bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒10‒17
fourteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Adv Mater. 2021 Oct 14. e2103790
      Cancer vaccines aim at eliciting tumor-specific responses for the immune system to identify and eradicate malignant tumor cells while sparing the normal tissues. Furthermore, cancer vaccines can potentially induce long-term immunological memory for antitumor responses, preventing metastasis and cancer recurrence, thus presenting an attractive treatment option in cancer immunotherapy. However, clinical efficacy of cancer vaccines has remained low due to longstanding challenges, such as poor immunogenicity, immunosuppressive tumor microenvironment, tumor heterogeneity, inappropriate immune tolerance, and systemic toxicity. Recently, bioinspired materials and biomimetic technologies have emerged to play a part in reshaping the field of cancer nanomedicine. By mimicking desirable chemical and biological properties in nature, bioinspired engineering of cancer vaccine delivery platforms can effectively transport therapeutic cargos to tumor sites, amplify antigen and adjuvant bioactivities, and enable spatiotemporal control and on-demand immunoactivation. As such, integration of biomimetic designs into delivery platforms for cancer vaccines can enhance efficacy while retaining good safety profiles, which contributes to expediting the clinical translation of cancer vaccines. Recent advances in bioinspired delivery platforms for cancer vaccines, existing obstacles faced, as well as insights and future directions for the field are discussed here.
    Keywords:  biomimetic materials; cancer immunotherapy; cancer vaccines; drug delivery; nanomedicine
  2. Nano Lett. 2021 Oct 14.
      Extracellular vesicles (EV)-based delivery of therapeutic mRNAs is challenged by the low loading efficiency. In this study, we designed a DNA aptamer consisting of two parts: the single strand part recognized the AUG region of target mRNA, preventing mRNA from translation and ribosome assembly; and the double strand part containing the elements recognized by the CD9-ZF (zinc finger) motifs, sorting DNA aptamer-mRNA complex into CD9-ZF engineered EVs. In vitro and in vivo studies revealed that the system could efficiently load functional mRNAs to the EVs. Furthermore, adipose specific delivery of loaded Pgc1α mRNA via the strategy could efficiently induce white adipocyte browning. Similarly, delivery of interleukin-10 (Il-10) mRNA via the strategy had potent anti-inflammatory effect in inflammatory bowel disease (IBD) mouse model. Together, our study has proposed an efficient strategy to load therapeutic mRNAs of interest into EVs, which could be used as a promising strategy for gene therapy.
    Keywords:  DNA aptamer; Extracellular vesicles; browning of white adipocytes; encapsulation; engineering; inflammatory bowel disease; therapeutic mRNA
  3. Exp Biol Med (Maywood). 2021 Oct 13. 15353702211035689
      MicroRNAs are related to the development of hepatocellular carcinoma and can serve as potential therapeutic targets. Therapeutic strategies increasing tumor-suppressive microRNAs and reducing oncogenic microRNAs have been developed. Herein, the effects of simultaneously altering two microRNAs using MS2 virus-like particles were studied. The sequences of microRNA-21-sponge and pre-microRNA-122 were connected and cloned into a virus-like particle expression vector. Virus-like particles containing microRNA-21-sponge and pre-microRNA-122 sequences were prepared and crosslinked with a cell-specific peptide targeting hepatocellular carcinoma cells. Delivery effects were studied using RT-qPCR and functional assays to investigate the level of target mRNAs, cell toxicity, and the effects of proliferation, invasion, and migration. Virus-like particles delivered miR-21-sponge into cells, with the Ct value reaching 10 at most. The linked pre-miR-122 was processed into mature miR-122. The mRNA targets of miR-21 were derepressed as predicted and upregulated 1.2-2.8-fold, and the expression of proteins was elevated correspondingly. Proliferation, migration, and invasion of HCC cells were inhibited by miR-21-sponge. Simultaneous delivery of miR-21-sponge and miR-122 further decreased proliferation, migration, and invasion by up to 34%, 63%, and 65%, respectively. And the combination promoted the apoptosis of HCC cells. In conclusion, delivering miR-21-sponge and miR-122 using virus-like particles modified by cell-specific peptides is an effective and convenient strategy to correct microRNA dysregulation in hepatocellular carcinoma cells and is a promising therapeutic strategy for hepatocellular carcinoma.
