Mitochondria-targeted Drug Delivery Research Articles

Investigation of the Nanoparticulation Method and Cell-Killing Effect following the Mitochondrial Delivery of Hydrophobic Porphyrin-Based Photosensitizers.

Photodynamic therapy is expected to be a less invasive treatment, and strategies for targeting mitochondria, the main sources of singlet oxygen, are attracting attention to increase the efficacy of photodynamic therapy and reduce its side effects. To date, we have succeeded in encapsulating the photosensitizer rTPA into MITO-Porter (MP), a mitochondria-targeted Drug Delivery System (DDS), aimed at mitochondrial delivery of the photosensitizer while maintaining its activity. In this study, we report the results of our studies to alleviate rTPA aggregation in an effort to improve drug efficacy and assess the usefulness of modifying the rTPA side chain to improve the mitochondrial retention of MITO-Porter, which exhibits high therapeutic efficacy. Conventional rTPA with anionic side chains and two rTPA analogs with side chains that were converted to neutral or cationic side chains were encapsulated into MITO-Porter. Low-MP (MITO-Porter with Low Drug/Lipid) exhibited high drug efficacy for all three types of rTPA, and in Low-MP, charged rTPA-encapsulated MP exhibited high drug efficacy. The cellular uptake and mitochondrial translocation capacities were similar for all particles, suggesting that differences in aggregation rates during the incorporation of rTPA into MITO-Porter resulted in differences in drug efficacy.

Activation of Mitochondrial Oxygen Consumption Rate by Delivering Coenzyme Q10 to Mitochondria of Rat Skeletal Muscle Cell (L6)

Numerous mitochondria are present in skeletal muscle cells. Muscle disease and aging impair mitochondrial functioning in the skeletal muscle. However, there have been few reports of therapeutic intervention via drug delivery to mitochondria owing to methodological difficulties. We surmised that mitochondrial activation is associated with improved skeletal muscle function. In this study, we attempted to activate the mitochondrial respiratory capacity in rat skeletal muscle cells (L6 cells) by delivering Coenzyme Q10 (CoQ10), a mitochondrial functional activator, to mitochondria using MITO-Porter, a nanoparticle that facilitates mitochondria-targeted drug delivery. Cellular uptake was confirmed by measuring the amount of fluorescence-modified MITO-Porter taken up by cells using flow cytometry. Intracellular dynamics of MITO-Porter was observed using confocal laser scanning microscopy. Mitochondrial function was assessed by measuring the mitochondrial oxygen consumption rate using an extracellular flux analyzer. The results indicated MITO-Porter-assisted delivery of CoQ10 to the mitochondria activated mitochondrial respiratory capacity in L6 cells. We believe that our results indicate the possibility of skeletal muscle therapy using mitochondrial drug delivery.

Exploiting nuclear-mitochondrial cross-talk in theranostics: Enhancing drug delivery and diagnostic precision

The dynamic interplay between nuclear and mitochondrial processes plays a pivotal role in cellular homeostasis and disease progression. Exploiting this nuclear-mitochondrial cross-talk has emerged as a promising avenue in the field of theranostics, offering enhanced drug delivery and diagnostic precision for a wide range of medical conditions, particularly cancer. This abstract provides a brief overview of the key concepts and recent advancements in this rapidly evolving field. Recent research has elucidated the significance of mitochondrial dysfunction in various diseases, including cancer. Mitochondria, often referred to as the “powerhouses” of the cell, not only regulate energy production but also contribute to critical processes such as apoptosis, ROS generation, and metabolic signaling. Dysregulation of these mitochondrial functions is frequently associated with disease pathogenesis. In theranostics, the targeted modulation of mitochondrial function holds great promise. Mitochondria-targeted drug delivery systems have been designed to selectively deliver therapeutic agents to these organelles, thereby mitigating mitochondrial dysfunction while minimizing off-target effects. This precise drug delivery enhances the therapeutic efficacy of anticancer drugs and reduces the risk of drug resistance. Moreover, the diagnostic potential of nuclear-mitochondrial cross-talk is being harnessed to develop novel biomarkers and imaging techniques. Mitochondrial DNA mutations and alterations in mitochondrial metabolism serve as valuable indicators of disease progression and drug responsiveness. Non-invasive imaging modalities, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), have been employed to visualize mitochondrial activity and assess therapeutic outcomes.

