bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒05‒29
sixteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Nature. 2022 May 25.
      Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.
  2. Proc Natl Acad Sci U S A. 2022 May 31. 119(22): e2122595119
      SignificanceThe rationale of local cancer immunotherapy is that the treated tumor cells can serve as a depot of tumor antigens and activate/mobilize the patient's immune system to address systemic diseases. However, the challenge is to coordinate several events involved in the activation of antitumor immune responses, colocalize and retain multiple therapies in tumors, and support the functions of immune cells. Our carrier polyethyleneimine-lithocholic acid conjugate (2E') addresses these challenges based on the amphiphilic structure and inherent immunostimulatory activity. 2E' codelivers hydrophobic drugs and nucleic acids and leverages their effects to eliminate primary tumors and protect the hosts from distant and recurrent diseases. The versatility of 2E' will enable the use of therapeutic combinations to improve clinical outcomes of cancer immunotherapy.
    Keywords:  immunoactive carrier; immunogenic cell death inducer; local immunotherapy; nucleic acids/nucleotides; polyethyleneimine-lithocholic acid conjugate
  3. Sci Adv. 2022 May 27. 8(21): eabm8478
      Administering medicines to 0- to 5-year-old children in a resource-limited environment requires dosage forms that circumvent swallowing solids, avoid on-field reconstitution, and are thermostable, cheap, versatile, and taste masking. We present a strategy that stands to solve this multifaceted problem. As many drugs lack adequate water solubility, our formulations used oils, whose textures could be modified with gelling agents to form "oleogels." In a clinical study, we showed that the oleogels can be formulated to be as fluid as thickened beverages and as stiff as yogurt puddings. In swine, oleogels could deliver four drugs ranging three orders of magnitude in their water solubilities and two orders of magnitude in their partition coefficients. Oleogels could be stabilized at 40°C for prolonged durations and used without redispersion. Last, we developed a macrofluidic system enabling fixed and metered dosing. We anticipate that this platform could be adopted for pediatric dosing, palliative care, and gastrointestinal disease applications.
  4. Adv Healthc Mater. 2022 May 24. e2200340
      Mucus is a complex barrier for pharmacological treatments and overcoming it is one of the major challenges faced during transmucosal drug delivery. To tackle this issue, we introduce a novel class of glycosylated nanoparticles, named "mucosomes", which are based on the most important protein constituting mucus, the mucin. Mucosomes were designed to improve drug absorption and residence time on the mucosal tissues. We have been able to produce mucosomes (150-300 nm), functionalized with glycans, and loaded with the desired drug in a single one-pot synthetic process and, with this method, we have been able to load a wide range of small, and macro, molecules with different physicochemical properties. Various in vitro models were used to test the mucoadhesive properties of mucosomes. The presence of functional glycans was indicated by the interaction with lectins. Mucosomes were proven to be storable at 4°C after lyophilization, and administration through a nasal spray does not modify the morphology of the mucosomes. In vitro and in vivo tests indicated mucosomes did not induced adverse effects under the investigated conditions. We propose mucosomes as a ground-breaking nanosystem, that could be applied in several pathological contexts, especially in mucus-related disorders. This article is protected by copyright. All rights reserved.
    Keywords:  drug-delivery; mucin; mucoadhesivity; mucosomes; mucus; nanoparticles; one-pot
  5. Nat Commun. 2022 May 27. 13(1): 2978
      Low CFTR mRNA expression due to nonsense-mediated mRNA decay (NMD) is a major hurdle in developing a therapy for cystic fibrosis (CF) caused by the W1282X mutation in the CFTR gene. CFTR-W1282X truncated protein retains partial function, so increasing its levels by inhibiting NMD of its mRNA will likely be beneficial. Because NMD regulates the normal expression of many genes, gene-specific stabilization of CFTR-W1282X mRNA expression is more desirable than general NMD inhibition. Synthetic antisense oligonucleotides (ASOs) designed to prevent binding of exon junction complexes (EJC) downstream of premature termination codons (PTCs) attenuate NMD in a gene-specific manner. We describe cocktails of three ASOs that specifically increase the expression of CFTR-W1282X mRNA and CFTR protein upon delivery into human bronchial epithelial cells. This treatment increases the CFTR-mediated chloride current. These results set the stage for clinical development of an allele-specific therapy for CF caused by the W1282X mutation.
