bims-drudre 2021-09-12 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2021‒09‒12
twenty-one papers selected by
Ceren Kimna
Technical University of Munich

In Situ Covalent Functionalization of DNA Origami Virus-like Particles.
Linear-Dendritic Polymer-Platinum Complexes Forming Well-Defined Nanocapsules for Acid-Responsive Drug Delivery.
Delivery of Oligonucleotide Therapeutics: Chemical Modifications, Lipid Nanoparticles, and Extracellular Vesicles.
Protease Responsive Nanogels for Transcytosis across the Blood-Brain Barrier and Intracellular Delivery of Radiopharmaceuticals to Brain Tumor Cells.
Quercetin-Loaded Ceria Nanocomposite Potentiate Dual-Directional Immunoregulation via Macrophage Polarization against Periodontal Inflammation.
Photosensitizer with High Efficiency Generated in Cells via Light-Induced Self-Oligomerization of 4,6-Dibromothieno[3,4-b]thiophene Compound Entailing a Triphenyl Phosphonium Group.
Engineering a "three-in-one" hirudin prodrug to reduce bleeding risk: A proof-of-concept study.
A Multifunctional Bioactive Glass-Ceramic Nanodrug for Post-Surgical Infection/Cancer Therapy-Tissue Regeneration.
A therapeutic convection-enhanced macroencapsulation device for enhancing β cell viability and insulin secretion.
Spatiotemporally controlled calcitonin delivery: Long-term and targeted therapy of skeletal diseases.
DNA Logic Circuits for Multiple Tumor Cells Identification Using Intracellular MicroRNA Molecular Bispecific Recognition.
Congener-Induced Sulfur-Related Metabolism Interference Therapy Promoted by Photothermal Sensitization for Combating Bacteria.
Mucoadhesive versus Mucopenetrating nanoparticles for oral delivery of insulin.
DNA-Based Smart Reagent for Detecting Alzheimer's Associated MicroRNAs.
Potential Pulse-Facilitated Active Adsorption of Lubricin Polymer Brushes Can Both Accelerate Self-Assembly and Control Grafting Density.
Interaction-based ion selectivity exhibited by self-assembled, cross-linked zwitterionic copolymer membranes.
On-Demand Drug Release from Click-Refillable Drug Depots.
Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis.
Ligand-Sensitized Near-Infrared to Visible Linear Light Upconversion in a Discrete Molecular Erbium Complex.
Boosting Photothermal Theranostics via TICT and Molecular Motions for Photohyperthermia Therapy of Muscle-Invasive Bladder Cancer.
A Prehepatectomy Circulating Exosomal microRNA Signature Predicts the Prognosis and Adjuvant Chemotherapeutic Benefits in Colorectal Liver Metastasis.

ACS Nano. 2021 Sep 07.

In Situ Covalent Functionalization of DNA Origami Virus-like Particles.

Grant A Knappe, Eike-Christian Wamhoff, Benjamin J Read, Darrell J Irvine, Mark Bathe.

  DNA origami is a powerful nanomaterial for biomedical applications due in part to its capacity for programmable, site-specific functionalization. To realize these applications, scalable and efficient conjugation protocols are needed for diverse moieties ranging from small molecules to biomacromolecules. Currently, there are no facile and general methods for in situ covalent modification and label-free quantification of reaction conversion. Here, we investigate the postassembly functionalization of DNA origami and the subsequent high-performance liquid chromatography-based characterization of these nanomaterials. Following this approach, we developed a versatile DNA origami functionalization and characterization platform. We observed quantitative in situ conversion using widely accessible click chemistry for carbohydrates, small molecules, peptides, polymers, and proteins. This platform should provide broader access to covalently functionalized DNA origami, as illustrated here by PEGylation for passivation and HIV antigen decoration to construct virus-like particle vaccines.

Keywords:  DNA nanotechnology; DNA origami; bioconjugation; click chemistry; nanoparticles; reaction characterization

DOI:  https://doi.org/10.1021/acsnano.1c03158
ACS Appl Mater Interfaces. 2021 Sep 09.

Linear-Dendritic Polymer-Platinum Complexes Forming Well-Defined Nanocapsules for Acid-Responsive Drug Delivery.

Kexin Liu, Jiajia Xiang, Guowei Wang, Hongxia Xu, Ying Piao, Xiangrui Liu, Jianbin Tang, Youqing Shen, Zhuxian Zhou.

  Polymeric nanocapsules hold considerable applications in cancer drug delivery, but the synthesis of well-defined nanocapsules with a tunable drug release property remains a significant challenge in fabrication. Herein, we demonstrate a supramolecular complexation strategy to assemble small molecular platinum (Pt) compounds into well-defined nanocapsules with high drug loading, acidity-sensitivity, and tunable Pt releasing profile. The design utilizes poly(ethylene glycol)-dendritic polylysine-G4/amides to complex with Pt compounds, forming stable nanocapsules with diameters approximately ∼20 nm and membrane thickness around several nanometers. The stability, drug content, and release profiles are tunable by tailoring the dendritic structure. The designated polymer-Pt nanocapsules, PEG-G4/MSA-Pt, showed sustained blood retention, preferential tumor accumulation, enhanced cellular uptake, lysosomal drug release, and nuclear delivery capability. PEG-G4/MSA-Pt showed enhanced antitumor efficacy compared to free cisplatin and other nanocapsules, which stopped the progression of both A549 cell xenografts and patient-derived xenografts (PDXs) of hepatocellular carcinoma on a mice tumor model. Thus, we believe this strategy is promising for developing Pt-based nanomedicine for cancer drug delivery.

