Polyproline‐Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Abstract Mitochondria play critical roles in regulating cell fate, with dysfunction correlating the development of multiple diseases, emphasizing need for engineered nanomedicines that cross biological barriers. Said often target fluctuating mitochondrial properties and/or present inefficient/insufficient cytosolic delivery (resulting poor overall activity), while many require complex synthetic procedures involving targeting residues (hindering clinical translation). The synthesis/characterization polypeptide‐based penetrating diblock copolymers poly‐L‐ornithine (PLO) and polyproline (PLP) (PLO n ‐PLP m , n:m ratio 1:3) are described as mitochondria‐targeting nanocarriers. Synthesis involves a simple two‐step methodology based on N‐carboxyanhydride ring‐opening polymerization, scale‐up optimization using “design experiments” approach. molecular mechanisms behind targetability therapeutic activity investigated through physical/biological processes themselves or moieties poly‐L‐glutamic (PGA)‐based conjugate. Diblock prompt rapid entry via energy‐independent recognize mitochondria mitochondria‐specific phospholipid cardiolipin (CL). Stimuli‐driven conditions polarization dynamics, which decrease efficacy depending disease type/stage, do not compromise copolymer uptake/targetability. exhibit inherent concentration‐dependent anti‐tumorigenic at level. conjugate possesses improved safety, significant penetration, accumulation recognition. These findings may support efficient safe mitochondrial‐targeting nanomedicines.

Language: Английский

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Nanocarriers for targeted drug delivery in the vascular system: focus on endothelium

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: Oct. 12, 2024

Endothelial cells (ECs) are pivotal in maintaining vascular health, regulating hemodynamics, and modulating inflammatory responses. Nanocarriers hold transformative potential for precise drug delivery within the system, particularly targeting ECs therapeutic purposes. However, complex interactions between nanocarriers present significant challenges development clinical translation of nanotherapeutics. This review assesses recent advancements key strategies employing to ECs. It suggested that through physicochemical design surface modifications, can enhance specificity improve internalization efficiency Additionally, we elaborated on applications specifically designed treatment cardiovascular diseases, cancer metastasis, disorders. Despite these advancements, safety concerns, complexity vivo processes, challenge achieving subcellular remain obstacles effective with nanocarriers. A comprehensive understanding endothelial cell biology its interaction is crucial realizing full targeted systems.

Language: Английский

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Cationic and anionic PLGA-cholesterol hybrid nanoparticles as promising platforms to enhance the trypanocidal efficacy of benznidazole and drug delivery in Trypanosoma cruzi-infected cells

Biomedicine & Pharmacotherapy, Journal Year: 2025, Volume and Issue: 183, P. 117782 - 117782

Published: Jan. 5, 2025

Language: Английский

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Flow Cytometric Evaluation of Mitochondrial Health

Published: Jan. 1, 2025

Language: Английский

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Near Infrared‐Mediated Intracellular NADH Delivery Strengthens Mitochondrial Function and Stability in Muscle Dysfunction Model

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract Mitochondrial transfer emerges as a promising therapy for the restoration of mitochondrial function in damaged cells, mainly due to its limited immunogenicity. However, isolated mitochondria rapidly lose because they produce little energy outside cells. Therefore, this study investigates whether near infrared (NIR)‐mediated nicotinamide adenine dinucleotide (NADH) pre‐treatment enhances and stability mitochondria‐donor cells prior transplantation. Clinical applications NADH, an essential electron donor oxidative phosphorylation process, are restricted cellular uptake NADH. To address this, photo‐mediated method optimizes direct NADH delivery into increases absorption. L6 treated with irradiated NIR enhanced uptake, significantly improving production function. Importantly, improved functional characteristics maintained even after isolation from Primed mitochondria, i.e., those by NIR‐mediated (P‐MT), encapsulated fusogenic liposomes delivered muscle dysfunction. Compared conventional P‐MT promote greater recovery regeneration. These findings suggest that is effective strategy function, has potential lead novel treatments disorders degeneration.

Language: Английский

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Regulation of Mitochondrial Apoptosis via siRNA-Loaded Metallo-Alginate Hydrogels: A Localized and Synergistic Antitumor Therapy

Biomaterials, Journal Year: 2025, Volume and Issue: 318, P. 123164 - 123164

Published: Feb. 3, 2025

Preventing relapse after resection of a primary tumor continues to be an unmet clinical need. Development adjuvant biomaterials with the capacity kill residual cancer cells is importance. Here we developed library metallo-alginate hydrogels containing high concentrations metallic ions such as Ca2+ in combination Zn2+, Li+, or Mg2+ disrupt homeostasis mitochondria by local hyperthermia. To synergistically and suppress growth rechallenged tumors, embedded oncogene-silencing nucleic acids (mTOR siRNA) loaded into polymerc nanoparticles (NPs) composed poly (β-amino esters) hydrogels, targeting that activate multi-drug resistance pathways PI3K/AKT/mTOR. Metabolomic studies showed alterations Warburg effect, mitochondrial transport, TCA cycle, confirming cell damage. In vivo this targeted therapy mice demonstrated sex-dependent effect. Male B16F10-tumor-bearing treated synergistic restrained growth. contrast, no therapeutic effect was observed female counterparts. Our results demonstrate situ-formed NP-loaded can modulate two distinct immune signaling networks are relevant for enhancing death. On basis our findings, emerges promising strategy translation.

