bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒01‒17
seventeen papers selected by
Ceren Kimna
Technical University of Munich

  1. Science. 2021 Jan 12. pii: eabf6840. [Epub ahead of print]
      Protection against SARS-CoV-2 and SARS-related emergent zoonotic coronaviruses is urgently needed. We made homotypic nanoparticles displaying the receptor-binding domain (RBD) of SARS-CoV-2 or co-displaying SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses that represent threats to humans (mosaic nanoparticles; 4-8 distinct RBDs). Mice immunized with RBD-nanoparticles, but not soluble antigen, elicited cross-reactive binding and neutralization responses. Mosaic-RBD-nanoparticles elicited antibodies with superior cross-reactive recognition of heterologous RBDs compared to sera from immunizations with homotypic SARS-CoV-2-RBD-nanoparticles or COVID-19 convalescent human plasmas. Moreover, sera from mosaic-RBD-immunized mice neutralized heterologous pseudotyped coronaviruses equivalently or better after priming than sera from homotypic SARS-CoV-2-RBD-nanoparticle immunizations, demonstrating no immunogenicity loss against particular RBDs resulting from co-display. A single immunization with mosaic-RBD-nanoparticles provides a potential strategy to simultaneously protect against SARS-CoV-2 and emerging zoonotic coronaviruses.
  2. Adv Healthc Mater. 2021 Jan 12. e2001803
      Most anticancer drugs, particularly paclitaxel (PTX), are suffering the challenges of cancer chemotherapy due to their poor water-solubility, high toxicity under effective therapeutic dosages, and multi-drug resistance. Currently, nanoscale drug delivery systems (DDSs) represent an efficient platform to overcome the above challenges. However, those DDSs generally need a careful design of conjugation, complexation, or co-self-assembly. Herein, a facile out-of-the-box nanocapsule is developed not only to be easily packed with on-demand hydrophobic anticancer drugs (up to 76% of loading efficiency for PTX), but also to be loaded with other concomitant drugs for synergy therapy (Itraconazole (ITA) here as P-glycoprotein inhibitor for drug resistance and antiangiogenic agent for combination therapy with PTX). Three kinds of biocompatible poly(ethylene glycol) dimethacrylates (PEGDM) derivatives usually as cross-linking agents are selected and successfully constructed adequate nanocapsules with single monomer as shell materials. More importantly, as-prepared nanocapsules have abilities of esterase triggering and lung targeting. Both in vitro and in vivo studies showed that the drug-loaded nanocapsules can effectively inhibit tumor growth and vascular proliferation in PTX-resistant tumor models without apparent systemic toxicity. The above results demonstrate that the nanocapsule system provides an effective and universal strategy for lung targeting, esterase triggering, and synergy therapy.
    Keywords:  controllable esterase response; high loading efficiency; lung targeting; multi-drug resistance; universal drug encapsulation
  3. Adv Mater. 2021 Jan 14. e2007293
      Using nanotechnology for improving the immunotherapy efficiency represents a major research interest in recent years. However, there are paradoxes and obstacles in using a single nanoparticle to fulfill all the requirements in the complicated immune activation processes. Herein, a supramolecular assembled programmable immune activation nanomedicine (PIAN) for sequentially finishing multiple steps after intravenous injection and eliciting robust antitumor immunity in situ is reported. The programmable nanomedicine is constructed by supramolecular assembly via host-guest interactions between poly-[(N-2-hydroxyethyl)-aspartamide]-Pt(IV)/β-cyclodextrin (PPCD), CpG/polyamidoamine-thioketal-adamantane (CpG/PAMAM-TK-Ad), and methoxy poly(ethylene glycol)-thioketal-adamantane (mPEG-TK-Ad). After intravenous injection and accumulation at the tumor site, the high level of reactive oxygen species in the tumor microenvironment promotes PIAN dissociation and the release of PPCD (mediating tumor cell killing and antigen release) and CpG/PAMAM (mediating antigen capturing and transferring to the tumor-draining lymph nodes). This results in antigen-presenting cell activation, antigen presentation, and robust antitumor immune responses. In combination with anti-PD-L1 antibody, the PIAN cures 40% of mice in a colorectal cancer model. This PIAN provides a new framework for designing programmable nanomedicine as in situ cancer vaccine for cancer immunotherapy.
