Co-reporter:Ru Wen and Shanta Dhar
Chemical Science 2016 vol. 7(Issue 8) pp:5559-5567
Publication Date(Web):09 May 2016
DOI:10.1039/C6SC00481D
The down regulation of the cellular power generator, adenosine triphosphate (ATP) synthase, in various cancer cells plays an obstructive role in mitochondria-mediated cell death. Cancer cells up-regulate ATPase inhibitory factor 1 (IF1) and down-regulate β-F1-ATPase of ATP synthase to enhance aerobic glycolysis for tumor growth via inhibiting total ATP synthase activity in the oxidative phosphorylation (OXPHOS) pathway. Alpha-tocopheryl succinate (α-TOS), one of the most bioactive derivatives of vitamin E, can selectively induce apoptosis in numerous cancer cells. The cancer cell selective apoptosis inducing property of α-TOS is correlated to: mitochondrial destabilization, inhibition of anti-apoptotic B cell lymphoma 2 (Bcl2) and protein kinase C (PKC), caspase 3 activation, production of mitochondrial reactive oxygen species (ROS), and inhibition of succinate dehydrogenase activity of mitochondrial complex II, and interaction with complex I to some extent. There is no report which elucidates the effects of α-TOS on the cellular power generator, complex V or ATP synthase. Here, we report the activation of mitochondrial ATP synthase using a suitably designed chemical formulation of α-TOS for the first time. A mitochondria targeted α-TOS nanoparticle formulation demonstrated enhanced cytotoxicity and mitochondrial activities in cancer cells by inhibiting Bcl2 protein and activating ATP synthase. The modulation of ATP synthase in cancer cells by the engineered formulation of α-TOS can be promising for solid cancers with compromised ATP synthase.
Co-reporter:Akil A. Kalathil, Anil Kumar, Bhabatosh Banik, Timothy A. Ruiter, Rakesh K. Pathak and Shanta Dhar
Chemical Communications 2016 vol. 52(Issue 1) pp:140-143
Publication Date(Web):16 Oct 2015
DOI:10.1039/C5CC07316B
For better use of cyclooxygenase dependent anti-inflammatory properties and mitochondrial activities of aspirin, new hydrophobic analogues of aspirin were developed and successfully encapsulated in polymeric nanoparticles (NPs). In vivo anti-inflammatory effects of these NPs using a mouse model demonstrated unique properties of an optimized aspirin analogue to inhibit production of pro-inflammatory and enrichment of anti-inflammatory cytokines.
Co-reporter:Dr. Rakesh K. Pathak ; Shanta Dhar
Chemistry - A European Journal 2016 Volume 22( Issue 9) pp:3029-3036
Publication Date(Web):
DOI:10.1002/chem.201503866
Abstract
Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin-based therapy. A unique dual-acting chemotherapeutic modality, Platin-B, a prodrug of cisplatin and pipobroman-mimicking alkylating agent, was constructed to circumvent tumor resistance. Platin-B exhibited a superior cytotoxicity profile in cisplatin-resistant cancer cells. Enhanced activity and the ability to overcome cancer-induced resistance of Platin-B was related to adduct formation with intracellular glutathione, followed by the activity of Platin-B on the mitochondria of cells, along with its conventional nuclear activity. Alkylating moieties present on Platin-B enhanced its cellular and subcellular concentration and protected it from early drug sequestration by biological thiols.
Co-reporter:Rakesh K. Pathak
Journal of the American Chemical Society 2015 Volume 137(Issue 26) pp:8324-8327
Publication Date(Web):June 18, 2015
DOI:10.1021/jacs.5b03078
A single magic bullet is not enough for treatment of metastatic cancers. However, administration of a combination of free drugs can be extremely challenging because of the inability to control the correct choice of dosages and definitive delivery of the effective drug ratio at the target tissue due to the differences in pharmacokinetics and biodistribution of individual drugs. Here we report an engineered biodegradable polymer containing combination therapeutics that can be self-assembled into a controlled release nanoparticle with abilities to deliver multiple therapeutics in a predefined ratio following temporal release patterns. This platform technology can lead to a rationally designed combination therapy.
