bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒05‒22
seventeen papers selected by
Ceren Kimna
Technical University of Munich

  1. Adv Healthc Mater. 2022 May 16. e2102770
      The self-delivery of sonosensitizers and immunomodulators to tumor areas, which is highly recommended for enhancing sonodynamic immunotherapy, remains a challenge. Herein, a self-delivery nanodrug (HB-NLG8189, drug loading: approximately 100 wt%) was developed by the small-molecule self-assembly of HB (a new clinical photosensitizer) and NLG8189 (indoleamine-(2,3)-dioxygenase (IDO) pathway inhibitor) for sonodynamic-augmented immunotherapy; this preparation method ensured the absence of excipient-related toxicity and immunogenicity. To evade immune recognition and prolong the circulation time, the HB-NLG8189 nanodrugs were camouflaged using macrophage cell membranes (MPCMs). The constructed HB-NLG8189@MPCM nanodrugs showed an ability to preferentially accumulate within tumors. Upon ultrasound triggering, the HB-NLG8189@MPCM was able to generate reactive oxygen species (ROS) efficiently for robust sonodynamic therapy; it induced immunogenic cell death, initiated an antitumor immune response to activate tumor-specific effector T cells, and promoted the secretion of inflammatory cytokines. The concomitant delivery of NLG8189 reversed the immunosuppressive tumor microenvironment by restraining IDO-1 activation and promoting the intratumoral infiltration of regulatory T cells. Sonodynamic-augmented immunotherapy with HB-NLG8189@MPCM significantly inhibited the growth of both primary and distant tumors with little systemic toxicity. Our biomimetic self-delivery nanodrug provides a promising paradigm for improving sonodynamic immunotherapy. This article is protected by copyright. All rights reserved.
    Keywords:  Biomimetic self-delivery nanodrug; Immunogenetic cell death; Immunotherapy; Sonodynamic therapy; macrophage membrane
  2. Adv Mater. 2022 May 16. e2201562
      Proteins are essential elements for almost all life activities. The emergence of nanotechnology offers innovative strategies to create a diversity of nanoparticles with intrinsic capacities of mimicking the functions of proteins. These artificial mimics are produced in a cost-efficient and controllable manner, with their protein-mimicking performances comparable or superior to those of natural proteins. Moreover, they can be endowed with additional functionalities that are absent in natural proteins, such as cargo loading, active targeting, membrane penetrating and multi-stimuli responding. Therefore, protein-mimicking nanoparticles have been utilized more and more often in biosystems for a wide range of applications including detection, imaging, diagnosis and therapy. To highlight recent progresses in this broad field, we herein summarize representative protein-mimicking nanoparticles that fall into one of the four distinct categories: mimics of enzymes (nanozymes), mimics of fluorescent proteins, nanoparticles with high affinity binding to specific proteins or DNA sequences, and mimics of protein scaffolds. This review covers their sub-classifications, characteristic features, functioning mechanisms as well as the extensive exploitation of their great potential for biological and biomedical purposes. Finally, the challenges and prospects in future development of protein-mimicking nanoparticles are discussed. This article is protected by copyright. All rights reserved.
    Keywords:  fluorescent protein mimics; nanozymes; protein scaffold mimics; protein-mimicking nanoparticles; protein/DNA binding nanoparticles
  3. J Control Release. 2022 May 12. pii: S0168-3659(22)00282-6. [Epub ahead of print]
      Delivery of nucleic acids, such as mRNA, to immune cells has become a major focus in the past decade with ionizable lipid nanoparticles (LNPs) emerging as a clinically-validated delivery platform. LNPs-typically composed of ionizable lipids, cholesterol, phospholipids, and polyethylene glycol-have been designed and optimized for a variety of applications including cancer therapies, vaccines, and gene editing. However, LNPs have only recently been investigated for delivery to T cells, which has various therapeutic applications including the engineering of T cell immunotherapies. While several LNP formulations have been evaluated for mRNA delivery, recent work has demonstrated that the utilization of cholesterol analogs may enhance mRNA delivery. Other studies have shown that cholesterols modified with hydroxyl groups can alter endocytic recycling mechanisms. Here, we engineered a library of LNPs incorporating hydroxycholesterols to evaluate their impact on mRNA delivery to T cells by leveraging endosomal trafficking mechanisms. Substitution of 25% and 50% 7α-hydroxycholesterol for cholesterol in LNPs enhanced mRNA delivery to primary human T cells ex vivo by 1.8-fold and 2.0-fold, respectively. Investigation of endosomal trafficking revealed that these modifications also increase late endosome production and reduce the presence of recycling endosomes. These results suggest that hydroxyl modification of cholesterol molecules incorporated into LNP formulations provides a mechanism for improving delivery of nucleic acid cargo to T cells for a range of immunotherapy applications.