Keywords:  controlled release; platinum drug delivery; polymeric nanocapsule; self-assembly; well-defined structure

DOI:  https://doi.org/10.1021/acsami.1c12156
ACS Nano. 2021 Sep 10.

Delivery of Oligonucleotide Therapeutics: Chemical Modifications, Lipid Nanoparticles, and Extracellular Vesicles.

Jeremy P Bost, Hanna Barriga, Margaret N Holme, Audrey Gallud, Marco Maugeri, Dhanu Gupta, Taavi Lehto, Hadi Valadi, Elin K Esbjörner, Molly M Stevens, Samir El-Andaloussi.

  Oligonucleotides (ONs) comprise a rapidly growing class of therapeutics. In recent years, the list of FDA-approved ON therapies has rapidly expanded. ONs are small (15-30 bp) nucleotide-based therapeutics which are capable of targeting DNA and RNA as well as other biomolecules. ONs can be subdivided into several classes based on their chemical modifications and on the mechanisms of their target interactions. Historically, the largest hindrance to the widespread usage of ON therapeutics has been their inability to effectively internalize into cells and escape from endosomes to reach their molecular targets in the cytosol or nucleus. While cell uptake has been improved, "endosomal escape" remains a significant problem. There are a range of approaches to overcome this, and in this review, we focus on three: altering the chemical structure of the ONs, formulating synthetic, lipid-based nanoparticles to encapsulate the ONs, or biologically loading the ONs into extracellular vesicles. This review provides a background to the design and mode of action of existing FDA-approved ONs. It presents the most common ON classifications and chemical modifications from a fundamental scientific perspective and provides a roadmap of the cellular uptake pathways by which ONs are trafficked. Finally, this review delves into each of the above-mentioned approaches to ON delivery, highlighting the scientific principles behind each and covering recent advances.

Keywords:  RNA therapeutics; cellular uptake; endosomal escape; extracellular vesicles; intracellular trafficking; lipid nanoparticles; oligonucleotide; oligonucleotide delivery

DOI:  https://doi.org/10.1021/acsnano.1c05099
Adv Healthc Mater. 2021 Sep 06. e2100812

Protease Responsive Nanogels for Transcytosis across the Blood-Brain Barrier and Intracellular Delivery of Radiopharmaceuticals to Brain Tumor Cells.

Smriti Singh, Natascha Drude, Lena Blank, Prachi Bharat Desai, Hiltrud Königs, Stephan Rütten, Karl-Josef Langen, Martin Möller, Felix M Mottaghy, Agnieszka Morgenroth.

  Despite profound advances in treatment approaches, gliomas remain associated with very poor prognoses. The residual cells after incomplete resection often migrate and proliferate giving a seed for highly resistant gliomas. The efficacy of chemotherapeutic drugs is often strongly limited by their poor selectivity and the blood brain barrier (BBB). Therefore, the development of therapeutic carrier systems for efficient transport across the BBB and selective delivery to tumor cells remains one of the most complex problems facing molecular medicine and nano-biotechnology. To address this challenge, a stimuli sensitive nanogel is synthesized using pre-polymer approach for the effective delivery of nano-irradiation. The nanogels are cross-linked via matrix metalloproteinase (MMP-2,9) substrate and armed with Auger electron emitting drug 5-[125 I]Iodo-4"-thio-2"-deoxyuridine ([125 I]ITdU) which after release can be incorporated into the DNA of tumor cells. Functionalization with diphtheria toxin receptor ligand allows nanogel transcytosis across the BBB at tumor site. Functionalized nanogels efficiently and increasingly explore transcytosis via BBB co-cultured with glioblastoma cells. The subsequent nanogel degradation correlates with up-regulated MMP2/9. Released [125 I]ITdU follows the thymidine salvage pathway ending in its incorporation into the DNA of tumor cells. With this concept, a highly efficient strategy for intracellular delivery of radiopharmaceuticals across the challenging BBB is presented.

Keywords:  blood−brain barrier; brain tumors; diphtheria toxin receptors; nanogels; radiolabeled thymidine analogue

DOI:  https://doi.org/10.1002/adhm.202100812
Small. 2021 Sep 09. e2101505

Quercetin-Loaded Ceria Nanocomposite Potentiate Dual-Directional Immunoregulation via Macrophage Polarization against Periodontal Inflammation.

Yu Wang, Chunyan Li, Yao Wan, Manlin Qi, Qiuhan Chen, Yue Sun, Xiaolin Sun, Jiao Fang, Li Fu, Lin Xu, Biao Dong, Lin Wang.

