[Development of a nanomachine for efficient drug delivery to the brain].

Recently, bottom-up technologies, in particular the utilization of self-assembly of functional polymers to form nanostructures in solutions have been collecting attention. These technologies are being explored for various applications, especially for usage in therapeutics. One of the goals of such studies is to develop a drug delivery system (DDS) that delivers bioactive substances to specific targets within our body, eliciting the desired functionality.

Triphenylphosphonium-modified catiomers enhance mRNA delivery through stabilized polyion complexation.

Nanocarriers based on cationic materials play a central role in the success of mRNA-based therapies. Traditionally, amine-bearing lipids and polymers have been successfully employed for creating mRNA-loaded nanocarriers, though they still present challenges, such as physical and biological instability, limiting both delivery efficiency and therapeutic potential. Non-amine cations could be a promising avenue in addressing these limitations.

Folic acid-mediated enhancement of the diagnostic potential of luminescent europium-doped hydroxyapatite nanocrystals for cancer biomaging.

Early and accurate cancer diagnosis is crucial for improving patient survival rates. Luminescent nanoparticles have emerged as a promising tool in fluorescence bioimaging for cancer diagnosis. To enhance diagnostic accuracy, ligands promoting endocytosis into cancer cells are commonly incorporated onto nanoparticle surfaces.

Site preference and local structural stability of Bi(III) substitution in hydroxyapatite using first-principles simulations.

Bismuth (Bi(III)) substitution in hydroxyapatite (HAp) lattice confers unique properties such as antibacterial, catalytic, radiosensitization, and conductive properties while preserving the innate bioactivity. Understanding the local structural changes upon Bi substitution is essential for controlling the stability and optimizing the properties of HAp. Despite numerous experimental studies, the precise substitution behaviors, such as site preference and structural stability, remain incompletely understood.

Multi-Armed Star-Shaped Block Copolymers of Poly(ethylene glycol)-Poly(furfuryl glycidol) as Long Circulating Nanocarriers.

Multi-arm star-shaped block copolymers with precisely tuned nano-architectures are promising candidates for drug delivery. Herein, we developed 4- and 6-arm star-shaped block copolymers consisting of poly(furfuryl glycidol) (PFG) as the core-forming segments and biocompatible poly(ethylene glycol) (PEG) as the shell-forming blocks. The polymerization degree of each block was controlled by adjusting the feeding ratio of a furfuryl glycidyl ether and ethylene oxide.

Adsorption of l-buthionine sulfoximine on Bi(III) and Eu(III) co-substituted hydroxyapatite nanocrystals for enhancing radiosensitization effects.

Cancer theranostics combines therapeutic and diagnostic capabilities into a single system to treat cancer efficiently. Biocompatible nanomaterials can be engineered to exhibit cancer theranostic functions, for instance radiosensitization and photoluminescence. In this study, trivalent Bi and Eu ions were co-substituted into the lattice of hydroxyapatite (Bi(III):Eu(III) HAp) to develop a cancer theranostic nanocrystal.

Ligand Installation to Polymeric Micelles for Pediatric Brain Tumor Targeting.

Medulloblastoma is a life-threatening disease with poor therapeutic outcomes. In chemotherapy, low drug accumulation has been a cause of these outcomes. Such inadequate response to treatments has been associated with low drug accumulation, particularly with a limited cellular uptake of drugs.

Increased Enzyme Loading in PICsomes via Controlling Membrane Permeability Improves Enzyme Prodrug Cancer Therapy Outcome.

Mesoscopic-sized polyion complex vesicles (PICsomes) with semi-permeable membranes are promising nanoreactors for enzyme prodrug therapy (EPT), mainly due to their ability to accommodate enzymes in their inner cavity. Increased loading efficacy and retained activity of enzymes in PICsomes are crucial for their practical application. Herein, a novel preparation method for enzyme-loaded PICsomes, the stepwise crosslinking (SWCL) method, was developed to achieve both high feed-to-loading enzyme efficiency and high enzymatic activity under in vivo conditions.

Endocytosis-Like Vesicle Fission Mediated by a Membrane-Expanding Molecular Machine Enables Virus Encapsulation for In Vivo Delivery.

Biological membranes are functionalized by membrane-associated protein machinery. Membrane-associated transport processes, such as endocytosis, represent a fundamental and universal function mediated by membrane-deforming protein machines, by which small biomolecules and even micrometer-size substances can be transported via encapsulation into membrane vesicles. Although synthetic molecules that induce dynamic membrane deformation have been reported, a molecular approach enabling membrane transport in which membrane deformation is coupled with substance binding and transport remains critically lacking.

Peripheral administration of nanomicelle-encapsulated anti-Aβ oligomer fragment antibody reduces various toxic Aβ species in the brain.