    Keywords:  cancer vaccines; immunotherapy; nanomedicine; programmable nanomedicine; supramolecular assembly
  4. J Control Release. 2021 Jan 12. pii: S0168-3659(21)00025-0. [Epub ahead of print]
      Tumor-specific apoptosis-inducing ligands have attracted considerable attention in cancer therapy. But, the evasion of apoptosis by tumors can cause acquired resistance to the therapy. TNF-related apoptosis-inducing ligand (TRAIL) has been investigated as an ideal antitumor agent owing to its inherent tumor cell-specific apoptotic activity. However, there are several barriers to its wider application, including the inability for stable formation of the trimeric structure, poor stability and pharmacokinetics, and differences in the sensitivity of different tumor types. Especially, almost 70% of tumor cells have acquired resistance to TRAIL, leading to failure of TRAIL-based therapeutics in clinical trials. To overcome therapeutic efficiency limitations against TRAIL-resistant tumors, we exploited the characteristic of a naturally derived nanocage that not only delivers TRAIL in its native-like trimeric structure, but also delivers a drug (doxorubicin [DOX]) that re-sensitizes TRAIL-resistant tumor cells. These TRAIL-presenting nanocages (TTPNs) showed high loading efficiency, pH-dependent release profiles, and effective intracellular delivery of the re-sensitizing agent DOX. As a result, DOX-TTPNs efficiently re-sensitized TRAIL-resistant tumor cells to TRAIL-mediated apoptosis in vitro by regulating levels of the TRAIL receptor, DR5, and anti- and pro-apoptotic proteins involved in extrinsic and intrinsic apoptosis pathways. We further demonstrated the antitumor efficacy of DOX-TTPNs in vivo, showing that even at a very low dose, the incorporated DOX successfully re-sensitized tumors to the apoptotic effects of TRAIL, underscoring the potential of this platform as an antitumor agent. Given that other homotrimeric TNF superfamily ligands and immunotherapeutic agents can be substituted for TRAIL ligand and re-sensitizing drugs on the surface and in the inner cavity of the nanocage, respectively, this platform is potentially suitable for development of a broad range of anticancer or immunotherapeutic combinations.
    Keywords:  Protein Nanocage; Re-sensitization; Resistance; Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); Tumor-specific apoptosis
  5. Pancreatology. 2020 Dec 30. pii: S1424-3903(20)30877-2. [Epub ahead of print]
      Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related mortality within the next decade, with limited effective treatment options and a dismal long-term prognosis for patients. Genomic profiling has not yet manifested clinical benefits for diagnosis, treatment or prognosis in PDAC, due to the lack of available tissues for sequencing and the confounding effects of low tumour cellularity in many biopsy specimens. Increasing focus is now turning to the use of minimally invasive liquid biopsies to enhance the characterisation of actionable PDAC tumour genomes. Circulating tumour DNA (ctDNA) is the most comprehensively studied liquid biopsy analyte in blood and can provide insight into the molecular profile and biological characteristics of individual PDAC tumours, in real-time and in advance of traditional imaging modalities. This can pave the way for identification of new therapeutic targets, novel risk variants and markers of tumour response, to supplement diagnostic screening and provide enhanced scrutiny in treatment stratification. In the roadmap towards the application of precision medicine for clinical management in PDAC, ctDNA analyses may serve a leading role in streamlining candidate biomarkers for clinical integration. In this review, we highlight recent developments in the use of ctDNA-based liquid biopsies for PDAC and provide new insights into the technical, analytical and biological challenges that must be overcome for this potential to be realised.
    Keywords:  Biomarkers; Cell-free DNA (cfDNA); Circulating tumour DNA (ctDNA); Liquid biopsy; Precision medicine
  6. Trends Cancer. 2021 Jan 11. pii: S2405-8033(20)30339-3. [Epub ahead of print]
      Accumulating preclinical and clinical evidence indicates that high degrees of heterogeneity among malignant cells constitute a considerable obstacle to the success of cancer therapy. This calls for the development of approaches that operate - or enable established treatments to operate - despite such intratumoral heterogeneity (ITH). In this context, oncolytic peptides stand out as promising therapeutic tools based on their ability to drive immunogenic cell death associated with robust anticancer immune responses independently of ITH. We review the main molecular and immunological pathways engaged by oncolytic peptides, and discuss potential approaches to combine these agents with modern immunotherapeutics in support of superior tumor-targeting immunity and efficacy in patients with cancer.