  6. Small. 2022 May 26. e2201280
      Tissue bacterial infections are a major pathological factor in many diseases. Effects on this aspect are in focus for the development of coordinated therapeutic strategies for bacterial killing and anti-inflammation. Here, inspired by the biodetoxification capacity of immune cells, multifunctional biomimetic nanovesicles (MϕM-LPs) that are co-assembled by macrophage membranes and artificial lipids to deliver antibiotics for treating bacterial infections, are presented. The macrophage membrane endows the MϕM-LPs with the capacity of lipopolysaccharide and inflammatory cytokine neutralization, while the artificial lipid membrane can be further engineered to increase the fluidity and anchor to bacteria. In addition, the MϕM-LPs can deliver sufficient ciprofloxacin with controllable release to accomplish an excellent antibacterial activity and biodetoxification capacity in vitro. Based on these advantages, it is demonstrated in a mouse model of Staphylococcus aureus (S. aureus) focal infection, that a single injection of the biomimetic nanovesicles can effectively anchor to and eliminate S. aureus in the infected tissue and reduce inflammatory cytokine levels. Thus, the tissue regeneration and collagen deposition can be accelerated. These results indicate the potential values of integrating natural and artificial membrane materials as a multifunctional biomimetic drug delivery system to treat bacterial infections.
    Keywords:  anti-inflammation; antibacteria; biomimetics; macrophages; nanovesicles
  7. Nano Lett. 2022 May 23.
      Cancer vaccines are emerging as an attractive modality for tumor immunotherapy. However, their practical application is seriously impeded by the complex fabrication and unsatisfactory outcomes. Herein, we construct bacterial outer membrane vesicles (OMVs)-based in situ cancer vaccine with phytochemical features for photodynamic effects-promoted immunotherapy. By simply fusing thylakoid membranes with OMVs, bacteria-plant hybrid vesicles (BPNs) are prepared. After systemic administration, BPNs can target tumor tissues and stimulate the activation of immune cells, including dendritic cells (DCs). The photodynamic effects derived from thylakoid lead to the disruption of local tumors and then the release of tumor-associated antigens that are effectively presented by DCs, inducing remarkable tumor-specific CD8+T cell responses. Moreover, BPNs can efficiently ameliorate the immunosuppressive tumor microenvironment and further boost immune responses. Therefore, both tumor development and metastasis can be efficiently prevented. This work provides a novel idea for developing a versatile membrane-based hybrid system for highly efficient tumor treatment.
    Keywords:  bacterial outer membrane vesicles; immunotherapy; in situ cancer vaccination; photodynamic effects; thylakoid
  8. J Am Chem Soc. 2022 May 26.
      The development of lipid nanoparticle (LNP) formulations for targeting the bone microenvironment holds significant potential for nucleic acid therapeutic applications including bone regeneration, cancer, and hematopoietic stem cell therapies. However, therapeutic delivery to bone remains a significant challenge due to several biological barriers, such as low blood flow in bone, blood-bone marrow barriers, and low affinity between drugs and bone minerals, which leads to unfavorable therapeutic dosages in the bone microenvironment. Here, we construct a series of bisphosphonate (BP) lipid-like materials possessing a high affinity for bone minerals, as a means to overcome biological barriers to deliver mRNA therapeutics efficiently to the bone microenvironment in vivo. Following in vitro screening of BP lipid-like materials formulated into LNPs, we identified a lead BP-LNP formulation, 490BP-C14, with enhanced mRNA expression and localization in the bone microenvironment of mice in vivo compared to 490-C14 LNPs in the absence of BPs. Moreover, BP-LNPs enhanced mRNA delivery and secretion of therapeutic bone morphogenetic protein-2 from the bone microenvironment upon intravenous administration. These results demonstrate the potential of BP-LNPs for delivery to the bone microenvironment, which could potentially be utilized for a range of mRNA therapeutic applications including regenerative medicine, protein replacement, and gene editing therapies.