  Macrophage polarization toward M1 phenotype (pro-inflammation) is closely associated with the destructive phase of periodontal inflammation. Nanoceria is verified to inhibit M1 polarization of macrophages by the favorable ability of reactive oxygen species (ROS) scavenging. However, the function of nanoceria on macrophage polarization toward M2 phenotype (anti-inflammation) in reparative phase of periodontal inflammation is quite limited. In this work, by introducing an antioxidant drug quercetin onto nano-octahedral ceria, synergistic and intense regulation of host immunity against periodontal disease is realized. Such nanocomposite can control the phenotypic switch of macrophages by not only inhibition of M1 polarization for suppressing the damage in the destructive phase but also promotion of M2 polarization for regenerating the surrounding tissues in reparative phase of periodontal disease. As-prepared nanocomposite can effectively increase the M2/M1 ratio of macrophage polarization in inflammatory cellular models by lipopolysaccharide stimulation. More importantly, the nanocomposite also exerts an improved therapeutic potential against local inflammation by significant downregulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines in an animal model with periodontal inflammation. Therefore, this newly developed nanomedicine is efficient in ROS scavenging and driving pro-inflammatory macrophages to the anti-inflammatory phenotype to eliminate inflammation, thereby providing a promising candidate for treating periodontal inflammation.

Keywords:  ceria; inflammation; macrophage polarization; quercetin; reactive oxygen species

DOI:  https://doi.org/10.1002/smll.202101505
Adv Healthc Mater. 2021 Sep 08. e2100896

Photosensitizer with High Efficiency Generated in Cells via Light-Induced Self-Oligomerization of 4,6-Dibromothieno[3,4-b]thiophene Compound Entailing a Triphenyl Phosphonium Group.

Lingna Wang, Yanyan Huang, Yingjie Yu, Huifei Zhong, Haihua Xiao, Guanxin Zhang, Deqing Zhang.

  Photodynamic therapy (PDT) has emerged as an attractive alternative in cancer therapy, but therapeutic effects suffer from low photosensitizing efficiency and poor retention of photosensitizes in cancer cells. This paper reports the photosensitizers which show absorption and emission in the long-wavelength region and high photosensitizing efficiency can be formed in situ in cells from 4,6-dibromothieno[3,4-b]thiophene derivative (TT-5-P) after white light irradiation. The self-oligomerization of TT-5-P is uptaken in cells upon light irradiation-induced cell apoptosis simultaneously and efficiently. In addition, the formation of oligomers (TT-5-Ps) enhances the retention time in cells remarkably, which is advantageous for boosting the photodynamic therapy efficiency. Moreover, the selectivity toward tumor cells of TT-5-P can be improved obviously via the formation of complex of TT-5-P with albumin. This in situ photoinduced self-oligomerization strategy can be utilized to design effective biomaterials for long-term imaging and improved therapy.

Keywords:  aggregation-induced emission enhancement; albumin; photodynamic therapy; retention time; self-oligomerization

DOI:  https://doi.org/10.1002/adhm.202100896
J Control Release. 2021 Sep 01. pii: S0168-3659(21)00472-7. [Epub ahead of print]338 462-471

Engineering a "three-in-one" hirudin prodrug to reduce bleeding risk: A proof-of-concept study.

Yuanjun Zhu, Hu-Hu Han, Lin Zhai, Yi Yan, Xiaoyan Liu, Yinye Wang, Liandi Lei, Jian-Cheng Wang.

  An ideal anticoagulant should have at least three properties including targeted delivery to the thrombosis site, local activation or releasing to centralize the anti-thrombosis effects and thus reduce the bleeding risks, and long persistence in circulation to avoid repeated administration. In the present study, we sought to test a "three-in-one" strategy to design new protein anticoagulants. Based on these criteria, we constructed two hirudin prodrugs, R824-HV-ABD and ABD-HV-R824. The R824 peptide can bind phosphatidylserine on the surface of the procoagulant platelets and thus guide the prodrug to the thrombosis sites; albumin-binding domain (ABDs) can bind the prodrug to albumin, and thereby increase its persistence in circulation; the hirudin (HV) core in the prodrug is flanked by factor Xa recognition sites, thus factor Xa at the thrombosis site can cleave the fusion proteins and release the activated hirudin locally. Hirudin prodrugs were able to bind with procoagulant platelets and human serum albumin in vitro with high affinity, targeted concentrated and prevented the formation of occlusive thrombi in rat carotid artery injury model. Their effective time was significantly extended compared to native hirudin, and R824-HV-ABD showed a significantly improved half-life of about 24 h in rats. The bleeding time of prodrug-treated mice was much shorter than that of hirudin-treated mice. The results from the proof-of-concept studies, for the first time, demonstrate that "three-in-one" prodrug strategy may be a good solution for protein or peptide anticoagulants to reduce their bleeding risks.