A sojourn on mitochondria targeted drug delivery systems for cancer: Strategies, clinical and future prospects

Mitochondria, often referred to as the powerhouses of the cell, have emerged as promising targets for cancer therapy due to their pivotal roles in cell survival, apoptosis, and energy metabolism. This sojourn emphasizes the significance of mitochondria-targeted drug delivery systems in cancer therapeutics. The unique characteristics of cancer cell mitochondria, such as altered membrane potential and distinct lipid composition, offer an avenue for selective drug targeting. Several strategies have been explored to exploit these features, including the use of lipophilic cations, mitochondria-penetrating peptides, and nanocarriers tailored for mitochondrial delivery. Mitochondria-targeted drug delivery systems have demonstrated enhanced therapeutic efficacy and reduced systemic toxicity in preclinical models. Some of these systems have made a successful transition to clinical trials, illustrating their potential in real-world oncology settings. However, there remain challenges like intracellular barriers, potential off-target effects, and the complexity of tumor heterogeneity that must be addressed to fully harness the potential of mitochondria-targeted drug delivery systems. As research progresses, it is anticipated that innovative approaches and technologies will be developed to improve the specificity and efficacy of mitochondrial targeting, paving the way for more effective and safer cancer treatments in the future. This review serves as a comprehensive guide to the current state of mitochondria-targeted drug delivery systems for cancer, highlighting key strategies, clinical progress, and prospective avenues for future research.

Autonomous metal-organic framework nanorobots for active mitochondria-targeted cancer therapy.

Nanorobotic manipulation to access subcellular organelles remains unmet due to the challenge in achieving intracellular controlled propulsion. Intracellular organelles, such as mitochondria, are an emerging therapeutic target with selective targeting and curative efficacy. We report an autonomous nanorobot capable of active mitochondria-targeted drug delivery, prepared by facilely encapsulating mitochondriotropic doxorubicin-triphenylphosphonium (DOX-TPP) inside zeolitic imidazolate framework-67 (ZIF-67) nanoparticles. The catalytic ZIF-67 body can decompose bioavailable hydrogen peroxide overexpressed inside tumor cells to generate effective intracellular mitochondriotropic movement in the presence of TPP cation. This nanorobot-enhanced targeted drug delivery induces mitochondria-mediated apoptosis and mitochondrial dysregulation to improve the in vitro anticancer effect and suppression of cancer cell metastasis, further verified by in vivo evaluations in the subcutaneous tumor model and orthotopic breast tumor model. This nanorobot unlocks a fresh field of nanorobot operation with intracellular organelle access, thereby introducing the next generation of robotic medical devices with organelle-level resolution for precision therapy.

Enhanced protection against hypoxia/reoxygenation-induced apoptosis in H9c2 cells by puerarin-loaded liposomes modified with matrix metalloproteinases-targeting peptide and triphenylphosphonium

Based on the inhibition of mitochondrial permeability transition pore (mPTP) opening, puerarin (PUE) has a good potential to reduce myocardial ischemia/reperfusion injury (MI/RI). However, the lack of targeting of free PUE makes it difficult to reach the mitochondria. In this paper, we constructed matrix metalloproteinase-targeting peptide (MMP-TP) and triphenylphosphonium (TPP) cation co-modified liposomes loaded with PUE (PUE@T/M-L) for mitochondria-targeted drug delivery. PUE@T/M-L had a favorable particle size of 144.9 ± 0.8 nm, an encapsulation efficiency of 78.9 ± 0.6%, and a sustained-release behavior. The results of cytofluorimetric experiments showed that MMP-TP and TPP double-modified liposomes (T/M-L) enhanced intracellular uptake, escaped lysosomal capture, and promoted drug targeting into mitochondria. In addition, PUE@T/M-L enhanced the viability of hypoxia-reoxygenation (H/R) injured H9c2 cells by inhibiting mPTP opening and reactive oxygen species (ROS) production, reducing Bax expression and increasing Bcl-2 expression. It was inferred that PUE@T/M-L delivered PUE into the mitochondria of H/R injured H9c2 cells, resulting in a significant increase in cellular potency. Based on the ability of MMP-TP to bind the elevated expression of matrix metalloproteinases (MMPs), T/M-L had excellent tropism for Lipopolysaccharide (LPS) -stimulated macrophages and can significantly reduce TNF-α and ROS levels, thus allowing both drug accumulation in ischemic cardiomyocytes and reducing inflammatory stimulation during MI/RI. Fluorescence imaging results of the targeting effect using a DiR probe also indicated that DiR@T/M-L could accumulate and retain in the ischemic myocardium. Taken together, these results demonstrated the promising application of PUE@T/M-L for mitochondria-targeted drug delivery to achieve maximum therapeutic efficacy of PUE.