    Keywords:  Delivery; cancer therapy; competitive endogenous RNA; hepatocellular carcinoma; microRNA; virus-like particles
  4. Proc Natl Acad Sci U S A. 2021 Oct 19. pii: e2104826118. [Epub ahead of print]118(42):
      Nanoparticle (NP) stiffness has been shown to significantly impact circulation time and biodistribution in anticancer drug delivery. In particular, the relationship between particle stiffness and tumor accumulation and penetration in vivo is an important phenomenon to consider in optimizing NP-mediated tumor delivery. Layer-by-layer (LbL) NPs represent a promising class of multifunctional nanoscale drug delivery carriers. However, there has been no demonstration of the versatility of LbL systems in coating systems with different stiffnesses, and little is known about the potential role of LbL NP stiffness in modulating in vivo particle trafficking, although NP modulus has been recently studied for its impact on pharmacokinetics. LbL nanotechnology enables NPs to be functionalized with uniform coatings possessing molecular tumor-targeting properties, independent of the NP core stiffness. Here, we report that the stiffness of LbL NPs is directly influenced by the mechanical properties of its underlying liposomal core, enabling the modulation and optimization of LbL NP stiffness while preserving LbL NP outer layer tumor-targeting and stealth properties. We demonstrate that the stiffness of LbL NPs has a direct impact on NP pharmacokinetics, organ and tumor accumulation, and tumor penetration-with compliant LbL NPs having longer elimination half-life, higher tumor accumulation, and higher tumor penetration. Our findings underscore the importance of NP stiffness as a design parameter in enhancing the delivery of LbL NP formulations.
    Keywords:  cancer; drug delivery; liposomes; modulus; targeting
  5. Nat Biomed Eng. 2021 Oct 11.
      Because of the blood-tumour barrier and cross-reactivity with healthy tissues, immune checkpoint blockade therapy against glioblastoma has inadequate efficacy and is associated with a high risk of immune-related adverse events. Here we show that anti-programmed death-ligand 1 antibodies conjugated with multiple poly(ethylene glycol) (PEG) chains functionalized to target glucose transporter 1 (which is overexpressed in brain capillaries) and detaching in the reductive tumour microenvironment augment the potency and safety of checkpoint blockade therapy against glioblastoma. In mice bearing orthotopic glioblastoma tumours, a single dose of glucosylated and multi-PEGylated antibodies reinvigorated antitumour immune responses, induced immunological memory that protected the animals against rechallenge with tumour cells, and suppressed autoimmune responses in the animals' healthy tissues. Drug-delivery formulations leveraging multivalent ligand interactions and the properties of the tumour microenvironment to facilitate the crossing of blood-tumour barriers and increase drug specificity may enhance the efficacy and safety of other antibody-based therapies.
  6. Mol Ther Nucleic Acids. 2021 Dec 03. 26 547-556
      MicroRNAs (miRNAs) are small noncoding RNAs that regulate complex gene expression networks in eukaryotic cells. Because of their unique expression patterns, miRNAs are potential molecular markers for specific cell states. Although a system capable of imaging miRNA in living cells is needed to visually detect miRNA expression, very few fluorescence signal-on sensors that respond to expression of target miRNA (miR-ON sensors) are available. Here we report an miR-ON sensor containing a bidirectional promoter-driven Csy4 endoribonuclease and green fluorescent protein, ZsGreen1, for live-cell imaging of miRNAs with post-transcriptional feedback control. Csy4-assisted miR-ON (Csy4-miR-ON) sensors generate negligible background but respond sensitively to target miRNAs, allowing high-contrast fluorescence detection of miRNAs in various human cells. We show that Csy4-miR-ON sensors enabled imaging of various miRNAs, including miR-21, miR-302a, and miR-133, in vitro as well as in vivo. This robust tool can be used to evaluate miRNA expression in diverse biological and medical applications.