    Keywords:  CD8(+) cytotoxic T lymphocytes; LL-37; LTX-315; NK cells; antimicrobial peptides; genomic instability; immune checkpoint inhibitors
  7. Nat Commun. 2021 01 12. 12(1): 295
      Circular RNAs (circRNA) are a class of covalently closed single-stranded RNAs that have been implicated in cancer progression. Here we identify circNDUFB2 to be downregulated in non-small cell lung cancer (NSCLC) tissues, and to negatively correlate with NSCLC malignant features. Elevated circNDUFB2 inhibits growth and metastasis of NSCLC cells. Mechanistically, circNDUFB2 functions as a scaffold to enhance the interaction between TRIM25 and IGF2BPs, a positive regulator of tumor progression and metastasis. This TRIM25/circNDUFB2/IGF2BPs ternary complex facilitates ubiquitination and degradation of IGF2BPs, with this effect enhanced by N6-methyladenosine (m6A) modification of circNDUFB2. Moreover, circNDUFB2 is also recognized by RIG-I to activate RIG-I-MAVS signaling cascades and recruit immune cells into the tumor microenvironment (TME). Our data thus provide evidences that circNDUFB2 participates in the degradation of IGF2BPs and activation of anti-tumor immunity during NSCLC progression via the modulation of both protein ubiquitination and degradation, as well as cellular immune responses.
  8. ACS Nano. 2021 Jan 11.
      Development of second near-infrared (NIR-II) nanoparticles (NPs) with high biocompatibility, low toxicity, and high singlet oxygen quantum yield (ΦΔ) to prevent tumor recurrence is highly desirable in molecular imaging and photodynamic/immune combination therapy. Here, theranostic photosensitizer BODIPY (BDP)-I-N-anti-PD-L1 NPs were developed by encapsulating the photosensitizer BDP-I-N with amphipathic poly(styrene-co-chloromethylstyrene)-graft-poly(ethylene glycol) nanocarriers through self-assembly functionalization with programmed cell death-ligand 1 (PD-L1) monoclonal antibody. These NPs exhibit highly intensive luminescence in the NIR-II window (1000-1700 nm) to real-time imaging of immune checkpoint PD-L1, high singlet oxygen quantum yield (ΦΔ = 73%), and an eliminating effect of primary cancers. The NPs also allow for profiling PD-L1 expression as well as accumulating in MC38 tumor and enabling molecular imaging in vivo. Upon an 808 nm laser excitation, the targeted NPs produce an emission wavelength above 1200 nm to image a tumor to a normal tissue signal ratio (T/NT) at an approximate value of 14.1. Moreover, the MC38 tumors in mice are eliminated by combining photodynamic therapy and immunotherapy within 30 days, with no tumor recurrence within a period of 40 days. In addition, the tumors do not grow in the rechallenged mice within 7 days of inoculation. Such a strategy shows a durable immune memory effect against tumor rechallenging without toxic side effects to major organs.
    Keywords:  NIR-II fluorophore probe; immunotherapy; molecular imaging; photodynamic therapy; singlet oxygen quantum yield
  9. Drug Deliv Transl Res. 2021 Jan 14.
      In the twenty-first century, the collaboration of control engineering and the healthcare sector has matured to some extent; however, the future will have promising opportunities, vast applications, and some challenges. Due to advancements in processing speed, the closed-loop administration of drugs has gained popularity for critically ill patients in intensive care units and routine life such as personalized drug delivery or implantable therapeutic devices. For developing a closed-loop drug delivery system, the control system works with a group of technologies like sensors, micromachining, wireless technologies, and pharmaceuticals. Recently, the integration of artificial intelligence techniques such as fuzzy logic, neural network, and reinforcement learning with the closed-loop drug delivery systems has brought their applications closer to fully intelligent automatic healthcare systems. This review's main objectives are to discuss the current developments, possibilities, and future visions in closed-loop drug delivery systems, for providing treatment to patients suffering from chronic diseases. It summarizes the present insight of closed-loop drug delivery/therapy for diabetes, gastrointestinal tract disease, cancer, anesthesia administration, cardiac ailments, and neurological disorders, from a perspective to show the research in the area of control theory.