    Keywords:  Cholesterol; Endosomal trafficking; Lipid nanoparticles; mRNA delivery
  4. Adv Sci (Weinh). 2022 May 18. e2200353
      Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor cell proliferation, and inhibition of PPM1D expression in DIPG cells with PPM1D mutation effectively reduces the proliferation activity of tumor cells. Panobinostat effectively kills DIPG tumor cells, but its systemic toxicity and low blood-brain barrier (BBB) permeability limits its application. In this paper, a nano drug delivery system based on functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for targeted therapy of DIPG with PPM1D mutation is prepared. The nano drug delivery system has higher drug delivery efficiency and better therapeutic effect than free drugs. In vivo and in vitro experimental results show that the nano drug delivery system can deliver panobinostat and siRNA across the BBB and achieve a targeted killing effect of DIPG tumor cells, resulting in the prolonged survival of orthotopic DIPG mice. This study provides new ideas for the delivery of small molecule drugs and gene drugs for DIPG therapy.
    Keywords:  blood-brain barrier; diffuse intrinsic pontine glioma; macrophage exosomes; panobinostat; siRNA blood-brain barrier
  5. Acta Biomater. 2022 May 13. pii: S1742-7061(22)00284-7. [Epub ahead of print]
      Nanoparticles (NPs) modified with targeting ligands have often shown great potential in targeted drug delivery for tumor therapy. However, the clearance of NPs by the monocyte-phagocyte system (MPS) and the relatively low cellular uptake by tumor cells have significantly limited the antitumor efficacy of a variety of nanomedicines. Tumor microenvironment-mediated multidrug resistance also reduces the antitumor efficacy of internalized nanomedicines. Herein, we developed an innovative nanomedicine for combined chemo-photodynamic therapy of melanoma through targeted drug delivery and significantly improved the cellular uptake of the nanomedicine through the charge-reversal phenomenon. An amphiphilic platinum (IV)-polyethylenimine-chlorin e6 (Pt(IV)-PEI-Ce6) polymer was designed, prepared, and self-assembled into NPs (PPC) in an aqueous solution, and these NPs were subsequently coated with hyaluronic acid (HA) to afford PPC@HA. The surface-coated HA provided PPC with a negatively charged surface potential to reduce the clearance by the MPS during systemic circulation and enhanced the targeted delivery of PPC to CD44-overexpressing melanoma cells. Upon accumulation in the tumor site, hyaluronidase overexpressed in the tumor induced HA degradation to release the positively charged PPC, resulting in an increased internalization of PPC into tumor cells. Bioactive Pt(II) was released in response to high glutathione level in the tumor cells for effective tumor chemotherapy. Under 650 nm laser irradiation, Ce6 produced reactive oxygen species (ROS), thus driving photodynamic therapy. Finally, PPC@HA exhibited combined photodynamic-chemotherapeutic antitumor efficacy against the melanoma cells in mice. STATEMENT OF SIGNIFICANCE: Tumors are one of the greatest threats to human health, and chemotherapy has been one of the most common therapeutic modalities for treating tumors; however, many challenges related to chemotherapy remain, such as low delivery efficiency, side effects, and unsatisfactory therapeutic efficacy. Nanomedicines modified with targeting ligands have often shown great potential in improving targeted drug delivery for tumor therapy; however, the clearance of nanomaterials by the monocyte-phagocyte system and the relatively low cellular uptake by tumor cells have significantly limited the antitumor efficacy of a variety of nanomedicines. Herein, we developed a novel charge-reversal-based, hyaluronic acid-coated, Pt(IV) prodrug and chlorin e6-based nanomedicine to improve systemic circulation and targeted accumulation of the nanomedicine in the tumor tissue and to enhance its intracellular uptake. This nanomedicine may provide a potential new platform to improve the drug content inside tumor cells and to effectively inhibit tumor growth through combined chemotherapy and photodynamic therapy.
