Intracellular delivery of redox cycler-doxorubicin to the mitochondria of cancer cell by folate receptor targeted mitocancerotropic liposomes

Malhi, Sarandeep; Budhiraja, Abhishek; Arora, Sumit; Chaudhari, Kiran; Nepali, Kunal; Kumar, Raj; Sohi, Harmik; Murthy, R. S. R.

doi:10.1016/j.ijpharm.2012.04.030

Cited by 80 publications

(52 citation statements)

References 45 publications

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“…Meanwhile, compared to non-malignant cells, malignant cells are much more vulnerable to oxidative stress-induced cell death due to elevated production of endogenous ROS (11, 40, 41). Thus far, several cancer-specific ROS inducers were reported with promising results (42-44). Although Alternol was previously reported to induce ROS accumulation in gastric cancer cells, its functional significance on cell death was not determined (3).…”

Section: Discussionmentioning

confidence: 99%

Natural Compound Alternol Induces Oxidative Stress–Dependent Apoptotic Cell Death Preferentially in Prostate Cancer Cells

Tang

Chen

Huang

et al. 2014

Molecular Cancer Therapeutics

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Prostate cancers at the late stage of castration resistance are not responding well to most of current therapies available in clinic, reflecting a desperate need of novel treatment for this life-threatening disease. In this study, we evaluated the anti-cancer effect of a recently isolated natural compound Alternol in multiple prostate cancer cell lines with the properties of advanced prostate cancers in comparison to prostate-derived non-malignant cells. As assessed by trypan blue exclusion assay, a significant cell death was observed in all prostate cancer cell lines except DU145 but not in non-malignant (RWPE-1and BPH1) cells. Further analyses revealed that Alternol-induced cell death was an apoptotic response in a dose- and time-dependent manner, as evidenced by the appearance of apoptosis hallmarks such as Caspase-3 processing and PARP cleavage. Interestingly, Alternol-induced cell death was completely abolished by reactive oxygen species (ROS) scavengers, N-acetylcysteine (N-Ac) and dihydrolipoic acid (DHLA). We also demonstrated that the pro-apoptotic Bax protein was activated after Alternol treatment and was critical for Alternol-induced apoptosis. Animal xenograft experiments in nude mice showed that Alternol treatment largely suppressed tumor growth of PC-3 xenografts but not Bax-null DU-145 xenografts in vivo. These data suggest that Alternol might serve as a novel anticancer agent for late stage prostate cancer patient.

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Section: Discussionmentioning

confidence: 99%

Natural Compound Alternol Induces Oxidative Stress–Dependent Apoptotic Cell Death Preferentially in Prostate Cancer Cells

Tang

Chen

Huang

et al. 2014

Molecular Cancer Therapeutics

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“…After adding DIW (2 mL) to the polymer fi lm, the formed selfassembled NPs (i.e., TPCL1-FH NPs or TPCL2-FH NPs, respectively) in the aqueous dispersion were size-homogenized by sonication for 1 h and then additionally by extrusion at least ten times using a miniextruder (Avanti Polar Lipid, Alabama, USA) to obtain their small and homogenous size distribution. [ 31 ] The zeta-potentials and particle sizes of the formed TPCL-CD NPs (1 mL, 1 mg mL −1 ) and TPCL-FH NPs (1 mL, 0.5 mg mL −1 ) were measured with a zeta-potential and particle size analyzer (ELS-Z; Photal Otsuka Electronics Co., Osaka, Japan) with a fi xed wavelength of 677 nm and a constant angle of 90° at RT.…”

Section: Synthesis and Characterization Of Tpp-pcl-tpp (Tpcl) Polymersmentioning

confidence: 99%

Triphenylphosphonium‐Conjugated Poly(ε‐caprolactone)‐Based Self‐Assembled Nanostructures as Nanosized Drugs and Drug Delivery Carriers for Mitochondria‐Targeting Synergistic Anticancer Drug Delivery

