bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒02‒07
eighteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Nat Mater. 2021 Feb 04.
      Endosomal escape remains a fundamental barrier hindering the advancement of nucleic acid therapeutics. Taking inspiration from natural phospholipids that comprise biological membranes, we report the combinatorial synthesis of multi-tailed ionizable phospholipids (iPhos) capable of delivering messenger RNA or mRNA/single-guide RNA for gene editing in vivo. Optimized iPhos lipids are composed of one pH-switchable zwitterion and three hydrophobic tails, which adopt a cone shape in endosomal acidic environments to facilitate membrane hexagonal transformation and subsequent cargo release from endosomes. Structure-activity relationships reveal that iPhos chemical structure can control in vivo efficacy and organ selectivity. iPhos lipids synergistically function with various helper lipids to formulate multi-component lipid nanoparticles (called iPLNPs) for selective organ targeting. Zwitterionic, ionizable cationic and permanently cationic helper lipids enable tissue-selective mRNA delivery and CRISPR-Cas9 gene editing in spleen, liver and lungs (respectively) following intravenous administration. This rational design of functional phospholipids demonstrates substantial value for gene editing research and therapeutic applications.
  2. Sci Adv. 2021 Jan;pii: eaba1028. [Epub ahead of print]7(3):
      Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)-mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.
  3. Proc Natl Acad Sci U S A. 2021 Feb 09. pii: e2005191118. [Epub ahead of print]118(6):
      Intracellular delivery of messenger RNA (mRNA)-based cancer vaccine has shown great potential to elicit antitumor immunity. To achieve robust antitumor efficacy, mRNA encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells with concurrent innate immune stimulation to promote antigen presentation. Here, by screening a group of cationic lipid-like materials, we developed a minimalist nanovaccine with C1 lipid nanoparticle (LNP) that could efficiently deliver mRNA in antigen presenting cells with simultaneous Toll-like receptor 4 (TLR4) activation and induced robust T cell activation. The C1 nanovaccine entered cells via phagocytosis and showed efficient mRNA-encoded antigen expression and presentation. Furthermore, the C1 lipid nanoparticle itself induced the expression of inflammatory cytokines such as IL-12 via stimulating TLR4 signal pathway in dendritic cells. Importantly, the C1 mRNA nanovaccine exhibited significant antitumor efficacy in both tumor prevention and therapeutic vaccine settings. Overall, our work presents a C1 LNP-based mRNA cancer nanovaccine with efficient antigen expression as well as self-adjuvant property, which may provide a platform for developing cancer immunotherapy for a wide range of tumor types.
    Keywords:  TLR4; cancer immunotherapy; lipid-like material; mRNA nanovaccine; self-adjuvant
  4. Sci Adv. 2021 Jan;pii: eabe2620. [Epub ahead of print]7(4):
      Alternative means for drug delivery are needed to facilitate drug adherence and administration. Microneedles (MNs) have been previously investigated transdermally for drug delivery. To date, drug loading into MNs has been limited by drug solubility in the polymeric blend. We designed a highly drug-loaded MN patch to deliver macromolecules and applied it to the buccal area, which allows for faster delivery than the skin. We successfully delivered 1-mg payloads of human insulin and human growth hormone to the buccal cavity of swine within 30 s. In addition, we conducted a trial in 100 healthy volunteers to assess potential discomfort associated with MNs when applied in the oral cavity, identifying the hard palate as the preferred application site. We envisage that MN patches applied on buccal surfaces could increase medication adherence and facilitate the painless delivery of biologics and other drugs to many, especially for the pediatric and elderly populations.
  5. ACS Nano. 2021 Feb 01.
      Hepatocellular carcinoma recurrence and metastasis after microwave ablation (MWA) are challenges in the clinic. This study showed that mannose-derived carbon dots (Man-CDs) could effectively capture several "danger signals" (DS) after MWA treatment and then deliver DS specifically to dendritic cells (DCs). This improved delivery of DS to DCs enhanced the processing and presentation of tumor-associated antigens by DCs. The results demonstrated that intratumoral injection of Man-CDs after MWA therapy elicited a potent tumor-specific immune response and finally led to the effective suppression of both primary and distant tumors. MWA + Man-CD treatment could efficiently reject tumor cell rechallenge in vivo. This study demonstrated that Man-CD nanoparticles are effective adjuvants that can improve MWA therapy by eliciting a tumor-specific immune response.
