Mitochondria-targeting Nanoparticles Research Articles

Mitochondria-targeted nanoparticles based on glycated oat protein for enhanced curcumin bioavailability and antioxidant activity

Curcumin is a hydrophobic dietary supplement and can mitigate oxidative damage. However, the low bioavailability of curcumin impedes its application in functional foods. Protein-coated nanoparticles are susceptible to environmental stress and have limited ability to reach mitochondria, where reactive oxygen species are generated. To overcome this limitation, we prepared mitochondria-targeted nanoparticles by modifying glycosylated oat protein isolate with triphenylphosphonium bromide for the efficient delivery of curcumin. In this study, the curcumin was incorporated into the spherical nanoparticles with high entrapment efficiency and loading capacity. The nanoparticles increased the stability of curcumin during heat treatment and light irradiation. The bioavailability of curcumin was improved in the nanoparticles due to their strong resistance against in vitro gastric digestion and good permeability across the Caco-2 cell monolayer. The nanoparticles realized lysosomal escape and exhibited specific accumulation in mitochondria upon internalization by Caco-2 cells. The mitochondria-targeted nanoparticles with no cytotoxicity further enhanced the antioxidant activity of curcumin by preserving mitochondrial membrane potential, increasing antioxidant enzyme activities, decreasing the concentrations of intracellular reactive oxygen species and malondialdehyde. This study highlights the potential application of glycosylated proteins in developing nanocarriers for precise delivery of hydrophobic nutrients.

Mitochondria-targeted nanoparticles for encapsulating astaxanthin: exploring the reason for alleviating oxidative damage

Mitochondria-targeted nanoparticles for encapsulating astaxanthin: exploring the reason for alleviating oxidative damage

Mitochondria: The master regulator of aging

Mitochondria are ATP-producing organelles in eukaryotic organisms that serve as the cell’s power plants. Besides, mitochondria are integral to regulating cellular homeostasis and metabolism as a result of their essential roles in reactive oxygen species (ROS) production, bioenergetics, catabolism and anabolism, heme and iron-sulfur biosynthesis, iron and calcium homeostasis, apoptosis and signal transduction, as well as immunity and inflammation. It is well accepted that mitochondria are evolutionarily derived from endosymbiotic alphaproteobacteria within eukaryotic cells adapted for effective energy transduction. Although most of the mitochondrial DNA (mtDNA) is thought to have been transported to the eukaryotic nucleus during evolution, mitochondria may have preserved protein-coding genes within their own DNA. Accumulating data show that a progressive decline of mitochondria regulates aging. The present review aims to outline the role of mitochondria in various aspects of aging, including unfolded protein response, generation of ROS, and the contribution of somatic mtDNA mutations as well as inflammation in aging. Moreover, we propose mitochondria-targeted nanoparticles and mitochondrial genome editing as novel tools to modify mitochondrial genome aberrations.

Mitochondria-targeted nanoparticles overcome chemoresistance via downregulating BACH1/CD47 axis in ovarian carcinoma

The platinum-based chemotherapy is a routine strategy for the treatment of ovarian cancer, while it is prone to chemoresistance in clinical, which hinders the treatment. Therefore, it is urgently needed to elucidate the underlying mechanism of drug resistance and form the appropriate strategy. The sequencing results showed that cisplatin (DDP) resistant ovarian cancer overexpressed BTB and CNC homology 1 (BACH1), and up-regulated the “don't eat me” signal CD47. We identified that hemin, a BACH1 inhibitor, could effectively down-regulate BACH1 and simultaneously inhibit CD47. Moreover, hemin has a synergistic effect with DDP. We designed a pH-responsive nanoparticle (H/D@FA–CaP–NPs) in which folic acid (FA) ensured targeting of ovarian cancer cells, while hemin inhibited BACH1 as well as down-regulated CD47, achieving the promotion of apoptosis of tumor cells and inducing phagocytosis of tumors by macrophages. Moreover, hemin has a synergistic effect with DDP to promote apoptosis of tumor cells. Structurally, hemin and DDP was encapsulated within hydrophobic 1,2-distearoyl-sn‑glycero-3-phospho-ethanolamine (DSPE) to form a tight core, and hydrophilic polyethylene glycol 2000 (PEG2000) and calcium phosphate (CaP) formed the outside shell, and FA was modified on the surface of nanoparticles. In terms of function, (a) FA enhanced the active targeting of nanoparticles to tumors; (b) NPs targeted mitochondria to induce reactive oxygen species (ROS) production; (c) hemin encapsulated in nanoparticles could specifically target BACH1, thereby down regulating CD47; (d) hemin had a synergistic effect with DDP, thus augmenting the chemotherapy. Altogether, mitochondria-targeted nanoparticles H/D@FA–CaP–NPs promoted tumor apoptosis and mobilized phagocytosis to treat tumor, providing a novel scheme for clinical treatment of cisplatin-resistant ovarian carcinoma.