Background: Although a large amount of evidence has revealed that amyloid β (Aβ), especially Aβ oligomers, protofibrils, and pyroglutamated Aβs, participate primarily in the pathophysiological processes of Alzheimer's disease, most clinical trials of anti-Aβ antibody therapy have never acquired successful efficacy in human clinical trials, partly because peripheral administration of antibody medications was unable to deliver sufficient amounts of the molecules to the brain. Recently, we developed polymeric nanomicelles capable of passing through the blood-brain barrier that function as chaperones to deliver larger amounts of heavy molecules to the brain. Herein, we aimed to evaluate the efficacy of newly developed antibody 6H4 fragments specific to Aβ oligomers encapsulated in polymeric nanomicelles on the development of Alzheimer's disease pathology in Alzheimer's disease model mice at the age of emergence of early Alzheimer's disease pathology.

Effect of PEGylation on the Drug Release Performance and Hemocompatibility of Photoresponsive Drug-Loading Platform.

Coronary stenosis has been one of the most common heart diseases that drastically increases the risk of fatal disorders such as heart attack. Angioplasty using drug coated balloons (DCB) has been one of the most safe and promising treatments. To minimize the risk of thrombosis of such DCBs during intervention, a different approach that can secure high hemocompatibility under blood flow is necessary.

Stabilization of bicelles using metal-binding peptide for extended blood circulation.

A metal-binding peptide appending cholic acid, Chol-MBP, formed bicelles by mixing with 1,2-dipalmitoyl--3-phosphorylcholine (DPPC). Coordination of Chol-MBP with Cu stabilized DPPC bicelles against dilution and contamination of serum proteins, enabling extended blood circulation. This study demonstrates an effective supramolecular design of phospholipid bicelles with enhanced stability useful for membrane-based biomaterials.

Conjugation of glucosylated polymer chains to checkpoint blockade antibodies augments their efficacy and specificity for glioblastoma.

Because of the blood-tumour barrier and cross-reactivity with healthy tissues, immune checkpoint blockade therapy against glioblastoma has inadequate efficacy and is associated with a high risk of immune-related adverse events. Here we show that anti-programmed death-ligand 1 antibodies conjugated with multiple poly(ethylene glycol) (PEG) chains functionalized to target glucose transporter 1 (which is overexpressed in brain capillaries) and detaching in the reductive tumour microenvironment augment the potency and safety of checkpoint blockade therapy against glioblastoma. In mice bearing orthotopic glioblastoma tumours, a single dose of glucosylated and multi-PEGylated antibodies reinvigorated antitumour immune responses, induced immunological memory that protected the animals against rechallenge with tumour cells, and suppressed autoimmune responses in the animals' healthy tissues.

Enzymatically Transformable Polymersome-Based Nanotherapeutics to Eliminate Minimal Relapsable Cancer.

Prevention of metastatic and local-regional recurrence of cancer after surgery remains difficult. Targeting postsurgical premetastatic niche and microresiduals presents an excellent prospective opportunity but is often challenged by poor therapeutic delivery into minimal residual tumors. Here, an enzymatically transformable polymer-based nanotherapeutic approach is presented that exploits matrix metalloproteinase (MMP) overactivation in tumor-associated tissues to guide the codelivery of colchicine (microtubule-disrupting and anti-inflammatory agent) and marimastat (MMP inhibitor).

Vascular Bursts Act as a Versatile Tumor Vessel Permeation Route for Blood-Borne Particles and Cells.

Dynamic bursting in tumor vasculature has recently sparked interest as a novel particle transportation route for drug delivery. These bursts facilitate the transport of sub-100 nm nanoparticles into tumors, though their contribution on the access of other blood-borne particles remains unknown. To evaluate the versatility of this phenomenon, the in vivo kinetics of a variety of intravenously injected particles and their penetration in tumor xenografts and allografts are compared.

Phosphorylcholine-Installed Nanocarriers Target Pancreatic Cancer Cells through the Phospholipid Transfer Protein.

Phosphorylcholine (PC) has been used to improve the water solubility and biocompatibility of biomaterials. Here, we show that PC can also work as a ligand for targeting cancer cells based on their increased phospholipid metabolism. PC-installed multiarm poly(ethylene glycol)s and polymeric micelles achieved high and rapid internalization in pancreatic cancer cells.

Effect of Mixing Ratio of Oppositely Charged Block Copolymers on Polyion Complex Micelles for In Vivo Application.

Self-assembled supramolecular structures based on polyion complex (PIC) formation between oppositely charged polymers are attracting much attention for developing drug delivery systems able to endure harsh in vivo environments. As controlling polymer complexation provides an opportunity for engineering the assemblies, an improved understanding of the PIC formation will allow constructing assemblies with enhanced structural and functional capabilities. Here, we focused on the influence of the mixing charge ratio between block aniomers and catiomers on the physicochemical characteristics and in vivo biological performance of the resulting PIC micelles (PIC/m).

Blood-brain barrier-penetrating siRNA nanomedicine for Alzheimer's disease therapy.