    Keywords:  dendritic cells; hepatocellular carcinoma; immune responses; mannose-derived carbon dots; microwave ablation
  6. Nano Lett. 2021 Feb 01.
      Vaccines are one of utmost important weapons in modern medicine to fight a wide range of diseases. To achieve optimal vaccination effects, repeated injections of vaccines are often required, which would largely decrease patient comfort. Herein, an ultrasound-responsive self-healing hydrogel system loaded with nanovaccines is designed for remotely controlled tumor vaccine release and individualized cancer immunotherapy. The gel could be transformed into sol status in response to ultrasound treatment, allowing a burst release of nanovaccines, and self-healed to gel afterward. For mice with a single subcutaneous injection of nanovaccine-loaded gel and multiple ultrasound treatments, repeatedly released nanovaccines could elicit antitumor immune responses, which in combination with immune checkpoint blockade could effectively inhibit established tumors, and prevent postoperative tumor metastases and recurrence based on our personalized nanovaccine system. This work presents an easy-to-operate strategy to realize controllable and durable delivery of vaccines against cancer and potentially other types of diseases.
    Keywords:  Cancer immunotherapy; Nanovaccines; Remotely controllable delivery; Self-healing nanocomposite hydrogels; Ultrasound responsive
  7. Sci Adv. 2021 Feb;pii: eabe5819. [Epub ahead of print]7(6):
      The profound consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mandate urgent development of effective vaccines. Here, we evaluated an Amphiphile (AMP) vaccine adjuvant, AMP-CpG, composed of diacyl lipid-modified CpG, admixed with the SARS-CoV-2 Spike-2 receptor binding domain protein as a candidate vaccine (ELI-005) in mice. AMP modification efficiently delivers CpG to lymph nodes, where innate and adaptive immune responses are generated. Compared to alum, immunization with AMP-CpG induced >25-fold higher antigen-specific T cells that produced multiple T helper 1 (TH1) cytokines and trafficked into lung parenchyma. Antibody responses favored TH1 isotypes (IgG2c and IgG3) and potently neutralized Spike-2-ACE2 receptor binding, with titers 265-fold higher than natural convalescent patient COVID-19 responses; T cell and antibody responses were maintained despite 10-fold dose reduction in Spike antigen. Both cellular and humoral immune responses were preserved in aged mice. These advantages merit clinical translation to SARS-CoV-2 and other protein subunit vaccines.
  8. ACS Nano. 2021 Feb 02.
      Transarterial radioembolization (TARE) is considered the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). Iodine-131 (131I)-labeled lipiodol TARE is an effective treatment for HCC but has been withdrawn due to its poor retention in tumor lesions and significant distribution in normal tissues with severe side effects. In this work, a highly tumor-specific 131I-TARE agent with long-time retention is developed by simply introducing tyrosine to poly(vinyl alcohol) (PVA) drug-eluting microbeads (Tyr-PVA-DEBs). The labeling efficiency of 131I-labeled microbeads remains above 85% in 50% serum for 31 days. Micro-single-photon emission computed tomography/computed tomography (μSPECT/CT) evidences that the 131I-labeled microbeads accumulate in the orthotopic N1S1 hepatoma of rats for 31 days following intra-arterial injection. The cumulative radiation dose per cubic centimeter of the tumor is at least 13 678-fold higher than that of normal tissues. The highly tumor-selective radiation of the 131I-labeled microbeads allows localized delivery of 345.04 ± 139.16 Gy to the tumor following a single injection dose as low as 0.2 mCi of 131I. Moreover, the 131I-labeled microbeads are loaded with doxorubicin hydrochloride (DOX) through the carboxy groups on tyrosine of the polymer. The 131I-DOX-loaded microbeads present a synergetic antitumor effect without recurrence in comparison with the microbeads labeled with 131I or loading DOX alone, attributed to the sensitization of DOX to 131I-induced ionizing radiation damage to DNA under the embolization-induced hypoxia. Our results demonstrate a high tumor retention of 131I-labeled embolic agent for low-dose transarterial radio-chemoembolization (TARCE) with a synergetic therapeutic effect on treating HCC, showing potential for clinical application.