Effective magnetic hyperthermia induced by mitochondria-targeted nanoparticles modified with triphenylphosphonium-containing phospholipid polymers.

Magnetic hyperthermia (MHT) is a promising cancer treatment because tumor tissue can be specifically damaged by utilizing the heat generated by nano-heaters such as magnetite nanoparticles (MNPs) under an alternating magnetic field. MNPs are taken up by cancer cells, enabling intracellular MHT. Subcellular localization of MNPs can affect the efficiency of intracellular MHT. In this study, we attempted to improve the therapeutic efficacy of MHT by using mitochondria-targeting MNPs. Mitochondria-targeting MNPs were prepared by the modification of carboxyl phospholipid polymers containing triphenylphosphonium (TPP) moieties that accumulate in mitochondria. The mitochondrial localization of polymer-modified MNPs was supported by transmission electron microscopy observations of murine colon cancer CT26 cells treated with polymer-modified MNPs. In vitro and in vivo MHT using polymer-modified MNPs revealed that the therapeutic effects were enhanced by introducing TPP. Our results indicate the validity of mitochondria targeting in enhancing the therapeutic outcome of MHT. These findings will pave the way for developing a new strategy for the surface design of MNPs and therapeutic strategies for MHT.

Platin-C containing nanoparticles: a recipe for the delivery of curcumin-cisplatin combination chemotherapeutics to mitochondria.

The success story of cisplatin spans over six decades now and yet it continues to be the key player in most chemotherapeutic regimens. Numerous efforts have been made to improve its efficacy, address its shortcomings, and overcome drug resistance. One such strategy is to develop new platinum(IV)-based prodrugs with functionally active ligands to deliver combination therapeutics. This strategy not only enables the drug candidate to access multiple drug targets but also enhances the kinetic inertness of platinum complexes and thereby ensures greater accumulation of active drugs at the target site. We report the synthesis of Platin-C, a platinum(IV)-based cisplatin prodrug tethered to the active component of ancient herbal medicine, curcumin, as one of the axial ligands. This combination complex showed improved chemotherapeutic efficacy in cisplatin resistant A2780/CP70 cell lines compared with the individual components. An amine-terminated biodegradable polymer was suitably functionalized with the triphenylphosphonium (TPP) cation to obtain a mitochondria-directed drug delivery platform. Quantification of Platin-C loading into these NPs using complementary techniques employing curcumin optical properties in high-performance liquid chromatography and platinum-based inductively coupled plasma mass spectrometry evidenced efficacious payload incorporation resulting in functional activities of both the components. Stability studies for a period of one week indicated that the NPs remain stable, enabling substantial loading and controlled release of the prodrug. The targeting nanoparticle (NP) platform was utilized to deliver Platin-C primarily in the mitochondrial network of cancer cells as monitored using confocal microscopy employing the green fluorescence of the curcumin pendant. Our studies showed that amine terminated NPs were relatively less efficient in their ability to target mitochondria despite being positively charged. This re-validated the importance of lipophilic positively charged TPP surface functionalities to successfully target cellular mitochondria. We validated the capabilities of Platin-C and its mitochondria-targeting nanoparticles towards inflicting mitochondria-directed activity in cisplatin-sensitive and cisplatin-resistant cell lines. Furthermore, our studies also demonstrated the effectiveness of Platin-C incorporated targeting NPs in attenuating cellular inflammatory markers by utilizing the curcumin component. This study advances our understanding of the cisplatin prodrug approach to combine chemotherapeutic and inflammatory effects in accessing combinatory pathways.

