation, the rotating robot-induced Doppler signals enable real-time localization and tracking in flowing and pulsatile flowing blood environments. Moreover, the robot can be selectively navigated along different paths by actively controlling the robot's orientation. We apply this autonomous strategy for localizing thrombus and accelerating thrombolysis rate. Compared with conventional tissue plasminogen activator (tPA) thrombolysis, the robot-enhanced shear stress and tPA convection near the clot-blood interface increase the unblocking and thrombolysis efficiency up to 4.8- and 3.5-fold, respectively. Such a medical imaging-guided navigation strategy provides simultaneous robot navigation and localization in complex dynamic biological environments, providing an intelligent approach toward real-time targeted delivery and diagnostic applications in vivo.
    Keywords:  dynamic biological environment; intelligent control; magnetic actuation; real-time navigation; small-scale robots; ultrasound Doppler imaging
  6. Angew Chem Int Ed Engl. 2022 Jan 04.
      CRISPR/Cas9 is emerging as a platform for gene therapeutics, and the treatment efficiency is expected to be enhanced by combination with other therapeutic agents. Herein, we report a proton-activatable DNA-based nanosystem that enables co-delivery of Cas9/sgRNA and DNAzyme for the combined gene therapy of cancer. Ultra-long ssDNA chains, which contained the recognition sequences of sgRNA in Cas9/sgRNA, DNAzyme sequence and HhaI enzyme cleavage site, were synthesized as the scaffold of the nanosystem. The DNAzyme cofactor Mn2+ was used to compress DNA chains to form nanoparticles and acid degradable polymer-coated HhaI enzymes were assembled on the surface of nanoparticles. In response to protons in lysosome, the polymer coating was decomposed and HhaI enzyme was consequently exposed to recognize and cut off the cleavage sites, thus triggering the release of Cas9/sgRNA and DNAzyme to regulate gene expressions to achieve a high therapeutic efficacy of breast cancer.
    Keywords:  DNA nanotechnology; DNAzyme; Gene editing; Gene therapy; rolling circle amplification
  7. Adv Mater. 2022 Jan 05. e2106682
      In view of the multiple pathological hallmarks of tumors, nanosystems for the sequential delivery of various drugs whose targets are separately located inside and outside tumor cells are desired for improved cancer therapy. However, current sequential delivery is mainly achieved through enzyme- or acid-dependent degradation of the nanocarrier, which would be influenced by the heterogeneous tumor microenvironment, and unloading efficiency of the drug acting on the target outside tumor cells is usually unsatisfactory. Here, we developed a light-triggered sequential delivery strategy based on a liposomal formulation of doxorubicin (DOX)-loaded small-sized polymeric nanoparticles (DOX-NP) and free sunitinib in the aqueous cavity. The liposomal membrane was doped with photosensitizer porphyrin-phospholipid (PoP) and hybridized with red blood cell membrane to confer biomimetic features. Near-infrared light-induced membrane permeabilization triggered the "ultrafast" and "thorough" release of sunitinib (100% release in 5 min) for antiangiogenic therapy and also MDSC inhibition to reverse the immunosuppressive tumor environment. Subsequently, the small-sized DOX-NP liberated from the liposomes was more easily uptaken by tumor cells for improved immunogenic chemotherapy. RNA sequencing and immune-related assay indicated therapeutic immune enhancement. This light-triggered sequential delivery strategy demonstrates the potency in cancer multimodal therapy against multiple targets in different spatial positions in tumor microenvironment. This article is protected by copyright. All rights reserved.