Co-reporter:Sean Marrache and Shanta Dhar
Chemical Science 2015 vol. 6(Issue 3) pp:1832-1845
Publication Date(Web):27 Oct 2014
DOI:10.1039/C4SC01963F
A key hallmark of many aggressive cancers is accelerated glucose metabolism. The enzymes that catalyze the first step of glucose metabolism are hexokinases. Elevated levels of hexokinase 2 (HK2) are found in cancer cells, but only in a limited number of normal tissues. Metabolic reprogramming of cancer cells using the energy blocker 3-bromopyruvate (3-BP), which inhibits HK2, has the potential to provide tumor-specific anticancer agents. However, the unique structural and functional characteristics of mitochondria prohibit selective subcellular targeting of 3-BP to modulate the function of this organelle for therapeutic gain. A mitochondria-targeted gold nanoparticle (T-3-BP-AuNP), decorated with 3-BP and delocalized lipophilic triphenylphosphonium cations to target the mitochondrial membrane potential (Δψm), was developed for delivery of 3-BP to cancer cell mitochondria by taking advantage of the higher Δψm in cancer cells compared to normal cells. In vitro studies demonstrated an enhanced anticancer activity of T-3-BP-AuNPs compared to the non-targeted construct NT-3-BP-AuNP or free 3-BP. The anticancer activity of T-3-BP-AuNPs was further enhanced upon laser irradiation by exciting the surface plasmon resonance band of AuNP and thereby utilizing a combination of 3-BP chemotherapeutic and AuNP photothermal effects. The lower toxicity of T-3-BP-NPs in normal mesenchymal stem cells indicated that these NPs preferentially kill cancer cells. T-3-BP-AuNPs showed an enhanced ability to modulate cancer cell metabolism by inhibiting glycolysis as well as demolishing mitochondrial oxidative phosphorylation. Our findings demonstrate that concerted chemo-photothermal treatment of glycolytic cancer cells with a single NP capable of targeting mitochondria, mediating simultaneous release of a glycolytic inhibitor and photothermal ablation, may have promise as a new anticancer therapy.
Co-reporter:Brittany Feldhaeusser, Simon R. Platt, Sean Marrache, Nagesh Kolishetti, Rakesh K. Pathak, David J. Montgomery, Lisa R. Reno, Elizabeth Howerth and Shanta Dhar
Nanoscale 2015 vol. 7(Issue 33) pp:13822-13830
Publication Date(Web):13 Jul 2015
DOI:10.1039/C5NR03447G
Intracranial neoplasia is a significant cause of morbidity and mortality in both human and veterinary patients, and is difficult to treat with traditional therapeutic methods. Cisplatin is a platinum (Pt)-containing chemotherapeutic agent approved by the Food and Drug Administration; however, substantial limitations exist for its application in canine brain tumor treatment due to the difficulty in crossing the blood-brain barrier (BBB), development of resistance, and toxicity. A modified Pt(IV)-prodrug of cisplatin, Platin-M, was recently shown to be deliverable to the brain via a biocompatible mitochondria-targeted lipophilic polymeric nanoparticle (NP) that carries the drug across the BBB and to the mitochondria. NP mediated controlled release of Platin-M and subsequent reduction of this prodrug to cisplatin allowed cross-links to be formed with the mitochondrial DNA, which have no nucleotide excision repair system, forcing the overactive cancer cells to undergo apoptosis. Here, we report in vitro effects of targeted Platin-M NPs (T-Platin-M-NPs) in canine glioma and glioblastoma cell lines with results indicating that this targeted NP formulation is more effective than cisplatin. In both the cell lines, T-Platin-M-NP was significantly more efficacious compared to carboplatin, another Pt-based chemotherapy, which is used in the settings of recurrent high-grade glioblastoma. Mitochondrial stress analysis indicated that T-Platin-M-NP is more effective in disrupting the mitochondrial bioenergetics in both the cell types. A 14-day distribution study in healthy adult beagles using a single intravenous injection at 0.5 mg kg−1 (with respect to Platin-M) of T-Platin-M-NPs showed high levels of Pt accumulation in the brain, with negligible amounts in the other analyzed organs. Safety studies in the beagles monitoring physical, hematological, and serum chemistry evaluations were within the normal limits on days 1, 7, and 14 after injection of either 0.5 mg kg−1 or 2 mg kg−1 or 2.2 mg kg−1 (with respect to Platin-M) of T-Platin-M-NPs. At all doses over the 14-day period, no neurotoxicity was observed based upon periodic neurological examinations and cerebrospinal fluid analysis. These studies demonstrated the translational nature of T-Platin-M-NPs for applications in the treatment of brain tumors.