Mitochondria-Targeted Nanosystem with Reactive Oxygen Species-Controlled Release of CO to Enhance Photodynamic Therapy of PCN-224 by Sensitizing Ferroptosis.

The apoptosis-resistant mechanism of photodynamic therapy (PDT) usually results in limited therapeutic efficacy. The development of new strategies for sensitizing targeted ferroptosis that bypass apoptosis resistance is of great significance to improve the antitumor efficacy of PDT. In this study, a novel amphiphilic copolymer whose main chain contains reactive oxygen species (ROS)-responsive groups and the end of side chains contains triphenylphosphine is synthesized, to encapsulate porphyrinic metal-organic framework PCN-224 via self-assembly which are hydrothermally synthesized by coordination of zirconium (IV) with tetra-kis(4-caboxyphenyl) porphyrin, and loaded carbon monoxide releasing molecule 401 (CORM-401) by their hollow structures (PCN-CORM), and finally, surface-coated with hyaluronic acid. The nanosystem can sequentially localize to mitochondria which is an important target to induce apoptosis and ferroptosis in cancer cells. Upon excitation with near-infrared light, PCN-224 is activated to produce amounts of ROS, and simultaneously triggers the rapid intracellular release of CO. More importantly, the released CO can sensitize ferroptosis and promote apoptosis to significantly enhance the antitumor efficacy of PCN-224 both in vitro and in vivo. These results illustrate that the mitochondria-targeted drug delivery system combined PDT with CO leads to an effective antitumor efficacy, which maybe a promising way to enhance the treatment efficiency of PDT.

Mitochondrial Dysfunction: Pathophysiology and Mitochondria-Targeted Drug Delivery Approaches.

Mitochondria are implicated in a wide range of functions apart from ATP generation, and, therefore, constitute one of the most important organelles of cell. Since healthy mitochondria are essential for proper cellular functioning and survival, mitochondrial dysfunction may lead to various pathologies. Mitochondria are considered a novel and promising therapeutic target for the diagnosis, treatment, and prevention of various human diseases including metabolic disorders, cancer, and neurodegenerative diseases. For mitochondria-targeted therapy, there is a need to develop an effective drug delivery approach, owing to the mitochondrial special bilayer structure through which therapeutic molecules undergo multiple difficulties in reaching the core. In recent years, various nanoformulations have been designed such as polymeric nanoparticles, liposomes, inorganic nanoparticles conjugate with mitochondriotropic moieties such as mitochondria-penetrating peptides (MPPs), triphenylphosphonium (TPP), dequalinium (DQA), and mitochondrial protein import machinery for overcoming barriers involved in targeting mitochondria. The current approaches used for mitochondria-targeted drug delivery have provided promising ways to overcome the challenges associated with targeted-drug delivery. Herein, we review the research from past years to the current scenario that has identified mitochondrial dysfunction as a major contributor to the pathophysiology of various diseases. Furthermore, we discuss the recent advancements in mitochondria-targeted drug delivery strategies for the pathologies associated with mitochondrial dysfunction.

Muscle Delivery of Mitochondria-Targeted Drugs for the Treatment of Sarcopenia: Rationale and Perspectives.