    Keywords:  Biological systems; Cancer treatment; Cardiac ailments; Closed-loop control; Control system; Drug delivery; GI tract; Insulin therapy; Neurological disorders
  10. Adv Sci (Weinh). 2020 Jan;8(1): 2002135
      Organoids are three-dimensional self-renewing and organizing clusters of cells that recapitulate the behavior and functionality of developed organs. Referred to as "organs in a dish," organoids are invaluable biological models for disease modeling or drug screening. Currently, organoid culture commonly relies on an expensive and undefined tumor-derived reconstituted basal membrane which hinders its application in high-throughput screening, regenerative medicine, and diagnostics. Here, we introduce a novel engineered plant-based nanocellulose hydrogel is introduced as a well-defined and low-cost matrix that supports organoid growth. Gels containing 0.1% nanocellulose fibers (99.9% water) are ionically crosslinked and present mechanical properties similar to the standard animal-based matrix. The regulation of the osmotic pressure is performed by a salt-free strategy, offering conditions for cell survival and proliferation. Cellulose nanofibers are functionalized with fibronectin-derived adhesive sites to provide the required microenvironment for small intestinal organoid growth and budding. Comparative transcriptomic profiling reveals a good correlation with transcriptome-wide gene expression pattern between organoids cultured in both materials, while differences are observed in stem cells-specific marker genes. These hydrogels are tunable and can be combined with laminin-1 and supplemented with insulin-like growth factor (IGF-1) to optimize the culture conditions. Nanocellulose hydrogel emerges as a promising matrix for the growth of organoids.
    Keywords:  hydrogels; nanocellulose; organoids; rheology; transcriptomic profile
  11. ACS Nano. 2021 Jan 13.
      In virtue of the inherent molecular recognition and programmability, DNA has recently become the most promising for high-performance biosensors. The rationally engineered nucleic acid architecture will be very advantageous to hybridization efficiency, specificity, and sensitivity. Herein, a robust and split-mode photoelectrochemical (PEC) biosensor for miRNA-196a was developed based on an entropy-driven tetrahedral DNA (EDTD) amplifier coupled with superparamagnetic nanostructures. The DNA tetrahedron structure features in rigidity and structural stability that contribute to obtain precise identification units and specific orientations, improving the hybridization efficiency, sensitivity, and selectivity of the as-designed PEC biosensor. Further, superparamagnetic Fe3O4@SiO2@CdS particles integrated with DNA nanostructures are beneficial for the construction of a split-mode, highly selective, and reliable PEC biosensor. Particularly, the enzyme- and hairpin-free EDTD amplifier eliminates unnecessary interference from the complex secondary structure of pseudoknots or kissing loops in typical hairpin DNAs, significantly lowers the background noise, and improves the detection sensitivity. This PEC biosensor is capable of monitoring miRNA-196a in practical settings with additional advantages of efficient electrode fabrication, stability, and reproducibility. This strategy can be extended to various miRNA assays in complex biological systems with excellent performance.
    Keywords:  DNA tetrahedron; biosensing; entropy-driven amplifier; microRNAs; superparamagnetism
  12. ACS Nano. 2021 Jan 15.
      Herein, we developed hybrid DNAzyme nanoparticles (NPs) to achieve light-induced carrier-free self-delivery of DNAzymes with sufficient cofactor supply and lysosome escape capacity. In this system, aggregation-induced emission (AIE) photosensitizer (PS) (TBD-Br) was grafted onto a phosphorothiolated DNAzyme backbone, which automatically self-assembled to form NPs and the surface phosphorothioate group could easily coordinate with the cofactor Zn2+ in the buffer. When the yielded hybrid DNAzyme NPs were located inside tumor cell lysosomes, the 1O2 from TBD-Br under light illumination could destroy lysosome structure and promote the Zn2+ coordinated DNAzyme NPs escape. Both in vitro and in vivo results demonstrated that the hybrid DNAzyme NPs could downregulate the early growth response factor-1 protein (EGR-1) to inhibit tumor cell growth in addition to induce tumor cell apoptosis by AIE PS (TBD-Br) under light irradiation.