Keywords:  Anticoagulant; Hirudin prodrug; Local activation; Procoagulant platelet; Serum albumin; Three-in-one

DOI:  https://doi.org/10.1016/j.jconrel.2021.08.058
ACS Nano. 2021 Sep 07.

A Multifunctional Bioactive Glass-Ceramic Nanodrug for Post-Surgical Infection/Cancer Therapy-Tissue Regeneration.

Wen Niu, Mi Chen, Yi Guo, Min Wang, Meng Luo, Wei Cheng, Yidan Wang, Bo Lei.

  The production of reactive oxygen species, persistent inflammation, bacterial infection, and recurrence after a tumor resection has become the main challenge in cancer therapy and post-surgical skin regeneration. Herein, we report a multifunctional branched bioactive Si-Ca-P-Mo glass-ceramic nanoparticle (BBGN) with inlaid molybdate nanocrystals for an effective post-surgical melanoma therapy or infection therapy and defected skin reconstruction. Mixed-valence molybdenum (Mo4+ and Mo6+) doped BBGN (BBGN-Mo) was first synthesized via a hydrothermally assisted classical synthesis of BGN, which enables the structure with a lot of free electrons and oxygen vacancies. The BBGN-Mo exhibits excellent photothermal, antibacterial, enzyme-like radical scavenging, and anti-inflammatory as well as promoted vascularized efficiencies. BBGN-Mo could kill drug-resistant methicillin-resistant Staphylococcus aureus (MRSA) bacteria in vitro (99.5%) and in vivo (97.0%) at a low photothermal temperature (42 °C) and efficiently enhance the MRSA-infected wound repair. Additionally, BBGN-Mo could effectively inhibit tumor recurrence (96.4%), continuously improve the wound anti-inflammation and vascularization microenvironment, and significantly promote the post-surgical skin regeneration. This work suggests that conventional bioceramics could be turned to the highly efficient nanodrug for treating the challenge of post-surgical cancer therapy or infection therapy and tissue regeneration, through the mixed-valence strategy.

Keywords:  bioactive glass nanoparticles; bioceramics; multifunctional biomaterials; post-surgical cancer therapy; tissue engineering

DOI:  https://doi.org/10.1021/acsnano.1c03214
Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2101258118. [Epub ahead of print]118(37):

A therapeutic convection-enhanced macroencapsulation device for enhancing β cell viability and insulin secretion.

Kisuk Yang, Eoin D O'Cearbhaill, Sophie S Liu, Angela Zhou, Girish D Chitnis, Allison E Hamilos, Jun Xu, Mohan K S Verma, Jaime A Giraldo, Yoshimasa Kudo, Eunjee A Lee, Yuhan Lee, Ramona Pop, Robert Langer, Douglas A Melton, Dale L Greiner, Jeffrey M Karp.

  Islet transplantation for type 1 diabetes treatment has been limited by the need for lifelong immunosuppression regimens. This challenge has prompted the development of macroencapsulation devices (MEDs) to immunoprotect the transplanted islets. While promising, conventional MEDs are faced with insufficient transport of oxygen, glucose, and insulin because of the reliance on passive diffusion. Hence, these devices are constrained to two-dimensional, wafer-like geometries with limited loading capacity to maintain cells within a distance of passive diffusion. We hypothesized that convective nutrient transport could extend the loading capacity while also promoting cell viability, rapid glucose equilibration, and the physiological levels of insulin secretion. Here, we showed that convective transport improves nutrient delivery throughout the device and affords a three-dimensional capsule geometry that encapsulates 9.7-fold-more cells than conventional MEDs. Transplantation of a convection-enhanced MED (ceMED) containing insulin-secreting β cells into immunocompetent, hyperglycemic rats demonstrated a rapid, vascular-independent, and glucose-stimulated insulin response, resulting in early amelioration of hyperglycemia, improved glucose tolerance, and reduced fibrosis. Finally, to address potential translational barriers, we outlined future steps necessary to optimize the ceMED design for long-term efficacy and clinical utility.

Keywords:  convection; macroencapsulation; stem cell–derived β cells; type 1 diabetes

DOI:  https://doi.org/10.1073/pnas.2101258118
J Control Release. 2021 Sep 02. pii: S0168-3659(21)00470-3. [Epub ahead of print]338 486-504

Spatiotemporally controlled calcitonin delivery: Long-term and targeted therapy of skeletal diseases.

Peng Yu, Yanpeng Liu, Jing Xie, Jianshu Li.

