Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(18), P. 13152 - 13173

Published: Sept. 10, 2021

In the development of central nervous system (CNS) drugs, blood–brain barrier (BBB) restricts many drugs from entering brain to exert therapeutic effects. Although novel delivery methods large molecule have been designed assist transport, small account for vast majority CNS used clinically. From this perspective, we review studies past five years that sought modify molecules increase exposure. Medicinal chemists make it easier cross BBB by improving diffusion, reducing efflux, and activating carrier transporters. On basis their excellent work, summarize strategies structural modification improve penetration. These are expected provide a reference future drugs.

Language: Английский

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Blood-brain barrier–penetrating single CRISPR-Cas9 nanocapsules for effective and safe glioblastoma gene therapy

Science Advances, Journal Year: 2022, Volume and Issue: 8(16)

Published: April 20, 2022

We designed a unique nanocapsule for efficient single CRISPR-Cas9 capsuling, noninvasive brain delivery and tumor cell targeting, demonstrating an effective safe strategy glioblastoma gene therapy. Our nanocapsules can be simply fabricated by encapsulating the Cas9/sgRNA complex within glutathione-sensitive polymer shell incorporating dual-action ligand that facilitates BBB penetration, selective release. evidenced promising tissue targeting led to high PLK1 editing efficiency in (up 38.1%) with negligible (less than 0.5%) off-target high-risk tissues. Treatment extended median survival time (68 days versus 24 nonfunctional sgRNA-treated mice). new system thus addresses various challenges demonstrate tumor-specific of Cas9 ribonucleoprotein improved treatment may potentially therapeutically useful other diseases.

Language: Английский

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Immune Exosomes Loading Self-Assembled Nanomicelles Traverse the Blood–Brain Barrier for Chemo-immunotherapy against Glioblastoma

ACS Nano, Journal Year: 2023, Volume and Issue: 17(2), P. 1464 - 1484

Published: Jan. 10, 2023

Effective drug delivery and prevention of postoperative recurrence are significant challenges for current glioblastoma (GBM) treatment. Poor is mainly due to the presence blood–brain barrier (BBB), primarily resistance GBM cells chemotherapeutic drugs an immunosuppressive microenvironment. Herein, a biomimetic nanodrug platform based on endogenous exosomes that could efficiently target brain without targeting modifications co-deliver pure nanomicelles immune adjuvants safe efficient chemo-immunotherapy against prepared. Inspired by self-assembly technology small molecules, tanshinone IIA (TanIIA) glycyrrhizic acid (GL), which inhibitors signal transducers activators transcription 3 from traditional Chinese medicine (TCM), self-assembled form TanIIA-GL (TGM). Endogenous serum selected coat nanomicelles, CpG oligonucleotides, agonists Toll-like receptor 9, anchored exosome membrane obtain loaded with TCM (CpG-EXO/TGM). Our results demonstrate CpG-EXO/TGM can bind free transferrin in blood, prolong blood circulation, maintain intact structures when traversing BBB cells. In microenvironment, strong anti-GBM effect attributed two factors: (i) highly uptake sufficient intracellular release induce apoptosis (ii) stimulation dendritic cell maturation induction tumor-associated macrophages polarization oligonucleotides generate responses. Further research found not only produce better efficacy combination temozolomide but also prevent recurrence.

Language: Английский

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The Bioavailability of Drugs—The Current State of Knowledge

Molecules, Journal Year: 2023, Volume and Issue: 28(24), P. 8038 - 8038

Published: Dec. 11, 2023

Drug bioavailability is a crucial aspect of pharmacology, affecting the effectiveness drug therapy. Understanding how drugs are absorbed, distributed, metabolized, and eliminated in patients' bodies essential to ensure proper safe treatment. This publication aims highlight relevance research its importance In addition biochemical activity, also plays critical role achieving desired therapeutic effects. may seem obvious, but it worth noting that can only produce expected effect if level concentration be achieved at point patient's body. Given differences between patients, dosages, administration forms, understanding controlling has become priority pharmacology. discusses basic concepts factors it. We looked various methods assessing bioavailability, both laboratory clinic. Notably, introduction new technologies tools this field vital achieve advances research. cases with poorly described providing deeper complex challenges they pose medical researchers practitioners. Simultaneously, article focuses on perspectives trends shape future regarding which development modern pharmacology context, offers an essential, meaningful contribution toward highlighting bioavailability's reliable patient The text identifies areas require further exploration.