Toxic aggregated amyloid-β accumulation is a key pathogenic event in Alzheimer's disease (AD), which derives from amyloid precursor protein (APP) through sequential cleavage by BACE1 (β-site APP cleavage enzyme 1) and γ-secretase. Small interfering RNAs (siRNAs) show great promise for AD therapy by specific silencing of BACE1. However, lack of effective siRNA brain delivery approaches limits this strategy.

Noncovalent Stabilization of Vesicular Polyion Complexes with Chemically Modified/Single-Stranded Oligonucleotides and PEG--guanidinylated Polypeptides for Intracavity Encapsulation of Effector Enzymes Aimed at Cooperative Gene Knockdown.

For the simultaneous delivery of antisense oligonucleotides and their effector enzymes into cells, nanosized vesicular polyion complexes (PICs) were fabricated from oppositely charged polyion pairs of oligonucleotides and poly(ethylene glycol) (PEG)--polypeptides. First, the polyion component structures were carefully designed to facilitate a multimolecular (or secondary) association of unit PICs for noncovalent (or chemical cross-linking-free) stabilization of vesicular PICs. Chemically modified, single-stranded oligonucleotides (SSOs) dramatically stabilized the multimolecular associates under physiological conditions, compared to control SSOs without chemical modifications and duplex oligonucleotides.

Targeting nanoparticles to the brain by exploiting the blood-brain barrier impermeability to selectively label the brain endothelium.

Current strategies to direct therapy-loaded nanoparticles to the brain rely on functionalizing nanoparticles with ligands which bind target proteins associated with the blood-brain barrier (BBB). However, such strategies have significant brain-specificity limitations, as target proteins are not exclusively expressed at the brain microvasculature. Therefore, novel strategies which exploit alternative characteristics of the BBB are required to overcome nonspecific nanoparticle targeting to the periphery, thereby increasing drug efficacy and reducing detrimental peripheral side effects.

Dual-Sensitive Nanomicelles Enhancing Systemic Delivery of Therapeutically Active Antibodies Specifically into the Brain.

Delivering therapeutic antibodies into the brain across the blood-brain barrier at a therapeutic level is a promising while challenging approach in the treatment of neurological disorders. Here, we present a polymeric nanomicelle (PM) system capable of delivering therapeutically effective levels of 3D6 antibody fragments (3D6-Fab) into the brain parenchyma for inhibiting Aβ aggregation. PM assembly was achieved by charge-converting 3D6-Fab through pH-sensitive citraconylation to allow complexation with reductive-sensitive cationic polymers.

Self-Boosting Catalytic Nanoreactors Integrated with Triggerable Crosslinking Membrane Networks for Initiation of Immunogenic Cell Death by Pyroptosis.

Synthetic polymer vesicles spur novel strategies for producing intelligent nanodevices with precise and specific functions. Engineering vesicular nanodevices with tunable permeability by a general platform without involving trade-offs between structural integrity, flexibility, and functionality remains challenging. Herein, we present a general strategy to construct responsive nanoreactors based on polyion complex vesicles by integrating stimuli-responsive linkers into a crosslinking membrane network.

Relationship between Bulk Physicochemical Properties and Surface Wettability of Hydrogels with Homogeneous Network Structure.

Controlling hydrogel surface wettability is of great importance in the viewpoint of engineering biomaterials that are in contact with cells and tissues. However, studies reporting how the hydrogel bulk properties would affect the surface is scarce, and thus it has been difficult to fabricate hydrogels with the desired properties. Also, there has been no effective method to elucidate this, due to the inhomogeneity introduced in the network structure of conventional hydrogels.

Systemic Brain Delivery of Antisense Oligonucleotides across the Blood-Brain Barrier with a Glucose-Coated Polymeric Nanocarrier.

Current antisense oligonucleotide (ASO) therapies for the treatment of central nervous system (CNS) disorders are performed through invasive administration, thereby placing a major burden on patients. To alleviate this burden, we herein report systemic ASO delivery to the brain by crossing the blood-brain barrier using glycemic control as an external trigger. Glucose-coated polymeric nanocarriers, which can be bound by glucose transporter-1 expressed on the brain capillary endothelial cells, are designed for stable encapsulation of ASOs, with a particle size of about 45 nm and an adequate glucose-ligand density.

Apoptotic Cell-Inspired Polymeric Particles for Controlling Microglial Inflammation toward Neurodegenerative Disease Treatment.

Apoptotic cells are known to suppress microglial inflammation in the brain by presenting phosphatidylserine. In this study, we newly designed polymeric particles that expose the anti-inflammatory site of phosphatidylserine to serve as an apoptotic cell-mimetic anti-inflammatory platform. The prepared anti-inflammatory particles showed no cytotoxicity and significantly inhibited the production of the inflammatory cytokine interleukin-6 against lipopolysaccharide stimulation in the microglia cell line MG6.