GSH-responsive sequential mitochondria-targeting nanoagents for photothermal-enhanced chemodynamic therapy

Mitochondria-targeting nanoparticles have proven to be promising platforms for cancer therapy. However, precise mitochondria targeting in the complex tumor environment is still challenging and requires more ingenious design. Herein, we developed the glutathione (GSH)-responsive nanoagents to target mitochondria in tumor cells precisely for photothermal-enhanced chemodynamic therapy (CDT). The nanoagents were designed by preparing the cubic shape of CuFeS2 nanoparticles that sequentially modified with mitochondrial-targeting peptide (KLAK) and integrin-targeting peptide (RGD), which KLAK and RGD were covalently conjugated via a disulfide bond. After being endocytosed into integrin-overexpressed tumor cells, disulfide bond was broken and RGD was separated from the nanoagents in the presence of overexpressed GSH. Then, the exposure of KLAK on the surface further aid the rustling nanoagents to target mitochondria. Under NIR laser irradiation, the surrounding temperature of the nanoagents would rise due to their excellent photothermal effect, resulting in the improvement of the Fenton reaction from the CuFeS2. It was well demonstrated that this photothermal-enhanced chemodynamic therapy nanoplatform could effectively damage the mitochondrial function and further induce the apoptosis of tumor cells. As a therapeutic platform with both tumor/mitochondria-targeting and PTT-enhanced CDT, our study has provided a new path in the field of cancer therapy.

Mitochondria-targeted CoQ10 loaded PLGA-b-PEG-TPP nanoparticles: Their effects on mitochondrial functions of COQ8B-/- HK-2 cells

Coenzyme Q10 (CoQ10) deficiency exhibits signs of multiple organ dysfunctions, particular subtypes present isolated kidney involvement progressing to chronic kidney disease. In these patients, early administration of oral CoQ10 has been shown to decrease proteinuria and to delay development of chronic kidney disease, which suggests that it may have a renoprotective potential in these patients. However, CoQ10 bioavailability in mitochondria is low, therefore its efficacy is limited. We aimed to develop mitochondria-targeted CoQ10 loaded poly(lactic-co-glycolic acid)-poly(ethylene glycol)-triphenylphosphonium nanoparticles (CoQ10-TPP-NPs) that would be more efficient in the treatment of CoQ10 nephropathies. These nanoparticles were found to have a size of approximately 150 nm and a zeta potential of + 20 mV. The entrapment efficiency of the nanoparticles was determined as 40%. Cytotoxicity studies showed no effect on the viability of the human kidney proximal tubule epithelial cells exposed to the nanoparticles. The efficacy of the formulated nanoparticles on in vitro disease model, which was developed in the human kidney proximal tubule epithelial cells by siRNA based silencing of the COQ8B, was evaluated through mitochondrial functions by means of metabolomic analyses. We showed that the treatment of COQ8B-/- cells with mitochondria-targeted nanoparticles was more effective in increasing the tricarboxylic acid cycle rate compared to free-CoQ10. Our formulation would be more effective in treatment of CoQ10-related nephropathies than conventional formulations.

Recent Advancements in Mitochondria-Targeted Nanoparticle Drug Delivery for Cancer Therapy.

