Nanosized Traditional Chinese Medicine Technology To Overcome The Blood-Brain Barrier
Overview
This review explores the intersection of traditional Chinese medicine (TCM) and nanotechnology, known as nano-TCM, as a promising avenue for overcoming the challenges posed by the blood-brain barrier (BBB) in treating central nervous system (CNS) diseases. While TCM has demonstrated efficacy in CNS disorders, the BBB limits its effectiveness by hindering drug delivery to the brain. Nano-TCM, leveraging nanotechnology, aims to surmount this barrier by facilitating the targeted delivery of TCM components to specific brain regions.
The review begins by elucidating the physiological and pathological mechanisms of the BBB, highlighting its role as a formidable obstacle to conventional TCM delivery. It then systematically categorizes common TCM remedies employed in CNS disease treatment and delineates various types of nanocarriers utilized for efficient TCM transport across the BBB.
Furthermore, the review explores innovative drug delivery strategies for nano-TCMs, including leveraging in vivo physiological properties and employing in vitro devices to bypass or traverse the BBB. This comprehensive approach aims to enhance the therapeutic efficacy of nano-TCMs in CNS disorders.
The subsequent section delves into the application of nano-TCMs in treating diverse CNS diseases, underscoring their potential in addressing conditions such as neurodegenerative disorders, stroke, and neuroinflammation. By providing insights into the therapeutic landscape, the review underscores the transformative impact of nano-TCMs in CNS disease management.
Lastly, the review anticipates future advancements by proposing design strategies for nano-TCMs aimed at optimizing delivery efficiency. It underscores the potential of nano-TCMs to broaden their application scope, offering promising prospects for treating a wider array of CNS diseases.
In essence, this review serves as a comprehensive roadmap for harnessing the synergistic potential of TCM and nanotechnology to revolutionize CNS disease treatment. By elucidating key mechanisms, discussing innovative delivery strategies, and exploring application prospects, it offers valuable insights into the evolving landscape of nano-TCMs in neuroscience therapeutics.
Introduction
The rising incidence of central nervous system (CNS) disorders, including neurodegenerative diseases like Parkinson’s and Alzheimer’s, underscores the urgent need for effective interventions. Traditional Chinese Medicine (TCM) has a long history of treating CNS ailments, with ancient texts prescribing remedies for conditions such as stroke. While TCM and its active compounds show promise in mitigating CNS damage, their limited ability to penetrate the blood-brain barrier (BBB) impedes their therapeutic efficacy.
The BBB, a critical CNS protective barrier, restricts the passage of substances from the bloodstream to the brain. This selective filtration mechanism poses significant challenges for drug delivery to the CNS, limiting the effectiveness of conventional TCM formulations. However, the emergence of nano-TCM, which harnesses nanotechnology to enhance drug delivery, offers a promising solution.
Nano-TCM involves the preparation of TCM extracts and active ingredients into nanoparticles, approximately 100 nm in size. By encapsulating or modifying TCM compounds onto nanocarriers, nano-TCM enhances solubility, stability, and bioavailability while facilitating BBB penetration. This enables targeted drug delivery to CNS tissues, thereby improving therapeutic outcomes for CNS diseases.
In this comprehensive review, we delve into the physiological and pathological aspects of the BBB, elucidating its significance in shaping nano-TCM delivery strategies. We explore various nanocarriers, their chemical compositions, and structural advantages for crossing the BBB. Additionally, we examine the transport mechanisms of nano-TCMs across the BBB and their applications in treating diverse CNS disorders.
Despite the potential of nano-TCMs, several challenges exist, including optimizing drug formulations, ensuring safety, and addressing regulatory hurdles. Nonetheless, nano-TCMs represent a promising frontier in modernizing TCM and revolutionizing the treatment of CNS diseases. As research in this field progresses, nano-TCMs hold tremendous potential for advancing clinical therapies and improving patient outcomes in the realm of CNS disorders.
Treating CNS diseases with Traditional Chinese Medicine (TCM)
Since 200 AD, Traditional Chinese Medicine (TCM) has been documented in medical cases and ancient texts for treating disorders related to the central nervous system (CNS). Over time, many of these prescriptions and herbal formulations have endured, playing a vital role in clinical healthcare within China and Chinese communities worldwide. Beyond its clinical applications, TCM serves as a significant source for modern drug development. By integrating ancient TCM principles with modern technologies, researchers have identified numerous active compounds from traditional herbs that exhibit neuroprotective properties. These compounds have undergone extensive pharmacological studies to elucidate their mechanisms of action against CNS diseases, leading to their application in clinical treatments.