  Bone is a connective tissue that support the entire body and protect the internal organs. However, there are great challenges on curing intractable skeletal diseases such as hypercalcemia, osteoporosis and osteoarthritis. To address these issues, calcitonin (CT) therapy is an effective treatment alternative to regulate calcium metabolism and suppress inflammation response, which are closely related to skeletal diseases. Traditional calcitonin formulation requires frequent administration due to the low bioavailability resulting from the short half-life and abundant calcitonin receptors distributed through the whole body. Therefore, long-term and targeted calcitonin delivery systems (LCDS and TCDS) have been widely explored as the popular strategies to overcome the intrinsic limitations of calcitonin and improve the functions of calcium management and inflammation inhibition in recent years. In this review, we first explain the physiological effects of calcitonin on bone remodeling: (i) inhibitory effects on osteoclasts and (ii) facilitated effects on osteoblasts. Then we summarized four strategies for spatiotemporally controlled delivery of calcitonin: micro-/nanomedicine (e.g. inorganic micro-/nanomedicine, polymeric micro-/nanomedicine and supramolecular assemblies), hydrogels (especially thermosensitive hydrogels), prodrug (PEGylation and targeting design) and hybrid biomaterials. Subsequently, we discussed the application of LCDS and TCDS in treating hypercalcemia, osteoporosis, and arthritis. Understanding and analyzing these advanced calcitonin delivery applications are essential for future development of calcitonin therapies toward skeletal diseases with superior efficacy in clinic.

Keywords:  Bone; Calcitonin; Long-term delivery; Osteoblasts; Osteoclast; Skeletal diseases; Targeted delivery

DOI:  https://doi.org/10.1016/j.jconrel.2021.08.056
Adv Healthc Mater. 2021 Sep 05. e2101130

DNA Logic Circuits for Multiple Tumor Cells Identification Using Intracellular MicroRNA Molecular Bispecific Recognition.

Qiqi Yang, Fan Yang, Wenhao Dai, Xiangdan Meng, Wei Wei, Yaru Cheng, Jinhong Dong, Huiting Lu, Haifeng Dong.

  The aberrant expression level of intracellular microRNAs (miRNAs) holds great promise for differentiating cell types at the molecular level. However, cell subtype discrimination based on a single miRNA molecular level is not sufficient and reliable. Herein, multiple identifiable and reporting modules are integrated into a single DNA circuit for multiple cancer cell subtypes identification based on miRNAs bispecific recognition. The DNA three-dimensional (3D) logic gate nano-hexahedron framework extends three recognition modules and three reporting modules to form three "AND" logic gates. Each Boolean operator "AND" returns an "ON" signal in the presence of bispecific miRNAs, simultaneously enabling three types of cell subtype identification. It not only enables the discrimination of cancer cells A549 and MCF-7 from normal cells NHDF but also successfully distinguishes different types of cancer cells. The bispecific intracellular miRNA controllable DNA circuit, with low signal-to-noise ratio, easily extends to various cell type discrimination by adjusting the miRNA species, provides huge opportunities for accurately differentiating multiple cell types at the molecular level.

Keywords:  DNA logic circuits; bispecific recognition; cells identification; microRNA detection

DOI:  https://doi.org/10.1002/adhm.202101130
Adv Mater. 2021 Sep 05. e2104410

Congener-Induced Sulfur-Related Metabolism Interference Therapy Promoted by Photothermal Sensitization for Combating Bacteria.

Renke He, Cheng Ding, Yao Luo, Geyong Guo, Jin Tang, Hao Shen, Qiaojie Wang, Xianlong Zhang.

  Metabolic homeostasis is vital for individual cells to keep alive. Stronger metabolic homeostasis allows bacteria to survive in vivo and do persistent harm to hosts, which is especially typical in implant-associated infection (IAI) with biofilm intervention. Herein, based on the competitive role of selenium (Se) and sulfur (S) in bacteria metabolism as congeners, a congener-induced sulfur-related metabolism interference therapy (SMIT) eradicating IAI is proposed by specific destruction of bacteria metabolic homeostasis. The original nanodrug manganese diselenide (MnSe2 ) is devised to generate permeable H2 Se in bacteria, triggered by the acidic microenvironment. H2 Se, the congener substitution of H2 S, as a bacteria-specific intermediate metabolite, can embed itself into the H2 S-utilization pathway and further alternatively disrupt the downstream sulfur-related metabolism state inside bacteria. A proteomic study indicates ribosome-related proteins are heavily downregulated and the basic metabolic pathways are mainly disordered after SMIT, revealing the destruction of bacteria metabolic homeostasis. The efficiency of SMIT is significantly promoted with the mild temperature sensitization provided by the photothermal treatment (PTT) of MnSe2 nanoparticles, verified by the proteomic study and the anti-IAI effect in vitro and in vivo. With the intelligent nanodrug, a PTT-promoted SMIT strategy against IAI is provided and a new insight into the interference design toward metabolic homeostasis with biochemical similarity is demonstrated.

Keywords:  antibacterials; congeners; implant-associated infection; metabolism interference; photothermal therapy

DOI:  https://doi.org/10.1002/adma.202104410
Acta Biomater. 2021 Sep 03. pii: S1742-7061(21)00579-1. [Epub ahead of print]

Mucoadhesive versus Mucopenetrating nanoparticles for oral delivery of insulin.

Hongbo Cheng, Zhixiang Cui, Shuang Guo, Xin Zhang, Yingnan Huo, Shirui Mao.