An impairment in mitochondrial homeostasis plays a crucial role in the process of aging and contributes to the incidence of age-related diseases, including sarcopenia, which is defined as an age-dependent loss of muscle mass and strength. Mitochondrial dysfunction exerts a negative impact on several cellular activities, including bioenergetics, metabolism, and apoptosis. In sarcopenia, mitochondria homeostasis is disrupted because of reduced oxidative phosphorylation and ATP generation, the enhanced production of reactive species, and impaired antioxidant defense. This review re-establishes the most recent evidence on mitochondrial defects that are thought to be relevant in the pathogenesis of sarcopenia and that may represent promising therapeutic targets for its prevention/treatment. Furthermore, we describe mechanisms of action and translational potential of promising mitochondria-targeted drug delivery systems, including molecules able to boost the metabolism and bioenergetics, counteract apoptosis, antioxidants to scavenge reactive species and decrease oxidative stress, and target mitophagy. Even though these mitochondria-delivered strategies demonstrate to be promising in preclinical models, their use needs to be promoted for clinical studies. Therefore, there is a compelling demand to further understand the mechanisms modulating mitochondrial homeostasis, to characterize powerful compounds that target muscle mitochondria to prevent sarcopenia in aged people.

Nanofibrillar peptide hydrogels for self-delivery of lonidamine and synergistic photodynamic therapy

The use of lonidamine (LND) in photodynamic therapy (PDT) provides a viable approach to develop low-dose PDT modules with high efficacy, for LND potentiates cytotoxicity of photosensitizers through dysregulation of mitochondrial function. Yet, the efficacy of LND is restricted by its low accumulation in cancer cells, especially in the mitochondrial compartments. To address the problem, we design an LND-derived self-assembling peptide molecule (LND-K) that dually targets integrin receptors and mitochondria of cancer cells. The targeted cellular delivery of LND-K gives higher efficacy in ablation of mitochondrial function in melanoma cells A375, as compared to free LND or the control molecule that lacks mitochondria-targeting moieties. To integrate LND-K in a typical PDT module, we develop a nanofibrillar hydrogel system through co-assembly of LND-K and TPPS4, an anionic photosensitizer that forms tight electrostatic interactions with cationic residues of LND-K. Notably, hydrogel formulation of LND-K/TPPS4 facilitates slow release of TPPS4 over 14 days in vitro, and displays a longer retention time than aqueous solution of TPPS4in vivo. By integrating a mitochondria-targeted molecule (LND-K) in a typical PDT module, we achieve synergistic killing of A375 cells with dual drugs, where LND-K not only serves as a chemotherapeutic drug, but also potentiates the cytotoxicities of TPPS4 toward A375 cells in vitro and in vivo. The peptide-based drug self-delivery system promises the development of efficacious combination treatments against cancer, that integrate cell sensitization with existing anticancer modules (e.g., chemotherapy and PDT) for enhanced therapeutic efficacy. Statement of significanceThis study reports the design and synthesis of a lonidamine (LND)-derived self-assembling peptide (LND-K) that dually targets integrin receptors and mitochondria of cancer cells. Under the precision guidance of a mitochondria-targeting sequence, LND-K-containing nanofibers target mitochondria and ablate mitochondrial functions. On one hand, the targeted delivery of LND-K reduces cell viabilities through a chemotherapy route; on the other hand, LND-K sensitizes cancer cells for subsequent PDT treatment with enhanced efficacy, which is mediated by induction of ROS, loss of mitochondrial membrane potential, and decrease of cellular ATP level. We believe that the design of mitochondria-targeted drug delivery systems with a self-assembling molecule provides a new approach to potentiate cytotoxicity of photosensitizers in a low-dose PDT module.

Mitochondria-targeted and multistage synergistic ROS-elevated drug delivery system based on surface decorated MnO2 with CeO2 for enhanced chemodynamic/chemotherapy