Co-reporter:Rakesh K. Pathak, Sean Marrache, Donald A. Harn, and Shanta Dhar
ACS Chemical Biology 2014 Volume 9(Issue 5) pp:1178
Publication Date(Web):March 11, 2014
DOI:10.1021/cb400944y
Tumor growth is fueled by the use of glycolysis, which normal cells use only in the scarcity of oxygen. Glycolysis makes tumor cells resistant to normal death processes. Targeting this unique tumor metabolism can provide an alternative strategy to selectively destroy the tumor, leaving normal tissue unharmed. The orphan drug dichloroacetate (DCA) is a mitochondrial kinase inhibitor that has the ability to show such characteristics. However, its molecular form shows poor uptake and bioavailability and limited ability to reach its target mitochondria. Here, we describe a targeted molecular scaffold for construction of a multiple DCA loaded compound, Mito-DCA, with three orders of magnitude enhanced potency and cancer cell specificity compared to DCA. Incorporation of a lipophilic triphenylphosphonium cation through a biodegradable linker in Mito-DCA allowed for mitochondria targeting. Mito-DCA did not show any significant metabolic effects toward normal cells but tumor cells with dysfunctional mitochondria were affected by Mito-DCA, which caused a switch from glycolysis to glucose oxidation and subsequent cell death via apoptosis. Effective delivery of DCA to the mitochondria resulted in significant reduction in lactate levels and played important roles in modulating dendritic cell (DC) phenotype evidenced by secretion of interleukin-12 from DCs upon activation with tumor antigens from Mito-DCA treated cancer cells. Targeting mitochondrial metabolic inhibitors to the mitochondria could lead to induction of an efficient antitumor immune response, thus introducing the concept of combining glycolysis inhibition with immune system to destroy tumor.
Co-reporter:Sean Marrache;Rakesh K. Pathak
PNAS 2014 Volume 111 (Issue 29 ) pp:10444-10449
Publication Date(Web):2014-07-22
DOI:10.1073/pnas.1405244111
Chemoresistance of cisplatin therapy is related to extensive repair of cisplatin-modified DNA in the nucleus by the nucleotide
excision repair (NER). Delivering cisplatin to the mitochondria to attack mitochondrial genome lacking NER machinery can lead
to a rationally designed therapy for metastatic, chemoresistant cancers and might overcome the problems associated with conventional
cisplatin treatment. An engineered hydrophobic mitochondria-targeted cisplatin prodrug, Platin-M, was constructed using a
strain-promoted alkyne–azide cycloaddition chemistry. Efficient delivery of Platin-M using a biocompatible polymeric nanoparticle
(NP) based on biodegradable poly(lactic-co-glycolic acid)-block-polyethyleneglycol functionalized with a terminal triphenylphosphonium cation, which has remarkable
activity to target mitochondria of cells, resulted in controlled release of cisplatin from Platin-M locally inside the mitochondrial
matrix to attack mtDNA and exhibited otherwise-resistant advanced cancer sensitive to cisplatin-based chemotherapy. Identification
of an optimized targeted-NP formulation with brain-penetrating properties allowed for delivery of Platin-M inside the mitochondria
of neuroblastoma cells resulting in ∼17 times more activity than cisplatin. The remarkable activity of Platin-M and its targeted-NP
in cisplatin-resistant cells was correlated with the hyperpolarization of mitochondria in these cells and mitochondrial bioenergetics
studies in the resistance cells further supported this hypothesis. This unique dual-targeting approach to controlled mitochondrial
delivery of cisplatin in the form of a prodrug to attack the mitochondrial genome lacking NER machinery and in vivo distribution
of the delivery vehicle in the brain suggested previously undescribed routes for cisplatin-based therapy.
Co-reporter:Dr. Rakesh K. Pathak;Sean Marrache;Joshua H. Choi;Trenton B. Berding;Dr. Shanta Dhar
Angewandte Chemie International Edition 2014 Volume 53( Issue 7) pp:1963-1967
Publication Date(Web):
DOI:10.1002/anie.201308899
Abstract
Cancer-associated inflammation induces tumor progression to the metastatic stage, thus indicating that a chemo-anti-inflammatory strategy is of interest for the management of aggressive cancers. The platinum(IV) prodrug Platin-A was designed to release cisplatin and aspirin to ameliorate the nephrotoxicity and ototoxicity caused by cisplatin. Platin-A exhibited anticancer and anti-inflammatory properties which are better than a combination of cisplatin and aspirin. These findings highlight the advantages of combining anti-inflammatory treatment with chemotherapy when both the drugs are delivered in the form of a single prodrug.