    Keywords:  Biomimetic; MDSC; Near-infrared light; multimodal therapy; sequential drug delivery
  8. Adv Healthc Mater. 2022 Jan 03. e2101375
      Interleukin-12 (IL12) is a pleiotropic cytokine with promising prospects for cancer immunotherapy. Though IL12 gene-based therapy could overcome the fatal hurdle of severe systemic toxicity, targeted delivery and tumor-located expression of IL12 gene remain the challenging issues yet to be solved. Photo-immunotherapy emerging as a novel and precise therapeutic strategy, which elaborately combines immune-activating agents with light-triggered photosensitizers for potentiated anticancer efficacy. Herein, an engineered stem cell-based biotherapy platform (MB/IL12-MSCs) incorporating immune gene plasmid IL12 and photosensitizer methylene blue (MB) was developed to realize tumor-homing delivery of therapeutic agents and photo-immunotherapy efficacy enhancement. The biotherapy platform retained tumor-tropic migration and penetration functions, which improved the intratumoral distribution of therapeutic agents, thereby promoting photodynamic effects and reinforcing immune responses. Importantly, MB/IL12-MSCs restricted the expression and distribution of IL12 at tumor site, which minimized potential toxicity while eliciting sufficient anticancer immunity. In noteworthy, activation of immunity induced by MB/IL12-MSCs established long-term systemic immunologic memory to prevent tumor relapse. The MB/IL12-MSCs outperform their monotherapy counterparts in breast tumor models, and the growth of tumor significantly arrested as well as re-challenging abscopal tumor growth slowdown. Collectively, this work reveals that MSCs-based strategy might advance more efficient, durable, and safer cancer photo-immunotherapy. This article is protected by copyright. All rights reserved.
    Keywords:  Cancer photo-immunotherapy; Interleukin-12; Magnetic mesoporous silica nanoparticles; Mesenchymal stem cell; Methylene blue
  9. Adv Sci (Weinh). 2022 Jan 06. e2104125
      Sonodynamic therapy (SDT) holds growing promise in deep-seated or large solid tumor treatment owing to its high tissue penetration depth ability; however, its therapeutic efficacy is often compromised due to the hypopermeable and hypoxic characteristics in the tumor milieu. Herein, a semiconducting polymer nanoparticle (SPNC) that synergistically enhances tumor penetration and alleviates tumor hypoxia is reported for sonodynamic therapy of large solid tumors. SPNC comprises a semiconducting polymer nanoparticle core as a sonodynamic converter coated with a poly (ethylene glycol) corona. An oxygen-modulating enzyme, catalase, is efficiently conjugated to the surface of nanoparticles via the coupling reaction. Superior to its counterpart SPNCs (SPNC2 (84 nm) and SPNC3 (134 nm)), SPNC with the smallest size (SPNC1 (35 nm)) can efficiently penetrate throughout the tumor interstitium to alleviate whole tumor hypoxia in a large solid tumor model. Upon ultrasound (US) irradiation, SPNC1 can remotely generate sufficient singlet oxygen to eradicate tumor cells at a deep-tissue depth. Such a single treatment of SPNC1-medicated sonodynamic therapy effectively inhibits tumor growth in a large solid tumor mouse model. Therefore, this study provides a generalized strategy to synergistically overcome both poor penetration and hypoxia of large tumors for enhanced cancer treatment.
    Keywords:  large solid tumor therapy; polymer nanoparticles; sonodynamic therapy; tumor hypoxia; tumor penetration
  10. Angew Chem Int Ed Engl. 2022 Jan 05.
      Bond exchange in a typical dynamic covalent polymer network allows access to macroscopic shape reconfigurability, but the network architecture is not altered. An opposite possibility is that the network architecture can be designed to switch to various topological states corresponding to different material properties. Achieving both in one network can expand the material scope, but their intrinsically conflicting mechanisms make it challenging. We design a dynamic covalent network that can undergo two orthogonal topological transformations, namely transesterification on the branched chains and olefin metathesis on the mainframe. This allows independent control of the macroscopic shape and molecular architecture. With this design, we illustrate a bottlebrush network with programmable shape and spatially definable mechanical properties. Our strategy paves a way to on-demand regulation of network polymers.
    Keywords:  bottlebrush polymer; orthogonal dynamic covalent bonds; topological transformation
  11. Adv Mater. 2022 Jan 06. e2108084
      Immunotherapy has emerged as one of the most powerful anti-cancer therapy classes but is stymied by the limits of existing preclinical models with respect to disease latency and reproducibility. In addition, the influence of differing immune microenvironments within tumors observed clinically and associated with immunotherapeutic resistance cannot be tuned to facilitate drug testing workflows without changing model system or laborious genetic approaches. To address this testing platform gap in the immune oncology drug development pipeline, we deployed engineered biomaterials as a scaffold to increase tumor formation rate, decrease disease latency, and diminish variability of immune infiltrates into tumors formed from murine mammary carcinoma cell lines implanted into syngeneic mice. By altering synthetic gel formulations that reshaped infiltrating immune cells within the tumor, responsiveness of the same tumor model to varying classes of cancer immunotherapies, including in situ vaccination with a molecular adjuvant and immune checkpoint blockade, diverged. These results demonstrate the significant role the local immune microenvironment plays in immunotherapeutic response. These engineered tumor immune microenvironments therefore improve upon the limitations of current breast tumor models used for immune oncology drug screening to enable immunotherapeutic testing relevant to the variability in tumor immune microenvironments underlying immunotherapeutic resistance seen in human patients. This article is protected by copyright. All rights reserved.