    Keywords:  Pt(IV) prodrug; charge-reversal; controlled drug release; photodynamic-chemotherapeutic therapy; targeted drug delivery
  6. Nano Lett. 2022 May 20.
      Despite the tremendous progresses of cancer immunotherapy, its current clinical responses rate in melanoma remains to be improved. Here, we have reported a skin penetrating tetrahedral framework nucleic acid immune adjuvant (FNAIA) to transdermally deliver chemotherapy drugs into melanoma to induce the immunogenic death of tumor cells and expose tumor antigens, which with assistance of CpG oligodeoxynucleotide incorporated in FNAIA could trigger systemic tumor-specific immune responses. Compared with free CpG, FNAIA could penetrate deeper into subcutaneous tumor tissues and more effectively stimulate dendritic cell maturation. Notably, doxorubicin-loaded FNAIA locally applied on the intact skin above the melanoma could effectively inhibit the growth of mouse B16F10 melanoma and increase tumor CD8+ T cell infiltration. Moreover, combined with immune checkpoint inhibitor, the growth of distant tumors could also be effectively inhibited, suggesting that this strategy could induce systemic immune responses. Therefore, this work provides a new idea for non-invasive treatment of skin cancer.
    Keywords:  DNA nanostructure; immunotherapy; melanoma; transdermal therapy
  7. ACS Nano. 2022 May 15.
      Ferroptosis therapy by catalyzing the Fenton reaction has emerged as a promising tumor elimination strategy for lung adenocarcinoma (ADC). However, the unsatisfactory Fenton reaction efficiency, strong intracellular antioxidant system, and insufficient lung drug accumulation limits the ferroptosis therapeutic effect. To address these issues, an inhalable nanoreactor was proposed by spontaneously adsorbing biomimetic protein corona (PC) composed of matrix metalloproteinase 2 responsive gelatin and glutamate (Glu) on the surface of cationic nanostructured lipid carriers (NLC) core loaded with ferrocene (Fc) and fluvastatin. The prepared Fc-NLC(F)@PC could be nebulized into lung lesions with 2.6 times higher drug accumulation and boost lipid peroxide production by 3.2 times to enhance ferroptosis therapy. Mechanically, fluvastatin was proved to inhibit monocarboxylic acid transporter 4 mediated lactate efflux, inducing tumor acidosis to boost Fc-catalyzing reactive oxygen species production, while the extracellular elevating Glu concentration was found to inhibit xCT (system Xc-) functions and further collapse the tumor antioxidant system by glutathione synthesis suppression. Mitochondrial dysfunction and cell membrane damage were involved in the nanoreactor-driven ferroptotic cell death process. The enhanced antitumor effects by combination of tumor acidosis and antioxidant system collapse were confirmed in an orthotopic lung ADC tumor model. Overall, the proposed nanoreactor highlights the pulmonary delivery approach for local lung ADC treatment and underscores the great potential of ferroptosis therapy.
    Keywords:  fenton reaction; ferroptosis therapy; lung adenocarcinoma; nanostructured lipid carriers; pulmonary delivery
  8. Nano Lett. 2022 May 16.
      Tumor-associated macrophages (TAMs) are a promising therapeutic target for cancers, but achieving multitarget therapy of TAMs is still challenging. Here, we develop a protein-crowned micelle system for targeted and synergistic TAM reprogramming to enhance cancer treatment. The doxorubicin-loaded micelles with a hemoglobin crown (Hb-DOXM) can bind with endogenous plasma haptoglobin to realize specific M2-type TAM targeting. Under the tumor hypoxic and acidic environments, Hb-DOXM can responsively release O2 and DOX to reduce the recruitment of TAMs by hypoxia remission and release DOX to kill M2-type TAMs and cancer cells. To reprogram TAMs adequately, the TAM-modulating drug celecoxib is further encapsulated (Hb-DOXM@Cel) to repolarize M2-type TAMs. The targeted and synergistic TAM reprogramming by Hb-DOXM@Cel can remodel the tumor microenvironment (TME) to an immunostimulatory microenvironment and augment the antitumor effect of cytotoxic T lymphocyte, thus strongly enhancing the DOX-based chemotherapy. The protein-crowned micelle strategy presents a targeted and synergistic TAM therapy tool for enhanced cancer treatment.