  Mucoadhesive and mucopenetrating nanoparticles are commonly designed to improve mucosal drug delivery efficiency. Herein, in order to better understand the contribution of mucoadhesion and mucopenetration in oral delivery of biomacromolecules, insulin-loaded poly (n-butylcyanoacrylate) nanoparticles (Ins/PBCA NPs) with different coating layers, chitosan (CS) or alginate (Alg), were designed and their different absorption enhancing mechanisms were explored. It was demonstrated that both the mucoadhesive (Ins/PBCA/CS) and the mucopenetrating (Ins/PBCA/CS/Alg) nanoparticles showed good stability and similar release profiles in the gastrointestinal fluid, the mucoadhesive nanoparticles presented an enrichment in mucus (70%, 10 min) while most of the mucopenetrating nanoparticles penetrated through the mucus (80%, 10 min). Uptake mechanism studies revealed clathrin- and caveolae-mediated endocytosis were mainly involved in the intestinal transport of mucoadhesive nanoparticles while caveolae-mediated endocytosis and macropinocytosis contributed to the absorption of mucopenetrating nanoparticles, and especially, M cells favored the absorption of mucoadhesive nanoparticles. In vivo studies revealed that the mucopenetrating nanoparticles had a fast onset of action while the mucoadhesive nanoparticles presented a sustained hypoglycemic effect in diabetic rats, and overall no significant difference in pharmacological availability was found between the mucopenetrating (8.80%) and mucoadhesive nanoparticles (8.44%). To sum up, due to the varied absorption mechanism in intestine, the mucoadhesive nanoparticles designed herein had a comparable effect in enhancing oral insulin absorption compared with the mucopenetrating nanoparticles.

Keywords:  insulin; mucoadhesion; mucopenetration; n-butylcyanoacrylate; nanoparticles; oral delivery

DOI:  https://doi.org/10.1016/j.actbio.2021.08.046
ACS Sens. 2021 Sep 07.

DNA-Based Smart Reagent for Detecting Alzheimer's Associated MicroRNAs.

Arun Richard Chandrasekaran, Ken Halvorsen.

  Alzheimer's disease (AD) is the most common neurodegenerative disorder, with significant research efforts devoted to identifying new biomarkers for clinical diagnosis and treatment. MicroRNAs have emerged as likely disease regulators and biomarkers for AD, now implicated as having roles in several biological processes related to progression of the disease. In this work, we use the miRacles assay (microRNA activated conditional looping of engineered switches) for single-step detection of AD-related microRNAs. The technology is based on conformationally responsive DNA nanoswitches that loop upon recognition of a target microRNA and report their on/off status through an electrophoretic readout. Unlike many methods, our approach directly detects native microRNAs without amplification or labeling, eliminating the need for expensive enzymes, reagents, and equipment. For known AD-related microRNA miR-107, we demonstrated sensitivity of ∼8 fM, specificity among four similar microRNAs of the same family, and simultaneous multiplexed detection of those four microRNA targets. Toward clinical use, we screened 56 AD-related microRNAs and found four that showed detectable differences between total RNA extracts derived from human healthy and AD brain samples. In the context of AD, this "smart reagent" could facilitate biomarker discovery, accelerate efforts to understand the role of microRNAs in AD, and have clinical potential as a diagnostic or monitoring tool for validated biomarkers.

Keywords:  Alzheimer’s disease; DNA nanoswitch; DNA nanotechnology; biomarkers; diagnostics; microRNAs; neurological disorders

DOI:  https://doi.org/10.1021/acssensors.1c01567
Langmuir. 2021 Sep 10.

Potential Pulse-Facilitated Active Adsorption of Lubricin Polymer Brushes Can Both Accelerate Self-Assembly and Control Grafting Density.

Duangruedee Khwannimit, Saimon M Silva, Pauline E Desroches, Anita F Quigley, Robert M I Kapsa, George W Greene, Simon E Moulton.

Self-assembled lubricin (LUB) monolayers are an effective antiadhesive coating for biomedical applications. Long deposition times and limited control over the monolayer grafting density remain impediments to commercialization and applications in advanced sensor technologies. This work describes a novel potential pulse-facilitated coating method that reduces coating times to mere seconds while also providing high-level control over the achieved grafting density. This is the first time that the potential pulse-facilitated method is applied for direct assembling of a large and complex polyelectrolyte.

DOI: https://doi.org/10.1021/acs.langmuir.1c02263
Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2022198118. [Epub ahead of print]118(37):

Interaction-based ion selectivity exhibited by self-assembled, cross-linked zwitterionic copolymer membranes.

Samuel J Lounder, Ayse Asatekin.

  Water filtration membranes with advanced ion selectivity are urgently needed for resource recovery and the production of clean drinking water. This work investigates the separation capabilities of cross-linked zwitterionic copolymer membranes, a self-assembled membrane system featuring subnanometer zwitterionic nanochannels. We demonstrate that selective zwitterion-anion interactions simultaneously control salt partitioning and diffusivity, with the permeabilities of NaClO4, NaI, NaBr, NaCl, NaF, and Na2SO4 spanning roughly three orders of magnitude over a wide range of feed concentrations. We model salt flux using a one-dimensional transport model based on the Maxwell-Stefan equations and show that diffusion is the dominant mode of transport for 1:1 sodium salts. Differences in zwitterion-Cl- and zwitterion-F- interactions granted these membranes with the ultrahigh Cl-/F- permselectivity (P Cl- /P F- = 24), enabling high fluoride retention and high chloride passage even from saline mixtures of NaCl and NaF.