Language: Английский

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Multifunctional Polypeptide-Based Nanoconjugates for Targeted Mitochondrial Delivery and Nonviral Gene Therapy

Chemistry of Materials, Journal Year: 2025, Volume and Issue: 37(4), P. 1457 - 1467

Published: Feb. 5, 2025

Despite recent advances in nanomedicine, developing multifunctional nanocarriers capable of targeted subcellular delivery and efficient gene therapy remains a significant challenge. This study reports the design, synthesis, evaluation novel polypeptide-based nanoconjugate that addresses this gap using sequential delivery, combining mitochondrial targeting nonviral therapy. We engineered poly-l-ornithine-based, polyethylene glycol-modified carrier introduced custom-designed trivalent compound (TRV3) into structure. TRV3, conjugated to polypeptide via redox-sensitive disulfide linker, incorporates well-described triphenylphosphonium moiety (TPP) for Cy5 fluorophore as model drug. The resulting (C-TRV3-A) demonstrated endosomal escape localization. Leveraging endosomolytic properties C-TRV3-A, we explored its potential vector After optimizing formulation stability VLC-3 anionic coating, developed plasmid DNA polyplexes exhibited enhanced transfection efficiency basic advanced triple-negative breast cancer cell culture models. represents advance field, offering chemically versatile platform simultaneous may be used treatments, among other pathologies.

Language: Английский

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Safety of nanoparticle therapies during pregnancy: A systematic review and meta-analysis

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: unknown, P. 113655 - 113655

Published: March 1, 2025

Language: Английский

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Introducing TAPY as a Versatile Alternative to TPP for Selective Mitochondrial Targeting in Cancer Cells

Bioconjugate Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

The understanding of diseases such as cancer and Alzheimer's, along with natural aging processes, heavily relies on the study mitochondrial function. Optical techniques like fluorescence imaging microscopy are pivotal for this purpose, enabling precise mapping subcellular structures, including mitochondria. In study, we explored TAPY (triarylpyridinium) cations, a novel family carriers resembling well-known triphenylphosphonium cation (TPP). Six TAPY-bodipy (BDP) dyads were prepared chemically characterized. Confocal Laser Scanning Microscopy (CLSM) studies demonstrated that systems delivered selectively to mitochondria cells (MCF-7, A549, HT-29). Remarkably, these did not target normal (HEK-293, HMEC-1), suggesting their potential use in distinguishing cancerous from healthy ones. A model compound comprised same bodipy cargo but attached TPP was also synthesized tested. Notably, preliminary comparative assays MCF-7 cells, dyad TAPY(OMe)-BDP outperformed derivative imaging, achieving twice final intensity. chemical diversity achievable cations is considerable, many derivatives being accessible starting readily available commercial products. This implies that, based strategy outlined carefully optimized targeted delivery could potentially be developed future alternatives or complements TPP, present work acting proof concept.

Language: Английский

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Pioneering Advances and Innovative Applications of Mesoporous Carriers for Mitochondria-Targeted Therapeutics

British Journal of Biomedical Science, Journal Year: 2024, Volume and Issue: 81

Published: Nov. 18, 2024

Mitochondria, known as the cell’s powerhouse, play a critical role in energy production, cellular maintenance, and stemness regulation non-cancerous cells. Despite their importance, using drug delivery systems to target mitochondria presents significant challenges due several barriers, including uptake limitations, enzymatic degradation, mitochondrial membranes themselves. Additionally, barriers organs be targetted, along with extracellular formed by physiological processes such reticuloendothelial system, contribute rapid elimination of nanoparticles designed for mitochondrial-based delivery. Overcoming these has led development various strategies, molecular targeting cell-penetrating peptides, genomic editing, nanoparticle-based systems, porous carriers, liposomes, micelles, Mito-Porters. Porous carriers stand out particularly promising candidates large pore size, surface area, ease functionalisation. Depending on they can classified micro-, meso-, or macroporous are either ordered non-ordered based both size uniformity. Several methods employed modifications polyethylene glycol (PEG), incorporation ligands like triphenylphosphonium, capping pores gold chitosan enable controlled triggered Photodynamic therapy is another approach, where drug-loaded generate reactive oxygen species (ROS) enhance targeting. Further advancements have been made form functionalised silica carbon nanoparticles, which demonstrated potential effective mitochondria. This review highlights approaches that utilise specifically focusing silica-based efficient vehicles mitochondria, paving way improved strategies therapies.

Language: Английский

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