    Keywords:  hemoglobin; protein-crowned micelle; synergistic therapy; tumor microenvironment; tumor-associated macrophages
  9. Adv Healthc Mater. 2022 May 16. e2200389
      Loading and eluting drugs on self-expandable metallic stents (SEMSs) can be challenging in terms of fabrication, mechanical stability, and therapeutic effects. In this study, a flexible 3-dimensional nanonetworked silica film (NSF) capable of withstanding mechanical stress during dynamic expansion is constructed to function as a drug delivery platform on an entire SEMS surface. Despite covering a broad curved area, the synthesized NSF is defect-free and thin enough to increase the stent strut diameter (110 μm) by only 0.4 percent (110.45 μm). The hydrophobic modification of the surface enables loading of 4.7 times the sirolimus concentration in NSF than Cypher™, polymer-coated commercial stent, which is based on the same thickness of coating layer. Furthermore, sirolimus-loaded NSF exhibits a twofold delay in release compared to the control group without NSF. The sirolimus-loaded NSF SEMS significantly suppresses stent-induced tissue hyperplasia than the control SEMS in the rat esophagus (all variables, p < 0.05). Thus, the developed NSF is a promising polymer-free drug delivery platform to efficiently treat esophageal stricture. This article is protected by copyright. All rights reserved.
    Keywords:  drug-eluting stents; dynamic expansion; nanonetworked film; polymer-free film; restenosis
  10. Small. 2022 May 18. e2201342
      Glioblastoma has a dismal prognosis and is a critical and urgent health issue that requires aggressive research and determined clinical efforts. Due to its diffuse and infiltrative growth in the brain parenchyma, complete neurosurgical resection is rarely possible. Here, pulsed microwave-induced thermoacoustic (MTA) therapy is proposed as a potential alternative modality to precisely and effectively eradicate in vivo orthotopic glioblastoma. A nanoparticle composed of polar amino acids and adenosine-based agonists is constructed with high microwave absorbance and selective penetration of the blood-brain barrier (BBB) at the tumor site. This nanoparticle can activate the adenosine receptor on the BBB to allow self-passage and tumor accumulation. The nanoparticle converts absorbed microwaves into ultrasonic shockwaves via the thermoacoustic cavitation effect. The ultrasonic shockwave can mechanically destroy tumor cells within a short range with minimal damage to adjacent normal brain tissue due to the rapid decay of the ultrasonic shockwave intensity. The deep tissue penetration characteristics of the microwave and the rapid decay of the ultrasonic shockwave make MTA therapy a promising glioblastoma cure including intact skin and skull.
    Keywords:  blood-brain barrier; lysine; precise treatments; pulsed microwave-induced thermoacoustic therapy
  11. J Nanobiotechnology. 2022 May 18. 20(1): 233
      BACKGROUND: Gastric cancer (GC) is a highly heterogeneous disease with many different histological and molecular subtypes. Due to their reduced systemic adverse effects, nanoformulation agents have attracted increasing attention for use in the treatment of GC patients in the clinic. To improve therapeutic outcomes, it is vitally necessary to provide individual medication references and guidance for use of these nanoformulations, and patient-derived organoids (PDOs) are promising models through which to achieve this goal.RESULTS: Using an improved enzymatic digestion process, we succeeded in constructing GC PDOs from surgically resected tumor tissues and endoscopic biopsies from GC patients; these PDOs closely recapitulated the histopathological and genomic features of the corresponding primary tumors. Next, we chose two representative paclitaxel (PTX) nanoformulations for comparative study and found that liposomal PTX outperformed albumin-bound PTX in killing GC PDOs at both the transcriptome and cellular levels. Our results further showed that the different distributions of liposomal PTX and albumin-bound PTX in PDOs played an essential role in the distinct mechanisms through which they kill PDOs. Finally, we constructed patient-derived xenografts model in which we verified the above distinct therapeutic outcomes via an intratumoral administration route.