  9. J Control Release. 2022 May 21. pii: S0168-3659(22)00291-7. [Epub ahead of print]347 508-520
      Mesenchymal stem cells (MSCs) are an attractive candidate for the treatment of inflammatory bowel disease (IBD), but their poor delivery rate to an inflamed colon is a major factor hampering the clinical potential of stem cell therapies. Moreover, there remains a formidable hurdle to overcome with regard to survival and homing in to injured sites. Here, we develop a strategy utilizing monodisperse hydrogel microcapsules with a thin intermediate oil layer prepared by a triple-emulsion drop-based microfluidic approach as an in-situ oral delivering carrier. The oral delivery of stem-cell-loaded hydrogel microcapsules (SC-HM) enhances MSC survival and retention in the hostile stomach environment due to the intermediate oil layer and low value of the overall stiffness, facilitating programmable cell release during gastrointestinal peristalsis. SC-HM is shown to induce tissue repair, reduce the colonic macrophage infiltration responsible for the secretion of the pro-inflammatory factors, and significantly mitigate the severity of IBD in a mouse model, where MSCs released by SC-HM successfully accumulate at the colonic crypt. Moreover, a metagenomics analysis reveals that SC-HM ameliorates the dysbiosis of specific bacterial genera, including Bacteroides acidifaciens, Lactobacillus (L.) gasseri, Lactobacillus reuteri, and L. intestinalis, implying optimization of the microorganism's composition and abundance. These findings demonstrate that SC-HM is a potential IBD treatment candidate.
    Keywords:  Colonic inflammation; Gut microbiota; Hydrogel microcapsule with a thin oil layer; Microfluidics; Stem cell oral delivery
  10. Adv Mater. 2022 May 23. e2201978
      Hypoxia as a characteristic feature of solid tumors, has a close relationship with tumor resistance to photodynamic therapy (PDT) and chemotherapy. Perfluorocarbon (PFC) was reported to relieve hypoxic in solid tumors by acting as an oxygen carrier via several nanostructures. However, the oxygen delivery process is mostly driven by a concentration gradient, which is uncontrollable. Herein, a photothermally controlled "oxygen bomb" PSPP-Au980 -D is designed by encapsulating a PFC core within a functionalized bilayer polymer shell. Near-infrared second window photothermal agent gold nanorods (AuNRs) with excellent photo-to-heat energy conversion ability are fabricated on the surface of a polymer shell via an innovative modified two-step seedless ex situ growth process to thermally trigger O2 release. Then, a programmed cascade therapy strategy is customized for hypoxic orthotopic pancreatic cancer. Firstly, PSPP-Au980 -D is irradiated by a 980 nm laser to photothermally trigger O2 infusing into the hypoxic tumor microenvironment, which is accompanied by local hyperemia and doxorubicin release. Subsequently, a 680 nm laser is executed to generate singlet oxygen in the oxygenated tumor microenvironment for PDT. This choreographed programmed cascade therapy strategy would provide a new route for suppressing hypoxic tumor growth under mild conditions based on controllable and effective oxygen release. This article is protected by copyright. All rights reserved.
    Keywords:  NIR-II photothermal; Oxygen burst release; Polymer-based composites; Programmed cascade therapy
  11. ACS Appl Mater Interfaces. 2022 May 26.
      Nanoprodrugs with responsive release properties integrate the advantages of stimuli-responsive prodrugs and nanotechnology. They would provide ultimate opportunity in fighting atherosclerosis. In this study, we synthesized a redox-responsive nanoprodrug of simvastatin (TPTS) by conjugating α-tocopherol polyethylene glycol derivative to the pharmacophore of simvastatin with a thioketal linker. TPTS formed nanoparticles and released parent simvastatin in the presence of hydrogen peroxide. Moreover, by taking advantage of the self-assembly behavior of TPTS, we developed a fibronectin-targeted delivery system (TPTS/C/T) to codelivery simvastatin prodrug and ticagrelor. In vitro and in vivo experiments indicated that TPTS and TPTS/C/T had good stability, which could reduce off-target leakage of drugs. They greatly inhibited the M1-type polarization of macrophages; reduced intracellular reactive oxygen species level and inflammatory cytokine; and TNF-α, MCP-1, and IL-1β were secreted by macrophage cells, thus providing enhanced anti-inflammatory and antioxidant effects compared with free simvastatin. TPTS/C/T realized targeted drug release to plaques and synergistic therapeutic effects of simvastatin and ticagrelor on atherosclerosis treatment in an ApoE-/- mouse model, resulting in excellent atherosclerosis therapeutic efficacy and a promising biosafety profile. Therefore, this study provides a new method for manufacturing statin nanodrugs and a new design idea for related responsive drug release nanosystems for atherosclerosis.