Mitochondria are critical subcellular organelles that produce most of the adenosine triphosphate (ATP) as the energy source for most eukaryotic cells. Moreover, recent findings show that mitochondria are not only the “powerhouse” inside cells, but also excellent targets for inducing cell death via apoptosis that is mitochondria-centered. For several decades, cancer nanotherapeutics have been designed to specifically target mitochondria with several targeting moieties, and cause mitochondrial dysfunction via photodynamic, photothermal, or/and chemo therapies. These strategies have been shown to augment the killing of cancer cells in a tumor while reducing damage to its surrounding healthy tissues. Furthermore, mitochondria-targeting nanotechnologies have been demonstrated to be highly efficacious compared to non-mitochondria-targeting platforms both in vitro and in vivo for cancer therapies. Moreover, mitochondria-targeting nanotechnologies have been intelligently designed and tailored to the hypoxic and slightly acidic tumor microenvironment for improved cancer therapies. Collectively, mitochondria-targeting may be a promising strategy for the engineering of nanoparticles for drug delivery to combat cancer.

Mitochondria-targeted nanoparticles in treatment of neurodegenerative diseases.

Neurodegenerative diseases (NDs) are a class of heterogeneous diseases that includes Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Mitochondria play an important role in oxidative balance and metabolic activity of neurons; therefore, mitochondrial dysfunction is associated with NDs and mitochondria are considered a potential treatment target for NDs. Several obstacles, including the blood-brain barrier (BBB) and cell/mitochondrial membranes, reduce the efficiency of drug entry into the target lesions. Therefore, a variety of neuron mitochondrial targeting strategies has been developed. Among them, nanotechnology-based treatments show especially promising results. Owing to their adjustable size, appropriate charge, and lipophilic surface, nanoparticles (NPs) are the ideal theranostic system for crossing the BBB and targeting the neuronal mitochondria. In this review, we discussed the role of dysfunctional mitochondria in ND pathogenesis as well as the physiological barriers to various treatment strategies. We also reviewed the use and advantages of various NPs (including organic, inorganic, and biological membrane-coated NPs) for the treatment and diagnosis of NDs. Finally, we summarized the evidence and possible use for the promising role of NP-based theranostic systems in the treatment of mitochondrial dysfunction-related NDs.

Nanoparticle-Mediated Routing of Antibiotics into Mitochondria in Cancer Cells.

In recent years, antibiotics have emerged as alternative medicines in cancer therapy due to their capability of mitochondrial dysfunction in cancer cells. However, antibiotics render collateral damage in noncancerous cells by targeting mitochondrial transcription and translational machinery. To address this, herein, we have engineered three different mitochondria-targeted cationic antibiotic (tigecycline)-loaded nanoparticles from cholesterol conjugates. Dynamic light scattering and electron microscopy confirmed the spherical morphology and a less than 200 nm hydrodynamic diameter for these nanoparticles. The triphenylphosphine-coated tigecycline-loaded nanoparticle (Mito-TPP-Tig-NP) was shown to be homed into the mitochondria of A549 lung cancer cells compared to the other cationic nanoparticles. These Mito-TPP-Tig-NPs indeed triggered mitochondrial morphology damage and generation of reactive oxygen species (ROS). All the mitochondria-targeted tigecycline-loaded nanoparticles showed improved cancer cell killing ability in A549 and HeLa cervical cancer cells compared to free tigecycline. Moreover, Mito-TPP-Tig-NPs showed much less toxicity toward noncancerous human embryonic kidney cells (HEK293) compared to free tigecycline. These antibiotic-loaded mitochondria-targeted nanoparticles can open up an avenue toward anticancer therapy.

Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output

Mitochondria, which play central roles in immunometabolic diseases, have their own genome. However, the functions of mitochondria-located noncoding RNAs are largely unknown due to the absence of a specific delivery system. By circular RNA (circRNA) expression profile analysis of liver fibroblasts from patients with nonalcoholic steatohepatitis (NASH), we observe that mitochondrial circRNAs account for a considerable fraction of downregulated circRNAs in NASH fibroblasts. By constructing mitochondria-targeting nanoparticles, we observe that Steatohepatitis-associated circRNA ATP5B Regulator (SCAR), which is located in mitochondria, inhibits mitochondrial ROS (mROS) output and fibroblast activation. circRNA SCAR, mediated by PGC-1α, binds to ATP5B and shuts down mPTP by blocking CypD-mPTP interaction. Lipid overload inhibits PGC-1α by endoplasmic reticulum (ER) stress-induced CHOP. Invivo, targeting circRNA SCAR alleviates high fat diet-induced cirrhosis and insulin resistance. Clinically, circRNA SCAR is associated with steatosis-to-NASH progression. Collectively, we identify a mitochondrial circRNA that drives metaflammation and serves as a therapeutic target for NASH.