    Keywords:  doxorubicin; hepatocellular carcinoma; iodine-131; transarterial radioembolization; tumor retention
  9. Adv Mater. 2021 Feb 01. e2007667
      For decades, bioadhesive materials have garnered great attention due to their potential to replace sutures and staples for sealing tissues during minimally invasive surgical procedures. However, the complexities of delivering bioadhesives through narrow spaces and achieving strong adhesion in fluid-rich physiological environments continue to present substantial limitations to the surgical translation of existing sealants. In this work, a new strategy for minimally invasive tissue sealing based on a multilayer bioadhesive patch, which is designed to repel body fluids, to form fast, pressure-triggered adhesion with wet tissues, and to resist biofouling and inflammation is introduced. The multifunctional patch is realized by a synergistic combination of three distinct functional layers: i) a microtextured bioadhesive layer, ii) a dynamic, blood-repellent hydrophobic fluid layer, and iii) an antifouling zwitterionic nonadhesive layer. The patch is capable of forming robust adhesion to tissue surfaces in the presence of blood, and exhibits superior resistance to bacterial adhesion, fibrinogen adsorption, and in vivo fibrous capsule formation. By adopting origami-based fabrication strategies, it is demonstrated that the patch can be readily integrated with a variety of minimally invasive end effectors to provide facile tissue sealing in ex vivo porcine models, offering new opportunities for minimally invasive tissue sealing in diverse clinical scenarios.
    Keywords:  antifouling materials; bioadhesives; minimally invasive surgery; origami-based manufacturing; wound sealing
  10. Sci Adv. 2021 Jan;pii: eabe3184. [Epub ahead of print]7(2):
      Bioinspired nano/microswarm enables fascinating collective controllability beyond the abilities of the constituent individuals, yet almost invariably, the composed units are of single species. Advancing such swarm technologies poses a grand challenge in synchronous mass manipulation of multimaterials that hold different physiochemical identities. Here, we present a dynamic thermal trapping strategy using thermoresponsive-based magnetic smart nanoparticles as host species to reversibly trap and couple given nonmagnetic entities in aqueous surroundings, enabling cross-species smart nanoparticle swarms (SMARS). Such trapping process endows unaddressable nonmagnetic species with efficient thermo-switchable magnetic response, which determines SMARS' cross-species synchronized maneuverability. Benefiting from collective merits of hybrid components, SMARS can be configured into specific smart modules spanning from chain, vesicle, droplet, to ionic module, which can implement localized or distributed functions that are single-species unachievable. Our methodology allows dynamic multimaterials integration despite the odds of their intrinsic identities to conceive distinctive structures and functions.
  11. Sci Adv. 2021 Feb;pii: eaba0776. [Epub ahead of print]7(6):
      Nanoparticle-based drug delivery faces challenges from the imprecise targeted delivery and the low bioavailability of drugs due to complex biological barriers. Here, we designed cascade-targeting, dual drug-loaded, core-shell nanoparticles (DLTPT) consisting of CD44-targeting hyaluronic acid shells decorated with doxorubicin (HA-DOX) and mitochondria-targeting triphenylphosphonium derivative nanoparticle cores loaded with lonidamine (LND) dimers (LTPT). DLTPT displayed prolonged blood circulation time and efficiently accumulated at the tumor site due to the tumor-homing effect and negatively charged hyaluronic acid. Subsequently, the HA-DOX shell was degraded by extracellular hyaluronidase, resulting in decreased particle size and negative-to-positive charge reversal, which would increase tumor penetration and internalization. The degradation of HA-DOX further accelerated the release of DOX and exposed the positively charged LTPT core for rapid endosomal escape and mitochondria-targeted delivery of LND. Notably, when DLTPT was used in combination with anti-PD-L1, the tumor growth was inhibited, which induced immune response against tumor metastasis.