    Keywords:  Csy4; fluorescent protein; live-cell imaging; microRNA; post-transcriptional feedback control
  7. J Hematol Oncol. 2021 Oct 15. 14(1): 169
      Altered metabolic patterns in tumor cells not only meet their own growth requirements but also shape an immunosuppressive microenvironment through multiple mechanisms. Noncoding RNAs constitute approximately 60% of the transcriptional output of human cells and have been shown to regulate numerous cellular processes under developmental and pathological conditions. Given their extensive action mechanisms based on motif recognition patterns, noncoding RNAs may serve as hinges bridging metabolic activity and immune responses. Indeed, recent studies have shown that microRNAs, long noncoding RNAs and circRNAs are widely involved in tumor metabolic rewiring, immune cell infiltration and function. Hence, we summarized existing knowledge of the role of noncoding RNAs in the remodeling of tumor metabolism and the immune microenvironment, and notably, we established the TIMELnc manual, which is a free and public manual for researchers to identify pivotal lncRNAs that are simultaneously correlated with tumor metabolism and immune cell infiltration based on a bioinformatic approach.
    Keywords:  Bioinformatic approach; Immune microenvironment; Noncoding RNAs; TIMELnc manual; Tumor metabolism
  8. Angew Chem Int Ed Engl. 2021 Oct 13.
      Lysosome-relevant cell death induced by lysosomal membrane permeabilization (LMP) has recently attracted increasing attention. However, nearly no studies show that currently available LMP inducers can evoke immunogenic cell death (ICD) or convert immunologically cold tumors to hot. Herein, we report a LMP inducer named TPE-Py-pYK(TPP)pY, which can respond to alkaline phosphatase (ALP), leading to formation of nanoassembies along with fluorescence and singlet oxygen turn-on. TPE-Py-pYK(TPP)pY tends to accumulate in ALP-overexpressed cancer cell lysosomes as well as induce LMP and rupture of lysosomal membranes to massively evoke ICD. Such LMP-induced ICD effectively converts immunologically cold tumors to hot as evidenced by abundant CD8+ and CD4+ T cells infiltration into the cold tumors. Exposure of ALP-catalyzed nanoassemblies in cancer cell lysosomes to light further intensifies the processes of LMP, ICD and cold-to-hot tumor conversion. This work thus builds a new bridge between lysosome-relevant cell death and cancer immunotherapy.
    Keywords:  alkaline phosphatase; enzyme-instructed self-assembly; immunologically cold/hot tumors; lysosomal membrane permeabilization; supramolecular self-assembling peptide
  9. Angew Chem Int Ed Engl. 2021 Oct 15.
      Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance. Modern approaches therefore seek new ways to deliver active platinum(II) to discrete nucleic acid targets. In the field of antigene therapy, triplex forming oligonucleotides (TFOs) have attracted interest for their ability to specifically recognise extended duplex DNA targets. Here, we report a click chemistry-based approach that combines alkyne-modified TFOs with azide-bearing cis-platinum(II) complexes-based on cisplatin, oxaliplatin, and carboplatin motifs-to generate a library of Pt(II)-TFO hybrids. These constructs can be assembled modularly and enable directed platinum(II) crosslinking to purine nucleobases on the target sequence under the guidance of the TFO. By covalently incorporating modifications of thiazole orange-a known DNA intercalating fluorophore-into Pt(II)-TFOs constructs, enhanced target binding and discrimination between target and  off -target sequences was achieved.
    Keywords:  Crosslinking; DNA Triplex; DNA hybrids; Platinum; click chemistry
  10. Adv Mater. 2021 Oct 10. e2104704
      Biomolecular condensates have been demonstrated as a ubiquitous phenomenon in biological systems and play a crucial role in controlling cellular functions. However, the spatiotemporal construction of artificial biomolecular condensates with functions remains challenging and has been less explored. Herein, a general approach is reported to construct biomolecular condensates (e.g., hydrogel) in the lysosome of living cells for cancer therapy and address multiple drug resistance induced by lysosome sequestration. Aromatic-motif-appended pH-responsive hexapeptide (LTP) derived from natural insulin can be uptaken by cancer cells mainly through caveolae-dependent endocytosis, ensuring the proton-triggered phase transformation (solution to hydrogel) of LTP inside the lysosome specifically. Lysosomal hydrogelation further leads to enlargement of the lysosome in cancer cells and increases the permeability of the lysosome, resulting in cancer cell death. Importantly, lysosomal assemblies can significantly improve the efficiency of current chemotherapy drugs toward multidrug resistance (MDR) cells in vitro and in xenograft tumor models. As an example of functional artificial condensates in lysosomes, this work provides a new strategy for controlling functional condensates formation precisely in the organelles of living cells and addressing MDR in cancer therapy.