Mitochondria-Targeting Organic Nanoparticles for Enhanced Photodynamic/Photothermal Therapy.

Organelle-targeting techniques have been proved to be promising approaches for enhanced cancer treatment, especially phototherapy, because it can greatly improve the efficiency of photosensitizers. In this work, we designed and synthesized a mitochondria-targeting diketopyrrolopyrrole-based photosensitizer (DPP2+) for synergistic photodynamic/photothermal therapy upon irradiation. The obtained mitochondria-targeting nanoparticles (DPP2+ NPs) could produce thermal energy and singlet oxygen under 635 nm laser irradiation with ideal cytocompatibility. Importantly, DPP2+ NPs are more likely to enter the cells and target mitochondria. In in vitro and in vivo antitumor experiments, DPP2+ NPs showed highly effective antitumor effects, suggesting that mitochondria-targeting photosensitizers have potential for cancer treatment. The present work provides an alternative strategy to mitochondria-targeting molecular engineering and highlights the potential of organic nanomaterials in biomedical fields and cancer treatment.

Tumor- and mitochondria-targeted nanoparticles eradicate drug resistant lung cancer through mitochondrial pathway of apoptosis

Chemotherapeutic drugs frequently encounter multidrug resistance. ATP from mitochondria helps overexpression of drug efflux pumps to induce multidrug resistance, so mitochondrial delivery as a means of “repurposing’’ chemotherapeutic drugs currently used in the clinic appears to be a worthwhile strategy to pursue for the development of new anti-drug-resistant cancer agents. TPP-Pluronic F127-hyaluronic acid (HA) (TPH), with a mitochondria-targeting triphenylphosphine (TPP) head group, was first synthesized through ester bond formation. Paclitaxel (PTX)-loaded TPH (TPH/PTX) nanomicelles exhibited excellent physical properties and significantly inhibited A549/ADR cells. After TPH/PTX nanomicelles entered acidic lysosomes through macropinocytosis, the positively charged TP/PTX nanomicelles that resulted from degradation of HA by hyaluronidase (HAase) in acidic lysosomes were exposed and completed lysosomal escape at 12 h, finally localizing to mitochondria over a period of 24 h in A549/ADR cells. Subsequently, TPH/PTX caused mitochondrial outer membrane permeabilization (MOMP) by inhibiting antiapoptotic Bcl-2, leading to cytochrome C release and activation of caspase-3 and caspase-9. In an A549/ADR xenograft tumor model and a drug-resistant breast cancer-bearing mouse model with lung metastasis, TPH/PTX nanomicelles exhibited obvious tumor targeting and significant antitumor efficacy. This work presents the potential of a single, nontoxic nanoparticle (NP) platform for mitochondria-targeted delivery of therapeutics for diverse drug-resistant cancers.

Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats

BackgroundCyclosporin A (CsA) is a promising therapeutic drug for myocardial ischemia reperfusion injury (MI/RI) because of its definite inhibition to the opening of mitochondrial permeability transition pore (mPTP). However, the application of cyclosporin A to treat MI/RI is limited due to its immunosuppressive effect to other normal organ and tissues. SS31 represents a novel mitochondria-targeted peptide which can guide drug to accumulate into mitochondria. In this paper, mitochondria-targeted nanoparticles (CsA@PLGA-PEG-SS31) were prepared to precisely deliver cyclosporin A into mitochondria of ischemic cardiomyocytes to treat MI/RI.ResultsCsA@PLGA-PEG-SS31 was prepared by nanoprecipitation. CsA@PLGA-PEG-SS31 showed small particle size (~ 50 nm) and positive charge due to the modification of SS31 on the surface of nanoparticles. CsA@PLGA-PEG-SS31 was stable for more than 30 days and displayed a biphasic drug release pattern. The in vitro results showed that the intracellular uptake of CsA@PLGA-PEG-SS31 was significantly enhanced in hypoxia reoxygenation (H/R) injured H9c2 cells. CsA@PLGA-PEG-SS31 delivered CsA into mitochondria of H/R injured H9c2 cells and subsequently increased the viability of H/R injured H9c2 cell through inhibiting the opening of mPTP and production of reactive oxygen species. In vivo results showed that CsA@PLGA-PEG-SS31 accumulated in ischemic myocardium of MI/RI rat heart. Apoptosis of cardiomyocyte was alleviated in MI/RI rats treated with CsA@PLGA-PEG-SS31, which resulted in the myocardial salvage and improvement of cardiac function. Besides, CsA@PLGA-PEG-SS31 protected myocardium from damage by reducing the recruitment of inflammatory cells and maintaining the integrity of mitochondrial function in MI/RI rats.ConclusionCsA@PLGA-PEG-SS31 exhibited significant cardioprotective effects against MI/RI in rats hearts through protecting mitochondrial integrity, decreasing apoptosis of cardiomyocytes and myocardial infract area. Thus, CsA@PLGA-PEG-SS31 offered a promising therapeutic method for patients with acute myocardial infarction.

Mitochondria-targeting nanomedicine: An effective and potent strategy against aminoglycosides-induced ototoxicity

We report a proof-of-concept for the development of mitochondria-targeting nanoparticles (NPs) loaded with geranylgeranylacetone (GGA) to protect against a wide range of gentamicin-induced ototoxicity symptoms in a zebrafish model. The polymeric NPs were functionalized with a mitochondrial-homing peptide (d‑Arg‑Dmt‑Orn‑Phe‑NH2) and exhibited greater mitochondrial uptake and lower gentamicin uptake in hair cells via mechanotransduction (MET) channels and tuned machinery in the hair bundle than the ordinary NPs did. Blockade of MET channels rapidly reversed this effect, indicating the reversible responses of hair cells to the targeting NPs were mediated by MET channels. Pretreatment of hair cells with mitochondria-targeting GGA-loaded NPs exhibited a superior acute or chronic protective efficacy against subsequent exposure to gentamicin compared with unmodified formulations. Mitochondrial delivery regulating the death pathway of hair cells appeared to cause the therapeutic failure of untargeted NPs. Thus, peptide-directed mitochondria-targeting NPs may represent a novel therapeutic strategy for mitochondrial dysfunction-linked diseases.

Mitochondria-targeting nanoparticles for enhanced microwave ablation of cancer.

Although microwave ablation is widely used in the treatment of hepatocellular carcinoma, it is only recommended for the therapy of cancer with a diameter of 3 cm or less because of the limited heat transmission radius. Mitochondria play an important role in the apoptotic events of tumor cells. Here, we developed mitochondria-targeting zirconia (ZrO2) complex nanoparticles (MZCNs) as nanoagents for efficient cancer therapy by microwave ablation. The MZCNs are composed of ZrO2 nanoparticles encapsulating the microwave-sensitive ionic liquid (IL) and co-decorated with the mitochondria-targeting molecule of triphenylphosphonium (TPP), and the tumor cell-targeting peptide iRGD. The cell experiment results reveal that the amount of MZCNs accumulated in the tumor is obviously increased by the synergistically targeted delivery of TPP and iRGD peptide after administration by intravenous injection. Besides, the in vitro experiments demonstrate that MZCNs are distributed preferentially in the mitochondria with the assistance of TPP molecules. More importantly, the in vivo experiments in mice administered with MZCNs show that the effective area with a temperature above 42 °C was about 2.8-fold larger than that of the controls due to the targeting effect and better microwave sensitivity of the MZCNs. As such, the cancer in mice can be eradicated without recurrence, demonstrating the MZCNs as promising nanoagents for efficient cancer therapy by microwave ablation.

Centrifugation-Free Magnetic Isolation of Functional Mitochondria Using Paramagnetic Iron Oxide Nanoparticles.