    Keywords:  atherosclerosis; prodrug; reactive oxygen species; statins
  12. Adv Drug Deliv Rev. 2022 May 20. pii: S0169-409X(22)00247-2. [Epub ahead of print] 114357
      Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers due to its aggressiveness and the challenges for early diagnosis and treatment. Recently, nanotechnology has demonstrated relevant strategies to overcome some of the major clinical issues in the treatment of PDAC. This review is focused on the pathological hallmarks of PDAC and the impact of nanotechnology to find solutions. It describes the use of nanoparticle-based systems designed for the delivery of chemotherapeutic agents and combinatorial alternatives that address the chemoresistance associated with PDAC, the development of combination therapies targeting the molecular heterogeneity in PDAC, the investigation of novel therapies dealing with the improvement of immunotherapy and handling the desmoplastic stroma in PDAC by remodeling the tumor microenvironment. A special section is dedicated to the design of nanoparticles for unique non-traditional modalities that could be promising in the future for the improvement in the dismal prognosis of PDAC.
    Keywords:  Nanoengineered approaches; cancer immunotherapy; combinatorial drug delivery; pancreatic ductal adenocarcinoma; stroma modulation; tumor microenvironment
  13. Sci Adv. 2022 May 27. 8(21): eabo5867
      Modern auscultation, using digital stethoscopes, provides a better solution than conventional methods in sound recording and visualization. However, current digital stethoscopes are too bulky and nonconformal to the skin for continuous auscultation. Moreover, motion artifacts from the rigidity cause friction noise, leading to inaccurate diagnoses. Here, we report a class of technologies that offers real-time, wireless, continuous auscultation using a soft wearable system as a quantitative disease diagnosis tool for various diseases. The soft device can detect continuous cardiopulmonary sounds with minimal noise and classify real-time signal abnormalities. A clinical study with multiple patients and control subjects captures the unique advantage of the wearable auscultation method with embedded machine learning for automated diagnoses of four types of lung diseases: crackle, wheeze, stridor, and rhonchi, with a 95% accuracy. The soft system also demonstrates the potential for a sleep study by detecting disordered breathing for home sleep and apnea detection.
  14. J Control Release. 2022 May 24. pii: S0168-3659(22)00292-9. [Epub ahead of print]
      Weakly basic small molecule drugs like clofazimine can be used as building blocks for endowing cells with unnatural structural and functional elements. Here, we describe how clofazimine represents a first-in-class mechanopharmaceutical device, serving to construct inert, inactive and stimulus responsive drug depots within the endophagolysosomal compartment of cells of living organisms. Upon oral administration, clofazimine molecules self-assemble into stable, membrane-bound, crystal-like drug inclusions (CLDI) that accumulate within macrophages to form a "smart" biocompatible, pathogen activatable mechanopharmaceutical device. Upon perturbation of the mechanism maintaining pH and ion homeostasis of these CLDIs, the inert encapsulated drug precipitates are destabilized, releasing bioactive drug molecules into the cell and its surrounding. The resulting increase in clofazimine solubility activates this broad-spectrum antimicrobial, antiparasitic, antiviral or cytotoxic agent within the infected macrophage. We present a general, molecular design strategy for using clofazimine and other small molecule building blocks for the cytoplasmic construction of mechanopharmaceutical devices, aimed at rapid deployment during infectious disease outbreaks, for the purpose of pandemic prevention.
    Keywords:  Drug targeting; Drug-delivery; Modeling and simulation; Pandemic response; Pharmacokinetics
  15. Nat Commun. 2022 May 26. 13(1): 2936
      Low-cost multi-omics sequencing is expected to become clinical routine and transform precision oncology. Viable computational methods that can facilitate tailored intervention while tolerating sequencing biases are in high demand. Here we propose a class of transparent and interpretable computational methods called integral genomic signature (iGenSig) analyses, that address the challenges of cross-dataset modeling through leveraging information redundancies within high-dimensional genomic features, averaging feature weights to prevent overweighing, and extracting unbiased genomic information from large tumor cohorts. Using genomic dataset of chemical perturbations, we develop a battery of iGenSig models for predicting cancer drug responses, and validate the models using independent cell-line and clinical datasets. The iGenSig models for five drugs demonstrate predictive values in six clinical studies, among which the Erlotinib and 5-FU models significantly predict therapeutic responses in three studies, offering clinically relevant insights into their inverse predictive signature pathways. Together, iGenSig provides a computational framework to facilitate tailored cancer therapy based on multi-omics data.