    Keywords:  hydrogels; lysosomal membrane permeabilization; multidrug resistance; peptides; self-assembly
  11. Sci Rep. 2021 Oct 12. 11(1): 20213
      Gut barrier dysfunction is often implicated in pathology following alcohol intoxication and burn injury. MicroRNAs (miRNAs) are negative regulators of gene expression that play a central role in gut homeostasis, although their role after alcohol and burn injury is poorly understood. We performed an integrated analysis of miRNA and RNA sequencing data to identify a network of interactions within small intestinal epithelial cells (IECs) which could promote gut barrier disruption. Mice were gavaged with ~ 2.9 g/kg ethanol and four hours later given a ~ 12.5% TBSA full thickness scald injury. One day later, IECs were harvested and total RNA extracted for RNA-seq and miRNA-seq. RNA sequencing showed 712 differentially expressed genes (DEGs) (padj < 0.05) in IECs following alcohol and burn injury. Furthermore, miRNA sequencing revealed 17 differentially expressed miRNAs (DEMs) (padj < 0.1). Utilizing the miRNet, miRDB and TargetScan databases, we identified both validated and predicted miRNA gene targets. Integration of small RNA sequencing data with mRNA sequencing results identified correlated changes in miRNA and target expression. Upregulated miRNAs were associated with decreased proliferation (miR-98-3p and miR-381-3p) and cellular adhesion (miR-29a-3p, miR-429-3p and miR3535), while downregulated miRNAs were connected to upregulation of apoptosis (Let-7d-5p and miR-130b-5p) and metabolism (miR-674-3p and miR-185-5p). Overall, these findings suggest that alcohol and burn injury significantly alters the mRNA and miRNA expression profile of IECs and reveals numerous miRNA-mRNA interactions that regulate critical pathways for gut barrier function after alcohol and burn injury.
  12. J Am Chem Soc. 2021 Oct 14.
      Cellular binding and entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are mediated by its spike glycoprotein (S protein), which binds with not only the human angiotensin-converting enzyme 2 (ACE2) receptor but also glycosaminoglycans such as heparin. Cell membrane-coated nanoparticles ("cellular nanosponges") mimic the host cells to attract and neutralize SARS-CoV-2 through natural cellular receptors, leading to a broad-spectrum antiviral strategy. Herein, we show that increasing surface heparin density on the cellular nanosponges can promote their inhibition against SARS-CoV-2. Specifically, cellular nanosponges are made with azido-expressing host cell membranes followed by conjugating heparin to the nanosponge surfaces. Cellular nanosponges with a higher heparin density have a larger binding capacity with viral S proteins and a significantly higher inhibition efficacy against SARS-CoV-2 infectivity. Overall, surface glycan engineering of host-mimicking cellular nanosponges is a facile method to enhance SARS-CoV-2 inhibition. This approach can be readily generalized to promote the inhibition of other glycan-dependent viruses.
  13. J Am Chem Soc. 2021 Oct 13.
      Drug-polymer conjugates that can self-assemble into nanoparticles are promising drug delivery systems that improve the drug bioavailability and allow their controlled release. However, despite the possibility of reaching high drug loadings, the efficiency of the drug release, mediated by cleavage of the drug-polymer linker, is a key parameter to obtain significant anticancer activity. To overcome the limitations of experimental characterizations and to gain a better understanding of such systems, we conducted a coarse-grained molecular dynamics simulation study on four representative drug-polymer conjugates obtained by the "drug-initiated" method and studied their supramolecular organization upon self-assembly. The prodrugs were composed of either a gemcitabine or a paclitaxel anticancer drug, either a propanoate or a diglycolate linker, and a polyisoprene chain. Our simulations gave crucial information concerning the spatial organization of the different components (e.g., drug, linker, polymer, etc.) into the nanoparticles and revealed that the linkers are not fully accessible to the solvent. Notably, some cleavage sites were either poorly hydrated or partially solvated. These observations might account for the low efficiency of drug release from the nanoparticles, particularly when the linker is too short and/or not hydrophilic/solvated enough. We believe that our theoretical study could be adapted to other types of polymer prodrugs and could guide the design of new polymer prodrug nanoparticles with improved drug release efficiency.
  14. Nat Commun. 2021 Oct 13. 12(1): 5981
      The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.