Cho

Kwon

et al. 2015

Adv Funct Materials

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For mitochondria‐targeting delivery, a coupling reaction between poly(ε‐caprolactone) diol (PCL diol) and 4‐carboxybutyltriphenylphosphonium (4‐carboxybutyl TPP) results in the synthesis of amphiphilic TPP‐PCL‐TPP (TPCL) polymers with a bola‐like structure. In aqueous environments, the TPCL polymer self‐assembled via cosolvent dispersion and film hydration, resulting in the formation of cationic nanoparticles (NPs) less than 50 nm in size with zeta‐potentials of approximately 40 mV. Interestingly, different preparation methods for TPCL NPs result in various morphologies such as nanovesicles, nanofibers, and nanosheets. In vitro cytotoxicity results with TPCL NPs indicate IC50 values of approximately 10–60 μg mL−1, suggesting their potential as anticancer nanodrugs. TPCL NPs can be loaded both with hydrophobic doxorubicin (Dox) and its hydrophilic salt form (Dox·HCl), and their drug loading contents are approximately 2–10 wt% depending on the loading method and the hydrophilicity/hydrophobicity of the drugs. Although Dox·HCl exhibits more cellular and nuclear uptake, resulting in greater antitumor effects than Dox, most drug‐loaded TPCL NPs exhibit higher mitochondrial uptake and approximately 2–7‐fold higher mitochondria‐to‐nucleus preference than free drugs, resulting in superior (approximately 7.5–18‐fold) tumor‐killing activity for most drug‐loaded TPCL NPs compared with free drugs. In conclusion, TPCL‐based nanoparticles have potential both as antitumor nanodrugs themselves and as nanocarriers for chemical therapeutics.

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“…{Fulda, 2010 #29}(ref) While the therapeutic potential of harnessing the mitochondrial disruptive effects of Dox has been contemplated for over a decade (18), only recently have specific molecular targeting strategies been employed to deliver Dox to mitochondria. Such strategies include liposome encapsulation (19), chemical conjugation of mitochondrial targeting moieties (20,21) chemical modification (22), and nanoparticle encapsulation (23), all of which have demonstrated the capacity to induce cell death in cancer cells, validating this therapeutic strategy. Particularly promising is the ability of these targeted compounds to overcome clinically relevant resistance mechanisms that exist outside of mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity

Jean¹,

Tulumello²,

Riganti

et al. 2015

ACS Chem. Biol.

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Abstract:The highly effective anticancer agent doxorubicin (Dox), is a frontline drug used to treat a number of cancers including leukemias, ovarian, prostate, breast, and lung cancer. While Dox has a high level of activity against cancer cells, treatment is often complicated by doselimiting cardiotoxicity. For many years, this debilitating side effect is thought to originate from the drug's direct activity in the mitochondria of cardiac cells, while recent studies have shown that these are primarily downstream effect from nuclear damage. Our lab has developed a mitochondrially-targeted derivative of Dox that enables the selective study of toxicity generated by the presence of Dox in the mitochondria of H9c2 rat cardiomyocytes. We demonstrate that mitochondria-targeted doxorubicin (mtDox) lacks any direct nuclear effects, which allows the cardiomyocytes to undergo mitochondrial biogenesis. This recovery response compensates for the mitotoxic effects of Dox and prevents cell death in cardiomyocytes. In accordance with these findings, cardiac toxicity was only observed in Dox but not mtDox treated mice. This study provides valuable insight into the development of methods to effectively limit the debilitating cardiotoxic effects of Dox, and potentially of other chemotherapeutics that exert effects on multiple subcellular organelles..

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Intracellular delivery of redox cycler-doxorubicin to the mitochondria of cancer cell by folate receptor targeted mitocancerotropic liposomes

Cited by 80 publications

References 45 publications

Natural Compound Alternol Induces Oxidative Stress–Dependent Apoptotic Cell Death Preferentially in Prostate Cancer Cells

Natural Compound Alternol Induces Oxidative Stress–Dependent Apoptotic Cell Death Preferentially in Prostate Cancer Cells

Triphenylphosphonium‐Conjugated Poly(ε‐caprolactone)‐Based Self‐Assembled Nanostructures as Nanosized Drugs and Drug Delivery Carriers for Mitochondria‐Targeting Synergistic Anticancer Drug Delivery

Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity

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