    CONCLUSIONS: This study demonstrates that GC PDOs are reliable tools for predicting nanoformulation efficacy.
    Keywords:  Albumin-bound paclitaxel; Gastric cancer; Liposomal paclitaxel; Nanoformulation; Patient-derived organoids
  12. J Control Release. 2022 May 12. pii: S0168-3659(22)00281-4. [Epub ahead of print]
      Therapeutic success in the treatment of pancreatic ductal adenocarcinoma (PDAC) is hindered by the extensive stroma associated to this disease. Stroma is composed of cellular and non-cellular components supporting and evolving with the tumor growth. One of the most studied mediators of cancer cell-stroma crosstalk is sonic hedgehog (SHh) pathway leading to the intense desmoplasia observed in PDAC tumors. Herein, we demonstrate that the use of mesoporous silica nanoparticles (MSNs) containing an SHh inhibitor, cyclopamine (CyP), and the combination of chemotherapeutic drugs (Gemcitabine (Gem)/cisplatin (cisPt)) as the main delivery system for the sequential treatment led to reduction in the tumor stroma along with an improvement in the treatment of PDAC. We synthesized two versions of the MSN-based platform containing the SHh inhibitor (CyP-MSNs) and the drug combination (PEG-Gem-cisPt-MSNs). In vitro and in vivo protein analysis show that CyP-MSNs effectively inhibited the SHh pathway. In addition, the sequential combination of CyP-MSNs followed by PEG-Gem-cisPt-MSNs led to effective stromal modulation, increased access of secondary PEG-Gem-cisPt-MSNs at the tumor site, and improved therapeutic performance in HPAF II xenograft mice. Taken together, our findings support the potential of drug delivery using MSN nanoparticles for stroma modulation and to prevent pancreatic cancer progression.
    Keywords:  Combination therapy; Mesoporous silica nanoparticles; Pancreatic cancer; SHh inhibitor; Tumor stroma
  13. Front Neurol. 2022 ;13 895316
      Vascular cognitive impairment and dementia (VCID) is a neurodegenerative disease that is recognized as the second leading cause of dementia after Alzheimer's disease (AD). The underlying pathological mechanism of VCID include crebromicrovascular dysfunction, blood-brain barrier (BBB) disruption, neuroinflammation, capillary rarefaction, and microhemorrhages, etc. Despite the high incidence of VCID, no effective therapies are currently available for preventing or delaying its progression. Recently, pathophysiological microRNAs (miRNAs) in VCID have shown promise as novel diagnostic biomarkers and therapeutic targets. Studies have revealed that miRNAs can regulate the function of the BBB, affect apoptosis and oxidative stress (OS) in the central nervous system, and modulate neuroinflammation and neurodifferentiation. Thus, this review summarizes recent findings on VCID and miRNAs, focusing on their correlation and contribution to the development of VCID pathology.
    Keywords:  apoptosis; blood-brain barrier; dementia; miRNAs; neurodifferentiation; neuroinflammation; oxidative stress; vascular cognitive impairment
  14. Small. 2022 May 19. e2201561
      Oral cancer has a high mortality rate, and its treatment often causes debilitating complications. More than 90% of oral cancers are oral squamous cell carcinomas (OSCCs) that may develop from clinically recognizable oral premalignant lesions (OPLs). To eradicate OPLs before they turn into cancers, a non-invasive topical formulation is developed based on a novel combination of synergistically acting oxaliplatin (OXP) and mycophenolate (MPS) embedded in a controlled-release mucoadhesive patch fabricated by computer-aided 3D printing. After multiple rounds of testing and optimization, a v6.4 ChemoPatch is designed, which shows sustained release of OXP and MPS in vitro, minimal side leakage of drugs, an average elastic modulus of 2.38 MPa, and suitable drug stability at 4 °C or below for up to 12 months. In vivo analyses show almost all patches adhere to the dorsal tongue surface for 4 hours, and display a sustained release of OXP and MPS to tongue tissue for 3-4 hours. When applied in the 4-nitroquinoline-1-oxide-induced OPL rat model, the OXP-MPS patch significantly ablates dysplastic lesions with no damage to normal epithelial cells and minimal systemic absorption and side effects. This study reports the design of a novel mucoadhesive ChemoPatch as a noninvasive therapy to treat OPLs.