Mitochondria-targeted drug delivery nano-platform for the generation of endogenous reactive oxygen species (ROS) are envisioned as a promising strategy for inducing cytotoxicity and inhibiting tumor growth. However, how to induce excessive ROS in cancer cell remains a challenge. Herein, mitochondria-targeted combination therapy platform of chemodynamic (CDT)/chemotherapy was constructed for enhanced generation of ROS based on the multistage synergistic effect of MnO2/CeO2-meditated Fenton-like reaction and glutathione (GSH) depletion, as well as camptothecin (CPT). After accumulation in mitochondria via surface targeting molecule TPP, the MnO2 depleted over-expressed GSH to generate Mn2+, which can convert endogenous H2O2 to highly toxic hydroxyl radicals (·OH) based on Fenton-like reaction, and outside surface CeO2 can elevate the ·OH level by Fenton-like reaction. Besides, the gradual depletion of over-expressed GSH decreased the scavenging effect on the highly reactive ·OH, improving the CDT efficacy. Additionally, the released CPT accompanied by the decomposition of MnO2 would further stimuli ROS generation in mitochondria, resulting in the amplified ROS effect. In vivo experiments suggested that the combination therapy platform performed obvious inhibition to tumor based on the enhanced CDT/chemotherapy, which provide a novel approach for the ROS-based cancer combination therapy.

Mitochondria-targeting folic acid-modified nanoplatform based on mesoporous carbon and a bioactive peptide for improved colorectal cancer treatment

Oral colon-targeted drug delivery systems (OCDDs) are designed to deliver the therapeutic agents to colonic disease sites to improve the effectiveness of drug treatment, increase bioavailability, and reduce systemic side effects and are beneficial for the treatment of colorectal cancer (CRC) and inflammatory bowel disease (IBD). However, concerns about the biosafety of OCDDs are increasing, and changes in the physiological environment of the gastrointestinal tract can affect the therapeutic efficacy of the drug. Herein, we report about an orally administered colon-accumulating mitochondria-targeted drug delivery nanoplatform (M27-39@FA-MCNs), which was synthesized using the small peptide, M27-39, and folic acid (FA)-modified mesoporous carbon nanoparticles (FA-MCNs). The phenolic resin polymerized with phloroglucinol and formaldehyde (PF) was used for fabricating MCNs using a one-step soft-template method. Folic acid (FA) can be covalently combined with chitosan-modified MCNs to obtain FA-MCNs. The M27-39@FA-MCNs were stable with a spherical morphology and an average diameter of 129 nm. The cumulative release rate of M27-39@FA-MCNs in the artificial gastric fluid (pH = 1.2) and intestinal fluid (pH = 6.8) for 6 h was 87.77%. This nanoplatform maintains the advantages of both FA and MCNs to improve the bioactivity of M27-39 with high drug accumulation in colorectal tumor tissues and the ease of excretion, thus ameliorating its biosafety and targetability. Furthermore, M27-39@FA-MCNs induced tumor-cell apoptosis and inhibited tumor growth by disrupting mitochondrial energy metabolism and regulating the mitochondrial apoptosis signaling pathway and immune inflammatory response. Thus, such a mitochondria-targeting FA-modified nanoplatform based on mesoporous carbon and a bioactive peptide may provide a precise strategy for CRC treatment. Statement of significanceIn this study, we constructed an orally administered colon-accumulating mitochondria-targeted drug delivery nanoplatform (M27-39@FA-MCNs), which was synthesized using the small peptide (M27-39) and folic acid-modified mesoporous carbon nanoparticles (FA-MCNs). M27-39@FA-MCNs increased the targeting ability of M27-39 toward mitochondria and colon based on the properties of FA-MCNs; they also increased M27-39 accumulation and residence time in colon tumors. Oral administration of M27-39@FA-MCNs remarkably alleviated colorectal cancer (CRC) by targeting tumor cell mitochondria and interfering with the mitochondrial energy metabolism process, and inducing apoptosis related P53/Caspase-3 mitochondrial pathway activation. Therefore, M27-39@FA-MCNs may provide a safe and precise therapeutic strategy for CRC.