    Keywords:  DNA nucleic acid enzyme; aggregation-induced emission; hybrid DNAzyme nanoparticles; lysosome escape; self-delivery
  13. Adv Healthc Mater. 2021 Jan 14. e2001894
      Endothelial cells (ECs) are an important target for therapy in a wide range of diseases, most notably atherosclerosis. Developing efficient nanoparticle (NP) systems that deliver RNA interference (RNAi) drugs specifically to dysfunctional ECs in vivo to modulate their gene expression remains a challenge. To date, several lipid-based NPs are developed and shown to deliver RNAi to ECs, but few of them are optimized to specifically target dysfunctional endothelium. Here, a novel, targeted poly(β-amino ester) (pBAE) NP is demonstrated. This pBAE NP is conjugated with VHPK peptides that target vascular cell adhesion molecule 1 protein, overexpressed on inflamed EC membranes. To test this approach, the novel NPs are used to deliver anti-microRNA-712 (anti-miR-712) specifically to inflamed ECs both in vitro and in vivo, reducing the high expression of pro-atherogenic miR-712. A single administration of anti-miR-712 using the VHPK-conjugated-pBAE NPs in mice significantly reduce miR-712 expression, while preventing the loss of its target gene, tissue inhibitor of metalloproteinase 3 (TIMP3) in inflamed endothelium. miR-712 and TIMP3 expression are unchanged in non-inflamed endothelium. This novel, targeted-delivery platform may be used to deliver RNA therapeutics specifically to dysfunctional endothelium for the treatment of vascular disease.
    Keywords:  atherosclerosis; endothelial inflammation; microRNA-712; poly(β-amino ester) nanoparticles; vascular cell adhesion molecule 1-targeting VHPK peptides
  14. Biomaterials. 2020 Dec 29. pii: S0142-9612(20)30867-X. [Epub ahead of print]269 120620
      Activated platelets can maintain tumor vessel integrity, thereby leading to limited tumor perfusion and suboptimal antitumor efficacy of nanoparticle-based drugs. Herein, to disrupt the tumor vascular endothelial barriers by inhibiting the transformation of resting platelets to activated platelets, a TM33 peptide-modified gelatin/oleic acid nanoparticle loaded with tanshinone IIA (TNA) was constructed (TM33-GON/TNA). TM33-GON/TNA could adhere to activated platelets by specifically binding their superficial P-selectin and release TNA into the extracellular space under matrix metalloproteinase-2 (MMP-2) stimulation, leading to local high TNA exposure. Thus, platelet activation, adhesion, and aggregation, which occur in the local environment around the activated platelets, were efficiently inhibited, leading to leaky tumor endothelial junctions. Accordingly, TM33-GON/TNA treatment resulted in a 3.2-, 4.0-, and 11.2-fold increase in tumor permeation of Evans blue (macromolecule marker), small-sized Nab-PTX (~10 nm), and large-sized DOX-Lip (~100 nm), respectively, without elevating drug delivery to normal tissues. Ultimately, TM33-GON/TNA plus Nab-PTX exhibited superior antitumor efficacy with minimal side effects in a murine pancreatic cancer model. In addition, the TM33-GON/TNA-induced disrupted endothelial junctions were reversibly restored after the treatment because the number of platelets was not reduced, which implies a low risk of the undesirable systemic bleeding. Hence, TM33-GON/TNA represents a clinically translational adjuvant therapy to magnify the antitumor efficacy of existing nanomedicines in pancreatic cancer and other tumors with tight endothelial lining.