In the subsequent sections, we highlight several key TCM natural compounds extensively utilized in both clinical practice and scientific research on CNS disorders. This overview encompasses their origins, therapeutic effects, mechanisms of action, and current challenges related to their delivery. Through this exploration, we aim to shed light on the rich heritage of TCM and its invaluable contributions to contemporary neuroscience, offering insights into potential avenues for further research and therapeutic development.
Active TCM Ingredients for CNS Diseases
Curcumin
Curcumin (CUR), derived from plants like turmeric and zedoary, showcases a myriad of pharmacological benefits, ranging from anti-inflammatory to antioxidant properties. Its potential extends to treating CNS-related disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and ischemic stroke.
In combating AD, CUR intervenes at multiple levels. It hampers the production of amyloid-beta (A𝛽), curtails plaque buildup, mitigates A𝛽-induced nerve cell damage, and regulates tau protein phosphorylation. Moreover, CUR’s ability to bind with A𝛽 not only disrupts fibril formation but also aids in detecting plaque deposition due to its fluorescent properties.
For PD, CUR proves beneficial by alleviating motor and behavioral impairments, reducing 𝛼-syn deposition, and preserving dopaminergic neurons. Its antioxidant attributes play a pivotal role in curbing oxidative stress, primarily by neutralizing reactive oxygen species (ROS).
In the realm of ischemic stroke, CUR exhibits anti-inflammatory effects, fosters neuroprotection during cerebral ischemia-reperfusion injury, and regulates apoptosis-related pathways, thereby bolstering cell survival and minimizing brain damage.
Furthermore, CUR demonstrates promising antitumor effects, particularly in glioblastoma (GBM). It inhibits tumor cell migration, proliferation, and survival through various signaling pathways, induces cell cycle arrest, activates autophagy, and promotes apoptosis, collectively impeding tumor growth and reducing the risk of recurrence.
In summary, CUR’s multifaceted mechanisms underscore its potential as a therapeutic agent in combating various diseases, including neurodegenerative disorders, stroke, and cancer. Its diverse pharmacological actions make it a promising candidate for further research and clinical applications in the field of medicine.
Quercetin
Quercetin (QCT), a flavonoid abundantly present in various plants and foods like apples, onions, and tomatoes, possesses a wide array of pharmacological properties. These include anti-allergic, anti-inflammatory, antimicrobial, anticancer, antiviral, antioxidant, and neuroprotective activities. Particularly relevant to neurodegenerative diseases, QCT demonstrates promising potential in combating disorders of the central nervous system (CNS), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and ischemic stroke.
In the context of AD, QCT exerts its beneficial effects through several mechanisms. It inhibits acetylcholinesterase activity, thereby improving cognitive function, and modulates astrocyte activity by regulating the release of neuroinflammatory cytokines. QCT also mitigates oxidative stress by neutralizing reactive oxygen species and activating antioxidant pathways. Additionally, it hampers the progression of AD by inhibiting tau protein phosphorylation and A𝛽 peptide aggregation.
In PD, QCT demonstrates neuroprotective properties by preventing neuronal damage and death through various pathways. It suppresses neural inflammation, enhances antioxidant enzyme levels, modulates dopamine metabolism, and inhibits the fibrillation of 𝛼-synuclein, thus slowing disease progression.
For ischemic stroke treatment, QCT primarily exerts neuroprotective effects by combating inflammation and oxidative stress responses. It regulates cytokine secretion, facilitates the transition of microglial cells to an anti-inflammatory phenotype, and alleviates reperfusion-induced neurotoxicity. QCT also enhances neuronal activity in key brain regions involved in stroke recovery.
In cancer therapy, particularly brain tumors like glioblastoma multiforme (GBM), QCT demonstrates anticancer effects through various mechanisms. It induces apoptosis and autophagy in tumor cells, inhibits cell proliferation, and impedes tumor invasion and metastasis. Moreover, QCT enhances the sensitivity of brain tumor cells to conventional radiotherapy and chemotherapy, offering a potential strategy to combat drug-resistant brain cancer.
Overall, QCT presents a multifaceted approach in the treatment of neurodegenerative diseases and cancer, making it a promising candidate for future therapeutic interventions. Its diverse mechanisms of action underscore its potential as a comprehensive treatment option for various CNS disorders and cancer types.