  12. Nat Commun. 2021 02 04. 12(1): 792
      The immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities.
  13. Sci Adv. 2021 Feb;pii: eaba2458. [Epub ahead of print]7(6):
      The poor understanding of the complex multistep process taken by nanocarriers during the delivery process limits the delivery efficiencies and further hinders the translation of these systems into medicine. Here, we describe a series of six self-assembled nanocarrier types with systematically altered physical properties including size, shape, and rigidity, as well as both in vitro and in vivo analyses of their performance in blood circulation, tumor penetration, cancer cell uptake, and anticancer efficacy. We also developed both data and simulation-based models for understanding the influence of physical properties, both individually and considered together, on each delivery step and overall delivery process. Thus, beyond finding that nanocarriers that are simultaneously endowed with tubular shape, short length, and low rigidity outperformed the other types, we now have a suit of theoretical models that can predict how nanocarrier properties will individually and collectively perform in the multistep delivery of anticancer therapies.
  14. Sci Adv. 2021 Jan;pii: eabe7174. [Epub ahead of print]7(4):
      The major impediments to the implementation of cancer immunotherapies are the sustained immune effect and the targeted delivery of these therapeutics, as they have life-threatening adverse effects. In this work, biomimetic metal-organic frameworks [zeolitic imidazolate frameworks (ZIFs)] are used for the controlled delivery of nivolumab (NV), a monoclonal antibody checkpoint inhibitor that was U.S. Food and Drug Administration-approved back in 2014. The sustained release behavior of NV-ZIF has shown a higher efficacy than the naked NV to activate T cells in hematological malignancies. The system was further modified by coating NV-ZIF with cancer cell membrane to enable tumor-specific targeted delivery while treating solid tumors. We envisage that such a biocompatible and biodegradable immunotherapeutic delivery system may promote the development and the translation of hybrid superstructures into smart and personalized delivery platforms.
  15. Proc Natl Acad Sci U S A. 2021 Feb 16. pii: e2020575118. [Epub ahead of print]118(7):
      Keratinocyte-derived carcinomas, including squamous cell carcinoma (SCC), comprise the most common malignancies. Surgical excision is the therapeutic standard but is not always clinically feasible, and currently available alternatives are limited to superficial tumors. To address the need for a nonsurgical treatment for nodular skin cancers like SCC, we developed a bioadhesive nanoparticle (BNP) drug delivery system composed of biodegradable polymer, poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG), encapsulating camptothecin (CPT). Nanoparticles (NPs) of PLA-HPG are nonadhesive NPs (NNPs), which are stealthy in their native state, but we have previously shown that conversion of the vicinal diols of HPG to aldehydes conferred NPs the ability to form strong covalent bonds with amine-rich surfaces. Herein, we show that these BNPs have significantly enhanced binding to SCC tumor cell surfaces and matrix proteins, thereby significantly enhancing the therapeutic efficacy of intratumoral drug delivery. Tumor injection of BNP-CPT resulted in tumor retention of CPT at ∼50% at 10 d postinjection, while CPT was undetectable in NNP-CPT or free (intralipid) CPT-injected tumors at that time. BNP-CPT also significantly reduced tumor burden, with a portion (∼20%) of BNP-CPT-treated established tumors showing histologic cure. Larger, more fully established PDV SCC tumors treated with a combination of BNP-CPT and immunostimulating CpG oligodeoxynucleotides exhibited enhanced survival relative to controls, revealing the potential for BNP delivery to be used along with local tumor immunotherapy. Taken together, these results indicate that percutaneous delivery of a chemotherapeutic agent via BNPs, with or without adjuvant immunostimulation, represents a viable, nonsurgical alternative for treating cutaneous malignancy.