Subcellular fractionation techniques are essential for cell biology and drug development studies. The emergence of organelle-targeted nanoparticle (NP) platforms necessitates the isolation of target organelles to study drug delivery and activity. Mitochondria-targeted NPs have attracted the attention of researchers around the globe, since mitochondrial dysfunctions can cause a wide range of diseases. Conventional mitochondria isolation methods involve high-speed centrifugation. The problem with high-speed centrifugation-based isolation of NP-loaded mitochondria is that NPs can pellet even if they are not bound to mitochondria. We report development of a mitochondria-targeted paramagnetic iron oxide nanoparticle, Mito-magneto, that enables isolation of mitochondria under the influence of a magnetic field. Isolation of mitochondria using Mito-magneto eliminates artifacts typically associated with centrifugation-based isolation of NP-loaded mitochondria, thus producing intact, pure, and respiration-active mitochondria. © 2017 by John Wiley & Sons, Inc.

A Prodrug of Two Approved Drugs, Cisplatin and Chlorambucil, for Chemo War Against Cancer.

Cancer cells maintain normal mitochondrial glutathione as one of the defense mechanisms to inhibit mitochondrial membrane polarization and hence apoptosis. A combinational therapeutic modality Platin-Cbl, a prodrug of FDA-approved chemotherapeutic agents, cisplatin and chlorambucil (Cbl), was synthesized and characterized to explore the potential of this compound to initiate chemo war on cancer cells using the active drugs, cisplatin and Cbl, when delivered to the cellular power house mitochondrion using a targeted nanoparticle designed to get associated with this organelle. Platin-Cbl demonstrated significantly high cytotoxic activity across a number of tumor cell lines as well as in a cisplatin-resistant cancer cell line compared with cisplatin or its mixture with Cbl suggesting its unique potency in cisplatin-resistant tumors. A mitochondria-targeted nanoparticle formulation of Platin-Cbl allowed for its efficacious mitochondrial delivery. In vitro studies documented high potency of Platin-Cbl nanoparticle formulations. Cisplatin-resistant cells upon treatment with Platin-Cbl were still able to manage energy production to a certain extent via fatty acid pathway; the advantage of using T-Platin-Cbl-NP is that this nanoparticle treatment causes impairment of all metabolic pathways in cisplatin-resistant cells forcing the cells to undergo efficient apoptosis. This study highlights a combination of several beneficial effects for a cascade of events to overcome resistance associated with single drug therapy. Mol Cancer Ther; 16(4); 625-36. ©2017 AACR.

Targeted delivery of geranylgeranylacetone to mitochondria by triphenylphosphonium modified nanoparticles: a promising strategy to prevent aminoglycoside-induced hearing loss.

Prevention of hair cell death is an important target for the prevention of hearing loss. Here, we report the engineering of biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) decorated with triphenylphosphonium (TPP) cations as a robust mitochondrial delivery platform, with the aim of preserving mitochondrial integrity and shutting off the initiation of cell death. Geranylgeranylacetone (GGA), a 70 kDa heat shock protein (HSP70) inducer, was used as a therapeutic molecule to attenuate gentamicin (Gen) induced hearing loss. The diameter of the mitochondria-targeting NPs is 145 nm and the encapsulation efficiency is 80.6%. Lysosomal escape and mitochondrial targeting studies indicated the promising therapeutic potential of TPP modified NPs. Finally, the zebrafish lateral line model was applied to verify the efficacy of the GGA loaded targeting NPs for preventing gentamicin-induced death hair cell. The results showed that the prepared targeted NPs provided significant protection: the survival of hair cells increased from 36% to 69% under acute exposure and from 20% to 62% under chronic exposure. In addition, targeted NPs exhibited significantly improved efficiency in alleviating gentamicin-induced hair cell damage compared with free drugs and untargeted NPs, supporting the hypothesis of mitochondrial targeting delivery in the treatment of aminoglycoside-induced hearing loss. These TPP modified NPs demonstrated promise for the treatment of mitochondrial dysfunction.