Language: Английский

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Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: Crossing or circumventing the blood–brain barrier (BBB) to manage neurological disorders

Advanced Drug Delivery Reviews, Journal Year: 2022, Volume and Issue: 189, P. 114485 - 114485

Published: Aug. 12, 2022

Language: Английский

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Intelligent Micro‐/Nanorobots for Cancer Theragnostic

Advanced Materials, Journal Year: 2022, Volume and Issue: 34(52)

Published: April 6, 2022

Cancer is one of the most intractable diseases owing to its high mortality rate and lack effective diagnostic treatment tools. Advancements in micro-/nanorobot (MNR)-assisted sensing, imaging, therapeutics offer unprecedented opportunities develop MNR-based cancer theragnostic platforms. Unlike ordinary nanoparticles, which exhibit Brownian motion biofluids, MNRs overcome viscous resistance an ultralow Reynolds number (Re << 1) environment by self-propulsion. This unique locomotion property has motivated advanced design functionalization as a basis for next-generation cancer-therapy platforms, potential precise distribution improved permeation therapeutic agents. Enhanced barrier penetration, imaging-guided operation, biosensing are additionally studied enable promising cancer-related applications MNRs. Herein, recent advances therapy comprehensively addresses, including actuation engines, diagnostics, medical targeted drug delivery; research that can have profound impact on over next decade highlighted.

Language: Английский

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Functionalized Nanomaterials Capable of Crossing the Blood–Brain Barrier

ACS Nano, Journal Year: 2024, Volume and Issue: 18(3), P. 1820 - 1845

Published: Jan. 9, 2024

The blood–brain barrier (BBB) is a specialized semipermeable structure that highly regulates exchanges between the central nervous system parenchyma and blood vessels. Thus, BBB also prevents passage of various forms therapeutic agents, nanocarriers, their cargos. Recently, many multidisciplinary studies focus on developing cargo-loaded nanoparticles (NPs) to overcome these challenges, which are emerging as safe effective vehicles in neurotheranostics. In this Review, first we introduce anatomical physiological functions BBB. Second, present endogenous exogenous transport mechanisms by NPs cross We report nanomaterials, carriers, cargos, with detailed uptake permeability characteristics. Third, describe effect regulating size, shape, charge, surface ligands affect permeability, can be exploited enhance promote classify typical functionalized nanomaterials developed for crossing. Fourth, provide comprehensive review recent progress functional polymeric applications multimodal bioimaging, therapeutics, drug delivery. Finally, conclude discussing existing directions, future perspectives employing

Language: Английский

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Oxidative stress, the blood–brain barrier and neurodegenerative diseases: The critical beneficial role of dietary antioxidants

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 13(10), P. 3988 - 4024

Published: July 16, 2023

In recent years, growing awareness of the role oxidative stress in brain health has prompted antioxidants, especially dietary to receive attention as possible treatments strategies for patients with neurodegenerative diseases (NDs). The most widely studied antioxidants include active substances such vitamins, carotenoids, flavonoids and polyphenols. Dietary are found usually consumed foods fresh fruits, vegetables, nuts oils gaining popularity due recently their potential preventive protective agents against NDs, well abundant natural sources, generally non-toxic nature, ease long-term consumption. This review article examines development explores ‘two-sidedness’ blood–brain barrier (BBB) a nervous system an impeding use drug medicinal products and/or supplements prevention therapy reviews BBB permeability common suplements efficacy treatment NDs. Finally, current challenges future directions NDs using discussed, useful information on is provided.

Language: Английский

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Mitochondrial-targeted and ROS-responsive nanocarrier via nose-to-brain pathway for ischemic stroke treatment

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 13(12), P. 5107 - 5120

Published: June 20, 2023

Oxidative stress injury and mitochondrial dysfunction are major obstacles to neurological functional recovery after ischemic stroke. The development of new approaches simultaneously diminish oxidative resist is urgently needed. Inspired by the overproduced reactive oxygen species (ROS) at neuron mitochondria, multifunctional nanoparticles with ROS-responsiveness mitochondrial-targeted (SPNPs) were engineered, achieving specific targeting delivery controllable drug release penumbra. Due nose-to-brain pathway, SPNPs which encapsulated in a thermo-sensitive gel intranasal administration directly delivered penumbra bypassing blood‒brain barrier (BBB) enhancing efficiency. potential for stroke treatment was systematically evaluated

Language: Английский

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Biomimetic Nanocomposites Camouflaged with Hybrid Cell Membranes for Accurate Therapy of Early‐Stage Glioma

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(29)

Published: May 18, 2023

Abstract Glioma features high fatality rate and short survival time of patients due to its fast growth speed invasiveness, hence timely treatment early‐stage glioma is extremely important. However, the blood brain barrier (BBB) severely prevents therapeutic agents from entering brain; meanwhile, non‐targeted distribution always causes side effects vulnerable cerebral tissues. Therefore, delivery systems that possess both BBB penetrability precise targeting ability are keenly desired. We herein proposed a hybrid cell membrane (HM) camouflage strategy construct nanocomposites, in which HM consisting metastatic breast cancer was prepared with simple fusion pathway. By coating onto drug‐loaded nanoparticles, as‐obtained biomimetic agent (termed HMGINPs) inherited satisfying homologous simultaneously two source cells. HMGINPs exhibited good biocompatibility superior efficacy towards glioma.

Language: Английский

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