Resveratrol
Resveratrol (RES), originally discovered in Veratrum grandiflorum, is a compound produced by various plants such as grapes, Japanese knotweed, cassia, blueberries, and peanuts. It belongs to the category of non-flavonoid polyphenol compounds and is characterized by its chemical formula C14H12O3. RES exhibits a wide range of pharmacological activities beneficial to health, including anti-inflammatory, antioxidant, anticancer, cardiovascular, and neuroprotective effects.
In the context of Alzheimer’s disease (AD), RES demonstrates neuroprotective effects through several mechanisms. As a SIRT1 activator, RES mitigates the impact of microglia-dependent A𝛽 toxicity on neurons by inhibiting the NF-𝜅B signaling pathway. Additionally, RES reduces the generation of reactive oxygen species (ROS) through antioxidant mechanisms, repairs mitochondrial dysfunction, and prevents nerve cells from taking up extracellular tau oligomers, thus improving cognitive impairments.
In the prevention and treatment of Parkinson’s disease (PD), RES plays a crucial role in neuroprotection by activating the Nuclear factor erythroid2-related factor 2 (Nrf2) signaling pathway and counteracting oxidative stress. It also decelerates neuroblast apoptosis, mitigates motor dysfunction induced by 6-hydroxydopamine in PD rats, and demonstrates anti-inflammatory properties, contributing to the amelioration of motor and cognitive dysfunctions.
Furthermore, RES exhibits protective activity against ischemic stroke by reducing inflammation, enhancing the survival of hypoxic neurons, and mitigating inflammation and oxidative stress levels. Its neuroprotective effects are mediated through the upregulation of the Nrf2/Heme Oxygenase-1 (HO-1) signaling pathway.
In terms of its anticancer properties, RES induces intrinsic apoptosis and autophagy in neuroblastoma cells, inhibits the proliferation and invasion of tumor cells in glioblastoma (GBM), and serves as a sensitizer to address chemotherapy resistance in GBM by enhancing chemosensitivity to temozolomide and doxorubicin.
Overall, RES emerges as a promising compound with diverse therapeutic potential, particularly in the realms of neuroprotection, cancer treatment, and cardiovascular health. Further research is warranted to explore its clinical applications and optimize its therapeutic efficacy.
Paclitaxel
Paclitaxel (PTXL), with the chemical formula C47H51NO14, originates from the bark of Taxus brevifolia and is characterized by a complex chemical structure. Its primary anticancer activity stems from specific structural elements, including the A-ring, C2 benzoyl group, C13 side chain, and oxygen-substituted ring, within its highly oxygenated tetracyclic framework.
Functioning as a crucial natural anticancer agent, PTXL stabilizes microtubule polymers by binding to 𝛽-tubulin, disrupting the mitotic process in the G2/M phase of cells. This disruption impedes tumor cell division and proliferation, ultimately leading to cancer cell death. Additionally, PTXL exhibits diverse anticancer effects by inducing autophagy, promoting cell apoptosis, and inhibiting tumor angiogenesis.
As a frontline treatment for cancer, PTXL is frequently combined with other anticancer drugs, particularly in treating brain cancer. Conjugating PTXL with linoleic acid enhances its cellular absorption and efficacy against gliomas. Polymeric nanomedicines loaded with PTXL and doxorubicin inhibit glioblastoma multiforme (GBM) growth and improve motor function in experimental models. Furthermore, combining PTXL with temozolomide enhances its antitumor efficacy against GBMs by modulating the Wnt/𝛽-Catenin signaling pathway.
In summary, PTXL stands as a pivotal anticancer agent, exerting its effects through microtubule stabilization and multiple mechanisms of action. Its versatility in combination therapies underscores its significance in combating various cancers, including brain tumors like GBMs.
Limitations of TCM for Treatment of CNS Diseases
Traditional Chinese Medicine (TCM) has long been esteemed for its efficacy in treating central nervous system (CNS) diseases, a legacy that persists from ancient times to the present. Despite its historical success, modern advancements have highlighted challenges associated with traditional formulations, particularly in terms of preparation, administration, and stability. The intricate composition and unclear mechanisms of action of traditional Chinese herbal compounds present further hurdles for research.
To address these challenges, contemporary TCM research has shifted focus towards exploring natural active ingredients extracted from various plants or minerals. These natural compounds, including flavonoids, polyphenols, polysaccharides, and alkaloids, hold promise for CNS disease treatment. However, many encounter physicochemical limitations such as poor solubility, bioavailability, and stability, hindering their clinical application.