    Keywords:  3D printing; bioengineering; biomaterials; mucoadhesive patches; oral cancer; oral premalignant lesions; topical drug delivery
  15. Nat Commun. 2022 May 20. 13(1): 2834
      Cancer recurrence after surgical resection (SR) is a considerable challenge, and the biological effect of SR on the tumor microenvironment (TME) that is pivotal in determining postsurgical treatment efficacy remains poorly understood. Here, with an experimental model, we demonstrate that the genomic landscape shaped by SR creates an immunosuppressive milieu characterized by hypoxia and high-influx of myeloid cells, fostering cancer progression and hindering PD-L1 blockade therapy. To address this issue, we engineer a radio-immunostimulant nanomedicine (IPI549@HMP) capable of targeting myeloid cells, and catalyzing endogenous H2O2 into O2 to achieve hypoxia-relieved radiotherapy (RT). The enhanced RT-mediated immunogenic effect results in postsurgical TME reprogramming and increased susceptibility to anti-PD-L1 therapy, which can suppress/eradicate locally residual and distant tumors, and elicits strong immune memory effects to resist tumor rechallenge. Our radioimmunotherapy points to a simple and effective therapeutic intervention against postsurgical cancer recurrence and metastasis.
  16. J Mater Chem B. 2022 May 19.
      The poor penetration into deep tumor tissues of nanomedicines could not inhibit the production of lactic acid by deep tumor glycolysis, which leads to the accumulation of lactic acid and promotes tumor metastasis. In order to increase tumor penetration, it remains challenging to avoid tumor metastasis by the direct degradation of the extracellular matrix (ECM). Herein, in order to increase tumor penetration, a nano-platform, which can reduce extracellular matrix (ECM) production, and inhibit the glycolysis of deep tumors by releasing ethylenediaminetetraacetic acid (EDTA) is reported. In this design, EDTA and indocyanine green (ICG) are encapsulated in the liposome by a thin-film hydration method, and folic acid (FA) and the polyethyleneimine polymer (FA-PEI) are applied to coat the surface of liposomes through electrostatic interactions, and the FA-EDTA/ICG-Lip nanoparticles are obtained. FA-EDTA/ICG-Lip NPs can release EDTA and ICG in lysosomes (pH 4.5) to reduce ECM production by down-regulating transforming growth factor β (TGF-β) and activating an immune response by inducing tumor cell immunogenic cell death (ICD), respectively. Simultaneously, EDTA inhibits glycolysis of deep tumors by chelating Mg2+. By avoiding tumor metastasis, the strategy of indirectly reducing ECM production is demonstrated to enhance tumor penetration and inhibit deep tumor glycolysis.
  17. Adv Sci (Weinh). 2022 May 20. e2105806
      Tumor heterogeneity is primarily responsible for treatment resistance and cancer relapses. Being critically important to address this issue, the timely evaluation of the appropriateness of therapeutic actions at the single-cell level is still facing challenges. By using multi-functionalized nano-systems with the delivery vector composed of histone for plasmids loading, hyaluronic acid for tumor targeting, and a fusion peptide for C-X-C motif chemokine receptor 4 (CXCR4) targeting as well as nuclear localization, the reprogramming of circulating tumor cells (CTCs) with in situ detection on biomarkers at the single-cell level is realized. By efficient co-delivery of the genome editing plasmid for CXCR4 knockout and molecular beacons for detection of upregulated mRNA biomarkers into CTCs in unprocessed whole blood, the therapeutic outcomes of genome editing at the single-cell level can be in situ evaluated. The single-cell analysis shows that CXCR4 in CTCs of cancer patients is efficiently downregulated, resulting in upregulated anticancer biomarkers such as p53 and p21. The study provides a facile strategy for in-depth profiling of cancer cell responses to therapeutic actions at single-cell resolution to evaluate the outcomes of treatments timely and conveniently.
    Keywords:  CRISPR-Cas9; circulating tumor cells; gene therapy; molecular beacons; targeting delivery