    Keywords:  biomaterials; breast cancer; cancer immunotherapy; drug screening; immunotherapy
  12. ACS Appl Mater Interfaces. 2022 Jan 06.
      Effective resolution of inflammation contributes to favorable tissue regenerative therapeutic outcomes. However, fine coordination of local immunomodulation in a timely manner is limited because of the lack of strategies for controlling disease dynamics. We developed an inflammation-responsive hydrogel (IFRep gel) as an effective therapeutic strategy for on-demand epigenetic modulation against disease dynamics in wound healing. The IFRep gel is designed to control drug release by cathepsins according to the state of inflammation for active disease treatment. The gel loaded with an inhibitor of the epigenetic reader bromodomain (BRD)4 regulates the translocation of nuclear factor erythroid 2 to the nucleus, where it promotes antioxidant gene expression to reverse the inflammatory macrophage state in vitro. In addition, on-demand BRD inhibition using the responsive hydrogel accelerates wound healing by controlling the early inflammatory phase and keratinocyte activation in vivo. Our data demonstrate the clinical utility of using the IFRep gel as a promising strategy for improving therapeutic outcomes in inflammation-associated diseases.
    Keywords:  anti-inflammation; drug release; epigenetic modulation; inflammation-responsive hydrogel; macrophage; wound healing
  13. Adv Mater. 2022 Jan 04. e2108992
      Implantable meshes used in tension-free repair operation facilitate treatment of internal soft tissue defect. However, clinical meshes fail to achieve anti-deformation, anti-adhesion and pro-healing properties simultaneously, leading to undesirable surgery outcomes. Herein, inspired by peritoneum, a novel biocompatible Janus porous PVA hydrogel (JPVA hydrogel) is developed to achieve efficient repair of internal soft tissue defect by the facile yet efficient strategy based on top-down solvent exchange. The densely porous and smooth bottom-surface of JPVA hydrogel minimizes adhesion of fibroblasts and does not trigger any visceral adhesion, and its loose extracellular matrix-like porous and rough top-surface can significantly improve fibroblast adhesion and tissue growth, leading to superior abdominal wall defect treatment to commercially available PP and PCO meshes. With unique anti-swelling property (swelling ratio: 6.4%), our JPVA hydrogel has long-lasting anti-deformation performance and maintains high mechanical strength after immersing in PBS for 14 days, enabling tolerance to the maximum abdominal pressure in internal wet environment. By integrating visceral anti-adhesion and defect pro-healing with anti-deformation, JPVA hydrogel patch shows great prospect for efficient internal soft tissue defect repair. This article is protected by copyright. All rights reserved.
    Keywords:  Janus porous hydrogel; anti-adhesion; anti-deformation; pro-healing; soft tissue defect repair
  14. Nat Biomed Eng. 2022 Jan 03.
      Hydrogels that provide mechanical support and sustainably release therapeutics have been used to treat tendon injuries. However, most hydrogels are insufficiently tough, release drugs in bursts, and require cell infiltration or suturing to integrate with surrounding tissue. Here we report that a hydrogel serving as a high-capacity drug depot and combining a dissipative tough matrix on one side and a chitosan adhesive surface on the other side supports tendon gliding and strong adhesion (larger than 1,000 J m-2) to tendon on opposite surfaces of the hydrogel, as we show with porcine and human tendon preparations during cyclic-friction loadings. The hydrogel is biocompatible, strongly adheres to patellar, supraspinatus and Achilles tendons of live rats, boosted healing and reduced scar formation in a rat model of Achilles-tendon rupture, and sustainably released the corticosteroid triamcinolone acetonide in a rat model of patellar tendon injury, reducing inflammation, modulating chemokine secretion, recruiting tendon stem and progenitor cells, and promoting macrophage polarization to the M2 phenotype. Hydrogels with 'Janus' surfaces and sustained-drug-release functionality could be designed for a range of biomedical applications.