Nanotechnology emerges as a pivotal solution to maximize the potential of TCM. By leveraging nanotechnology, several advantages are realized, including the diversification of TCM formulations, targeted drug delivery to mitigate side effects, enhancement of therapeutic effects, and improved pharmacokinetics. Additionally, nanotechnology facilitates the solubility and stability of TCM compounds, enhances bioavailability, reduces dosage requirements, and improves blood-brain barrier permeability.
In conclusion, the integration of modern advanced technologies, particularly nanotechnology, holds immense promise for optimizing TCM utilization. By overcoming existing challenges and revolutionizing administration and delivery methods, nanotechnology ensures the effective and efficient utilization of TCM resources, thus contributing to the advancement of CNS disease treatment.
Nanocarriers of Nano-TCM
The preparation of nano-TCM involves two primary approaches: nanosizing the active ingredients of traditional Chinese medicine (TCM) and combining these ingredients with nanocarriers. Nanosizing enhances the surface area of TCM particles, improving dissolution rates and overall efficacy. However, the combination with nanocarriers, a more common strategy, offers superior bioavailability and targeting. Nanocarriers, ranging from 1 to 100 nm, modulate drug characteristics and enhance delivery. They can be categorized into inorganic, organic, and hybrid types, each offering unique advantages.
Various mechanisms facilitate the transport of nano-TCMs across the blood-brain barrier (BBB) for CNS disease treatment. Passive targeting allows substances to diffuse through the BBB, while active targeting involves carrier-mediated or receptor-mediated transport. Nano-TCMs can also bypass the BBB through nasal delivery. Moreover, nanotechnology enhances BBB permeability via physical devices like magnetic fields, photothermal effects, and focused ultrasound.
Innovative preparation methods, including high-pressure microfluidization and spray drying, facilitate the reformulation of TCM into nano-scale formulations, improving their efficacy in targeting CNS cells and tissues. These advancements hold promise for the development of highly effective treatments for CNS diseases.
Conclusion
Traditional Chinese Medicine (TCM) faces a significant obstacle in effectively treating central nervous system (CNS) diseases due to the blood-brain barrier (BBB) permeability challenge. However, the emergence of nano-TCM has led to the development of novel and more efficient brain-targeted drug delivery systems. Nano-sized or modified TCM compounds typically rely on specific properties, physical structures, and functional modifications of nanocarriers to facilitate BBB traversal. Yet, ensuring the safety of the nano-TCM preparation process remains a concern, along with understanding the targets of action and related pharmacological mechanisms.
To address biosafety concerns, efforts are focused on improving the stability and safety of artificially prepared nanocarriers. Biomimetic nanomaterials, utilizing endogenous substances in the human body as carriers, are being explored to enhance biocompatibility and safety. Additionally, advancing the engineering of precision nanoparticles with meticulously tailored surfaces and structural heterogeneity can enhance targeting efficacy, biosafety, and therapeutic attributes of nanomedicine.
From a pathomechanistic perspective, research is directed towards developing new biomimetic nanomaterials for targeted drug delivery to the brain. For instance, conditions like rabies and melanoma, prone to brain metastasis, have shown BBB permeability with associated viral proteins or secreted exosomes. Utilizing “Trojan horse” approaches by encapsulating TCM within biomimetic nanomaterials is being considered.
Addressing performance concerns involves leveraging the unique characteristics of TCMs for specific CNS diseases. Aromatic TCMs that enhance BBB permeability, such as borneol, musk, and mint, may be beneficial for conditions like glioma, Alzheimer’s disease (AD), and Parkinson’s disease (PD). Conversely, conditions with compromised BBB, like heat stroke, require TCMs to diminish permeability and repair damage effectively.
While certain TCMs, like ruscogenin, schisandrin A, and ginsenoside Rb1, have shown promise in ameliorating BBB dysfunction, their incorporation into nanotechnology remains limited. Future exploration aims to comprehensively investigate the potential of TCMs for CNS diseases by enhancing their drug load and bioavailability using suitable nanocarriers.
In conclusion, nanotechnology offers improved prospects for the development and application of TCM treatments for CNS damage-related diseases. With ongoing advancements in nanotechnology and research breakthroughs, nano-TCM holds promise in unlocking more effective therapeutic avenues for CNS damage-related diseases in the future.
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