Tumor-Penetrating and Mitochondria-Targeted Drug Delivery Overcomes Doxorubicin Resistance in Lung Cancer

Tumor-Penetrating and Mitochondria-Targeted Drug Delivery Overcomes Doxorubicin Resistance in Lung Cancer

Mitochondrial targeted drug delivery combined with manganese catalyzed Fenton reaction for the treatment of breast cancer

In previous studies, we found that triphenylphosphine-modified doxorubicin (TPP-DOX) can effectively kill drug-resistant tumor cells, but its effect on sensitive tumor cells is weakened. In this research, with albumin from Bovine Serum (BSA) as a carrier, TPP-DOX@MnBSA (TD@MB) nanoparticles were prepared by co-loading TPP-DOX and manganese which can realize the combination of chemotherapy and chemodynamic therapy (CDT). The uniform and stable nano-spherical nanoparticle can promote drug uptake, achieve mitochondrial-targeted drug delivery, increase intracellular reactive oxygen species (ROS) and catalyze the production of highly toxic oxidative hydroxyl radicals (OH·), further inhibiting the growth of both sensitive and drug-resistant MCF-7 cells. Besides, TD@MB can down-regulate the stemness-related proteins and the metastasis-related proteins, potentially decreasing the tumor stemness and metastasis. In vivo experiment indicated that TD@MB was able to exert desired antitumor effect, good tumor targeting and biocompatibility.

Rational design of nanocarriers for mitochondria-targeted drug delivery

Well-developed mitochondria-targeted nanocarriers for function regulation are highly desirable. Numerous studies have been conducted on the treatment of mitochondria-related diseases; however, further improvements are required to develop more effective drug delivery methods. Herein, we comprehensively introduce recent developments progress in rational design of mitochondria-targeted nanocarriers, and discuss the different strategies of available nanocarriers for targeting mitochondria. We also highlight the advantages and disadvantages of various carrier systems that are currently in use. Finally, perspective on new generation for mitochondria-targeted delivery systems in the emerging area of drug-based therapeutics is also discussed.

Mitochondrion-targeted supramolecular "nano-boat" simultaneously inhibiting dual energy metabolism for tumor selective and synergistic chemo-radiotherapy.

Rationale: Tumor energy metabolism has been a well-appreciated target of cancer therapy; however, the metabolism change of cancer cells between oxidative phosphorylation and glycolysis poses a challenge to the above. In this study, we constructed an innovative mitochondrion-targeted supramolecular “nano-boat” based on peptide self-assembly for tumor combined chemo-radiotherapy by simultaneously inhibiting the dual energy metabolism.Methods: A lipophilic self-assembled peptide and a positively charged cyclen were integrated to fabricate a brand new mitochondrion-targeted nano-platform for the first time. The indices of mitochondrial dysfunction including mitochondrial membrane potential, apoptosis proteins expression and ultrastructure change were evaluated using a JC-1 probe, western blotting and biological transmission electron microscopy, respectively. Energy metabolism assays were conducted on a Seahorse XF24 system by detecting the oxygen consumption rate and the glycolytic proton efflux rate. The radio-sensitization effect was investigated by colony formation, the comet assay, and γ-H2AX staining.Results: The supramolecular “nano-boat” could selectively kill cancer cells by much higher enrichment and reactive oxygen species generation than those in normal cells. In the cancer cells treated with the supramolecular “nano-boat”, the dysfunctional morphological changes of the mitochondrial ultrastructure including swelling and pyknosis were evidently observed, and the endogenous mitochondrial apoptosis pathway was effectively triggered by abundant of cytochrome C leaking out. Concurrently, the dual metabolic pathways of glycolysis and oxidative phosphorylation were severely inhibited. More importantly, the supramolecular “nano-boat” displayed an excellent radio-sensitization effect with a sensitization enhancement ratio value as high as 2.58, and hence, in vivo efficiently combining radiotherapy yielded an enhanced chemo-radiotherapy effect.Conclusion: Our study demonstrated that the rationally designed peptide-based “nano-boat” could efficiently induce cancer cell apoptosis by the energy metabolism inhibition involving multiple pathways, which may provide the motivation for designing novel and universal mitochondria-targeted drug delivery systems for cancer therapy.

Mitochondrial temperature-responsive drug delivery reverses drug resistance in lung cancer

Reversal of cancer drug resistance remains a critical challenge in chemotherapy. Mitochondria-targeted drug delivery has been suggested to mitigate drug resistance in cancer. To overcome the intrinsic limitations in conventional mitochondrial targeting strategies, we develop mitochondrial temperature-responsive drug delivery to reverse doxorubicin (DOX) resistance in lung cancer. Results demonstrate that the thermoresponsive nanocarrier can prevent DOX efflux and facilitate DOX accumulation and mitochondrial targeting in DOX-resistant tumors. As a consequence, thermoresponsive nanocarrier enhances the cytotoxicity of DOX and reverses the drug resistance in tumor-bearing mice. This work represents the first example of mitochondrial temperature-responsive drug delivery for reversing cancer drug resistance.