Keywords:  biomimetic; ion separation; membranes; self-assembly; synthetic ion channel

DOI:  https://doi.org/10.1073/pnas.2022198118
Mol Pharm. 2021 Sep 08.

On-Demand Drug Release from Click-Refillable Drug Depots.

Sandeep Palvai, Christopher T Moody, Sharda Pandit, Yevgeny Brudno.

  Stimuli-responsive, on-demand release of drugs from drug-eluting depots could transform the treatment of many local diseases, providing intricate control over local dosing. However, conventional on-demand drug release approaches rely on locally implanted drug depots, which become spent over time and cannot be refilled or reused without invasive procedures. New strategies to noninvasively refill drug-eluting depots followed by on-demand release could transform clinical therapy. Here we report an on-demand drug delivery paradigm that combines bioorthogonal click chemistry to locally enrich protodrugs at a prelabeled site and light-triggered drug release at the target tissue. This approach begins with introduction of the targetable depot through local injection of chemically reactive azide groups that anchor to the extracellular matrix. The anchored azide groups then capture blood-circulating protodrugs through bioorthogonal click chemistry. After local capture and retention, active drugs can be released through external light irradiation. In this report, a photoresponsive protodrug was constructed consisting of the chemotherapeutic doxorubicin (Dox), conjugated to dibenzocyclooctyne (DBCO) through a photocleavable ortho-nitrobenzyl linker. The protodrug exhibited excellent on-demand light-triggered Dox release properties and light-mediated in vitro cytotoxicity in U87 glioblastoma cell lines. Furthermore, in a live animal setting, azide depots formed in mice through intradermal injection of activated azide-NHS esters. After i.v. administration, the protodrug was captured by the azide depots with intricate local specificity, which could be increased with multiple refills. Finally, doxorubicin could be released from the depot upon light irradiation. Multiple rounds of depot refilling and light-mediated release of active drug were accomplished, indicating that this system has the potential for multiple rounds of treatment. Taken together, these in vitro and in vivo proof of concept studies establish a novel method for in vivo targeting and on-demand delivery of cytotoxic drugs at target tissues.

Keywords:  bioorthogonal; click chemistry; drug delivery; photocleavage; stimuli-responsive

DOI:  https://doi.org/10.1021/acs.molpharmaceut.1c00535
Nature. 2021 Sep 08.

Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis.

Roarke A Kamber, Yoko Nishiga, Bhek Morton, Allison M Banuelos, Amira A Barkal, Felipe Vences-Catalán, Mingxin Gu, Daniel Fernandez, Jose A Seoane, David Yao, Katherine Liu, Sijie Lin, Kaitlyn Spees, Christina Curtis, Livnat Jerby-Arnon, Irving L Weissman, Julien Sage, Michael C Bassik.

Monoclonal antibody therapies targeting tumour antigens drive cancer cell elimination in large part by triggering macrophage phagocytosis of cancer cells1-7. However, cancer cells evade phagocytosis using mechanisms that are incompletely understood. Here we develop a platform for unbiased identification of factors that impede antibody-dependent cellular phagocytosis (ADCP) using complementary genome-wide CRISPR knockout and overexpression screens in both cancer cells and macrophages. In cancer cells, beyond known factors such as CD47, we identify many regulators of susceptibility to ADCP, including the poorly characterized enzyme adipocyte plasma membrane-associated protein (APMAP). We find that loss of APMAP synergizes with tumour antigen-targeting monoclonal antibodies and/or CD47-blocking monoclonal antibodies to drive markedly increased phagocytosis across a wide range of cancer cell types, including those that are otherwise resistant to ADCP. Additionally, we show that APMAP loss synergizes with several different tumour-targeting monoclonal antibodies to inhibit tumour growth in mice. Using genome-wide counterscreens in macrophages, we find that the G-protein-coupled receptor GPR84 mediates enhanced phagocytosis of APMAP-deficient cancer cells. This work reveals a cancer-intrinsic regulator of susceptibility to antibody-driven phagocytosis and, more broadly, expands our knowledge of the mechanisms governing cancer resistance to macrophage phagocytosis.

DOI: https://doi.org/10.1038/s41586-021-03879-4
J Am Chem Soc. 2021 Sep 09.

Ligand-Sensitized Near-Infrared to Visible Linear Light Upconversion in a Discrete Molecular Erbium Complex.

Bahman Golesorkhi, Soroush Naseri, Laure Guénée, Inès Taarit, Filipe Alves, Homayoun Nozary, Claude Piguet.