    Keywords:  Enzyme-responsive targeted nanoparticles; Inhibition of platelet activation; Pancreatic cancer; Tumor endothelial barriers; Tumor permeation
  15. Adv Healthc Mater. 2021 Jan 14. e2001680
      Cancer immunotherapy is set to emerge as the future of cancer therapy. However, recent immunotherapy trials in different cancers have yielded sub-optimal results, with durable responses seen in only a small fraction of patients. Engineered multifunctional nanomaterials and biological materials are versatile platforms that can elicit strong immune responses and improve anti-cancer efficacy when applied to cancer immunotherapy. While there are traditional systems such as polymer- and lipid-based nanoparticles, there is a wide variety of other materials with inherent and additive properties that can allow for more potent activation of the immune system. By synthesizing and applying multifunctional strategies, it allows for a more extensive and more effective repertoire of tools to use in the wide variety of situations that cancer presents itself. Here, several types of nanoscale and biological material strategies and platforms that provide their inherent benefits for targeting and activating multiple aspects of the immune system are discussed. Overall, this review aims to provide a comprehensive understanding of recent advances in the field of multifunctional cancer immunotherapy and trends that pave the way for more diverse and tactical regression of tumors through soliciting responses by either the adaptive or innate immune system, and even both simultaneously.
    Keywords:  biomaterials; cancer; immunotherapy; multifunctional materials; nanomaterials
  16. J Oncol. 2020 ;2020 2951921
      Background: Pancreatic cancer is a devastating disease; its lethality is related to rapid growth and tendency to invade adjacent organs and metastasize at an early stage.Objective: The aim of this study was to identify miRNAs and their gene targets involved in the invasive phenotype in pancreatic cancer to better understand the biological behaviour and the rapid progression of this disease.
    Methods: miRNA profiling was performed in isogenic matched high invasive and low-invasive subclones derived from the MiaPaCa-2 cell line and validated in a panel of pancreatic cancer cell lines, tumour, and normal pancreas. Online miRNA target prediction algorithms and gene expression arrays were used to predict the target genes of the differentially expressed miRNAs. miRNAs and potential target genes were subjected to overexpression and knockdown approaches and downstream functional assays to determine their pathological role in pancreatic cancer.
    Results: Differential expression analysis revealed 10 significantly dysregulated miRNAs associated with invasive capacity (Student's t-tests; P value <0.05; fold change = ±2). The expression of top upregulated miR-135b and downregulated let-7c miRNAs correlated with the invasive abilities of eight pancreatic cancer cell lines and displayed differential expression in pancreatic cancer and adjacent normal tissue specimens. Ectopic overexpression of let-7c decreased proliferation, invasion, and colony formation. Integrated analysis of miRNA-mRNA using in silico algorithms and experimental validation databases identified four putative gene targets of let-7c. One of these targets, SOX13, was found to be upregulated in PDAC tumour compared with normal tissue in TCGA and an independent data set by qPCR and immunohistochemistry. RNAi knockdown of SOX13 reduced the invasion and colony formation ability of pancreatic cancer cells.
    Conclusion: The identification of key miRNA-mRNA gene interactions and networks provide potential diagnostic and therapeutic strategies for better treatment options for pancreatic cancer patients.
  17. Adv Mater. 2021 Jan 14. e2007557
      Despite the critical breakthrough achieved by immune checkpoint blockade (ICB), the clinical benefits are usually restricted by inefficient infiltration of immune cells and immune-associated adverse effects. Noninvasive aerosol inhalation, as a definitive procedure for treatment of respiratory diseases, for ICB immunotherapy against lung metastasis, has not been realized to the best knowledge. Herein, an inhaled immunotherapeutic chitosan (CS)-antibody complex is developed for immunotherapy against lung cancer. In this system, CS is used as a carrier to assemble with anti-programmed cell death protein ligand 1 (aPD-L1) to enable efficient transmucosal delivery. Moreover, CS exhibits adjuvant effects to drive potent immune responses via activating the cyclic-di-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Interestingly, repeated inhalation of CS/aPD-L1 complex can effectively activate the immune system by promoting the infiltration of different immune cells especially CD8+ T cells around tumor lesions, and finally prolongs the survival of mice to 60 days. Thus, the work presents a unique aerosol inhalation delivery system for ICB antibody, which is promising for immunotherapy against lung metastasis without the concern of systemic toxicity.
    Keywords:  cancer immunotherapy; immune checkpoint blockade; inhalation; lung cancer; pulmonary drug delivery