Preparation and antitumor activity of triphenylphosphine-based mitochondrial targeting polylactic acid nanoparticles loaded with 7-hydroxyl coumarin.

Due to the low bioavailability and severe toxic side effects caused by the lack of selectivity of traditional chemotherapy drugs, the targeted delivery of chemotherapy drugs has become the key to tumor treatment. The activity and transmembrane potential of mitochondria in cancer cells were significantly higher than that of normal cells, making them a potential target for chemotherapeutic drug delivery. In this study, triphenylphosphine (TPP) based mitochondria targeting polylactic acid (PLLA) nanoparticles (TPP-PLLA NPs) were synthesized to improve the delivery efficiency of anticancer drugs. The carrier material was characterized by 1H NMR and FT-IR and 7-hydroxyl coumarin (7-HC) was successfully loaded into TPP-PLLA to form 7-HC/TPP-PLLA NPs. Further studies showed that TPP-PLLA NPs were primarily accumulated in the mitochondrial and 7-HC/TPP-PLLA NPs had higher antitumor activity. Taken together, our results indicated that TPP-PLLA NPs could be a promising mitochondria-targeted drug delivery system for cancer therapy.

Reversing Chemotherapy Resistance by a Synergy between Lysosomal pH-Activated Mitochondrial Drug Delivery and Erlotinib-Mediated Drug Efflux Inhibition.

Mitochondrial drug delivery has attracted increasing attention in various mitochondrial dysfunction-associated disorders such as cancer owing to the important role of energy production. Herein, we report a lysosomal pH-activated mitochondrial-targeting polymer nanoparticle to overcome drug resistance by a synergy between mitochondrial delivery of doxorubicin (DOX, an anticancer drug) and erlotinib-mediated inhibition of drug efflux. The obtained nanoparticles, DE-NPs could maintain negative charge and have long blood circulation while undergoing charge reversal at lysosomal pH after internalization by cancer cells. Thereafter, the acidity-activated polycationic and hydrophobic polypeptide domains boost lysosomal escape and mitochondrial-targeting drug delivery, leading to mitochondrial dysfunction, ATP suppression, and cell apoptosis. Moreover, the suppressed ATP supply and erlotinib enabled dual inhibition of drug efflux by DOX-resistant MCF-7/ADR cells, leading to significantly augmented intracellular DOX accumulation and a synergistic anticancer effect with a 17-fold decrease of IC50 relative to DOX. In vivo antitumor study demonstrates that DE-NPs efficiently suppressed the tumor burden in MCF-7/ADR tumor-bearing mice and led to negligible toxicity. This work establishes that a combination of mitochondrial drug delivery and drug efflux inhibition could be a promising strategy for combating multidrug resistance.

Effect of Montelukast Sodium and Graphene Oxide Nanomaterials on Mouse Asthma Model.

Because some asthma patients have different types of inflammatory cells in their bodies, they cannot get relief with traditional drugs. However, the nano drug delivery system can realize efficient drug delivery, inflammatory cells and intracellular targeting, and the apoptosis of inflammatory cells. This article aims to comprehensively evaluate the effects of montelukast sodium combined with graphene oxide nanomaterials on improving the clinical symptoms and airway inflammation of children with bronchial asthma, with a view to further improving the clinical treatment of children with bronchial asthma. The results show that montelukast sodium can improve lung function in patients with asthma, and also has important effects such as anti-inflammatory and regulating immune function. After exposure to graphene oxide, the level of oxidative stress in mice increased with brightness and humidity, demonstrating the role of T oxidative stress in the development of asthma. In addition, nanocarriers assist co-loaded drugs to deepen and enrich the pulmonary inflammation site, further achieving effective mitochondrial targeted drug delivery, thereby enhancing the inhibitory effect of anti-apoptotic proteins, leading to inflammatory cell apoptosis.