While the low-absorption cross section of lanthanide-based upconversion systems, in which the trivalent lanthanides (Ln3+) are responsible for converting low- to high-energy photons, has restricted their application to intense incident light, the emergence of a cascade sensitization through an organic dye antenna capable of broadly harvesting near-infrared (NIR) light in upconversion nanoparticles opened new horizons in the field. With the aim of pushing molecular upconversion within the range of practical applications, we show herein how the incorporation of an NIR organic dye antenna into the ligand scaffold of a mononuclear erbium coordination complex boosts the upconversion brightness of the molecule to such an extent that a low-power (0.7 W·cm-2) NIR laser excitation of [L6Er(hfa)3]+ (hfa = hexafluoroacetylacetonate) at 801 nm results in a measurable visible upconverted signal in a dilute solution (5 × 10-4 M) at room temperature. Connecting the NIR dye antenna to the Er3+ activator in a single discrete molecule cures the inherent low-efficient metal-based excited-state absorption mechanism with a powerful indirect sensitization via an energy transfer upconversion, which drastically improves the molecular-based upconverted Er3+-centered visible emission.

DOI: https://doi.org/10.1021/jacs.1c06865
Adv Healthc Mater. 2021 Sep 08. e2101063

Boosting Photothermal Theranostics via TICT and Molecular Motions for Photohyperthermia Therapy of Muscle-Invasive Bladder Cancer.

Sheng Zeng, Heqi Gao, Chuang Li, Shaoqiang Xing, Zhaoliang Xu, Qian Liu, Guangxue Feng, Dan Ding.

  The development of photothermal agents with high photothermal conversion efficiency (PCE) can help to reduce drug and laser dosage, but still remains a big challenge. Herein, a novel approach is reported to design photothermal agents with high PCE values by promoting nonradiative heat generation processes through the cooperation of twisted intramolecular charge transfer (TICT) and molecular motions. Within the designed molecule 2DMTT-BBTD, the tetraphenylethenes act as molecular rotors, the long alkyl chain grafted thiophene helps to twist the molecular geometry to facilitate TICT state formation and preserve molecular motions in aggregate, while the strong electron-withdrawing BBTD unit enhances TICT effect. 2DMTT-BBTD exhibits NIR-absorption and a high PCE value of 74.8% under 808 nm laser irradiation. Gambogic acid (GA) which surmounts tumor cell thermotolerance by inhibiting heat shock protein 90 (HSP90) expression is coloaded into the nanoparticles, RGD peptide is further introduced to the nanoparticle surface to improve tumor accumulation. The resultant nanoparticles facilitate the effective low-temperature hyperthermia therapy of muscle-invasive bladder cancer (MIBC) with minimal damage to surrounding heathy tissues. This work delivers a new design concept for development of highly efficient photothermal agents, which also provides a safer approach for noninvasive treatment of MIBC and other malignant tumors.

Keywords:  bladder cancer; heat shock protein; intramolecular charge transfer; molecular motions; photothermal therapies

DOI:  https://doi.org/10.1002/adhm.202101063
Cancers (Basel). 2021 Aug 24. pii: 4258. [Epub ahead of print]13(17):

A Prehepatectomy Circulating Exosomal microRNA Signature Predicts the Prognosis and Adjuvant Chemotherapeutic Benefits in Colorectal Liver Metastasis.

Yun Wang, Xiuxing Chen, Haocheng Lin, Xiaoqiang Sun, William Pat Fong, Xiaojun Wu, Zhizhong Pan, Yunfei Yuan, Jieying Liang, Deshen Wang, Ziming Du, Baocai Xing, Yuhong Li.

  BACKGROUND: The clinical risk score (CRS) for prediction and treatment decision in colorectal liver metastasis (CRLM) is important, but imprecise. Exosomal miRNAs play critical roles in CRLM-related biological behavior. However, an exosomal miRNA score system for predicting posthepatectomy survival and the adjuvant chemotherapy benefit of CRLM remains elusive.METHODS: miRNA sequencing was used to identify differentially expressed miRNAs, and the LASSO model was used to select miRNAs to construct the intent model. The predictive performance of the model was evaluated by the area under the ROC curve (AUC) in the training, internal validation, and external validation cohorts.
RESULTS: Sixteen differentially expressed exosomal miRNAs were identified, and four miRNAs were selected for model construction. Our model performed well in predicting prognosis with five-year AUCs of 0.70 (95% CI: 0.59-0.81), 0.70 (0.61-0.81), and 0.72 (057-0.86) in the training, internal, and external validation cohorts, respectively. miRNA classifier high-risk patients had better survival benefit from adjuvant chemotherapy regardless of CRS. All four miRNAs target signaling molecules play crucial roles in colorectal cancer metastasis, vesicle-related processing, and T cell activation. It also negatively correlated with the liver metastasis Immunoscore.
CONCLUSION: We developed a circulating exosomal miRNA signature that can predict the prognosis and guide adjuvant chemotherapy decisions after hepatectomy in CRLM.

Keywords:  colorectal cancer; exosomal miRNA; hepatectomy; liver metastasis; prognosis

DOI:  https://doi.org/10.3390/cancers13174258