    Keywords:  chemotherapy; drug delivery; immunotherapy; nanoparticle; squamous cell carcinoma
  16. ACS Nano. 2021 Feb 02.
      Peritoneal metastasis (PM) is considered as the terminal stage of metastatic colon cancer, with still poor median survival rate even with the best recent chemotherapy treatment. The current PM treatment combines cytoreductive surgery, which consists of resecting all macroscopic tumors, with hyperthermic intraperitoneal chemotherapy (HIPEC), which uses mild hyperthermia to boost the diffusion and cytotoxic effect of chemotherapeutic drugs. As HIPEC is performed via a closed circulation of a hot liquid containing chemotherapy, it induces uncontrolled heating and drug distribution in the whole peritoneal cavity with important off-site toxicity and a high level of morbidity. Here, we propose a safer precision strategy using near-infrared (NIR) photoactivated gold nanoparticles (AuNPs) coupled to the chemotherapeutic drug 5-fluorouracil (5-FU) to enable a spatial and temporal control of mild chemo-hyperthermia targeted to the tumor nodules within the peritoneal cavity. Both the 16 nm AuNPs and the corresponding complex with 5-FU (AuNP-5-FU) were shown as efficient NIR photothermal agents in the microenvironment of subcutaneous colon tumors as well as PM in syngeneic mice. Noteworthy, NIR photothermia provided additional antitumor effects to 5-FU treatment. A single intraperitoneal administration of AuNP-5-FU resulted in their preferential accumulation in tumor nodules and peritoneal macrophages, allowing light-induced selective hyperthermia, extended tumor necrosis, and activation of a pro-inflammatory immune response while leaving healthy tissues without any damage. From a translational standpoint, the combined and tumor-targeted photothermal and chemotherapy mediated by the AuNP-drug complex has the potential to overcome the current off-target toxicity of HIPEC in clinical practice.
    Keywords:  5-fluorouracil; carcinomatosis; gold nanoparticles; peritoneal metastasis; photothermal therapy
  17. Adv Mater. 2021 Feb 04. e2006003
      A photothermal genome-editing strategy is described to improve immune checkpoint blockade (ICB) therapy by CRISPR/Cas9-mediated disruption of PD-L1 and mild-hyperthermia-induced activation of immunogenic cell death (ICD). This strategy relies on a supramolecular cationic gold nanorod that not only serves as a carrier to deliver CRISPR/Cas9 targeting PD-L1, but also harvests the second near-infrared-window (NIR-II) light and converts into mild hyperthermia to induce both ICD and gene expression of Cas9. The genomic disruption of PD-L1 significantly augments ICB therapy by improving the conversion of dendritic cells to T cells, followed by promoting the infiltration of cytotoxic T lymphocytes into tumors, thereby reprogramming immunosuppressive tumor microenvironment into immunoactive one. Such a therapeutic modality greatly inhibits the activity of primary and metastatic tumors and exhibits long-term immune memory effects against both rechallenged and recurrent tumors. The current therapeutic strategy for synergistic PD-L1 disruption and ICD activation represents an appealing way for cancer immunotherapy.
    Keywords:  CRISPR/Cas9; gene delivery; immune checkpoint blockade; immunogenic cell death; nanomedicine
  18. Sci Adv. 2021 Feb;pii: eabe9444. [Epub ahead of print]7(6):
      Conjugate vaccines are among the most effective methods for preventing bacterial infections. However, existing manufacturing approaches limit access to conjugate vaccines due to centralized production and cold chain distribution requirements. To address these limitations, we developed a modular technology for in vitro conjugate vaccine expression (iVAX) in portable, freeze-dried lysates from detoxified, nonpathogenic Escherichia coli. Upon rehydration, iVAX reactions synthesize clinically relevant doses of conjugate vaccines against diverse bacterial pathogens in 1 hour. We show that iVAX-synthesized vaccines against Francisella tularensis subsp. tularensis (type A) strain Schu S4 protected mice from lethal intranasal F. tularensis challenge. The iVAX platform promises to accelerate development of new conjugate vaccines with increased access through refrigeration-independent distribution and portable production.