Co-reporter:Dr. Rakesh K. Pathak;Sean Marrache;Joshua H. Choi;Trenton B. Berding;Dr. Shanta Dhar
Angewandte Chemie 2014 Volume 126( Issue 7) pp:1994-1998
Publication Date(Web):
DOI:10.1002/ange.201308899
Abstract
Cancer-associated inflammation induces tumor progression to the metastatic stage, thus indicating that a chemo-anti-inflammatory strategy is of interest for the management of aggressive cancers. The platinum(IV) prodrug Platin-A was designed to release cisplatin and aspirin to ameliorate the nephrotoxicity and ototoxicity caused by cisplatin. Platin-A exhibited anticancer and anti-inflammatory properties which are better than a combination of cisplatin and aspirin. These findings highlight the advantages of combining anti-inflammatory treatment with chemotherapy when both the drugs are delivered in the form of a single prodrug.
Co-reporter:Dr. Rakesh K. Pathak;Christopher D. McNitt;Dr. Vladimir V. Popik;Dr. Shanta Dhar
Chemistry - A European Journal 2014 Volume 20( Issue 23) pp:6861-6865
Publication Date(Web):
DOI:10.1002/chem.201402573
Abstract
The ability to rationally design and construct a platform technology to develop new platinum(IV) [PtIV] prodrugs with functionalities for installation of targeting moieties, delivery systems, fluorescent reporters from a single precursor with the ability to release biologically active cisplatin by using well-defined chemistry is critical for discovering new platinum-based therapeutics. With limited numbers of possibilities considering the sensitivity of PtIV centers, we used a strain-promoted azide–alkyne cycloaddition approach to provide a platform, in which new functionalities can easily be installed on cisplatin prodrugs from a single PtIV precursor. The ability of this platform to be incorporated in nanodelivery vehicle and conjugation to fluorescent reporters were also investigated.
Co-reporter:Sean Marrache, Joshua H. Choi, Smanla Tundup, Dhillon Zaver, Donald A. Harn and Shanta Dhar
Integrative Biology 2013 vol. 5(Issue 1) pp:215-223
Publication Date(Web):26 Jul 2012
DOI:10.1039/C2IB20125A
A therapeutic technology that combines the phototoxic and immune-stimulating ability of photodynamic therapy (PDT) with the widespread effectiveness of the immune system can be very promising to treat metastatic breast cancer. We speculated that the knowledge of molecular mechanisms of existing multi-component therapies could provide clues to aid the discovery of new combinations of an immunostimulant with a photosensitizer (PS) using a nanoparticle (NP) delivery platform. Therapeutic challenges when administering therapeutic combinations include the choice of dosages to reduce side effects, the definitive delivery of the correct drug ratio, and exposure to the targets of interest. These factors are very difficult to achieve when drugs are individually administered. By combining controlled release polymer-based NP drug delivery approaches, we were able to differentially deliver zinc phthalocyanine (ZnPc) based PS to metastatic breast cancer cells along with CpG-ODN, a single-stranded DNA that is a known immunostimulant to manage the distant tumors in a temporally regulated manner. We encapsulated ZnPc which is a long-wavelength absorbing PS within a polymeric NP core made up of poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG). After coating the outside of the polymeric core with gold NPs (AuNPs), we further modified the AuNP surface with CpG-ODN. In vitro cytotoxicity using 4T1 metastatic mouse breast carcinoma cells shows significant photocytotoxicity of the hybrid NPs containing both ZnPc and CpG-ODN after irradiation with a 660 nm LASER light and this activity was remarkably better than either treatment alone. Treatment of mouse bone marrow derived dendritic cells with the PDT-killed 4T1 cell lysate shows that the combination of PDT with a synergistic immunostimulant in a single NP system results in significant immune response, which can be used for the treatment of metastatic cancer.
Co-reporter:Sean Marrache, Smanla Tundup, Donald A. Harn, and Shanta Dhar
ACS Nano 2013 Volume 7(Issue 8) pp:7392
Publication Date(Web):July 30, 2013
DOI:10.1021/nn403158n
One of the limitations for clinical applications of dendritic cell (DC)-based cancer immunotherapy is the low potency in generating tumor antigen specific T cell responses. We examined the immunotherapeutic potential of a mitochondria-targeted nanoparticle (NP) based on a biodegradable polymer and zinc phthalocyanine (ZnPc) photosensitizer (T-ZnPc-NPs). Here, we report that tumor antigens generated from treatment of breast cancer cells with T-ZnPc-NPs upon light stimulation activate DCs to produce high levels of interferon-gamma, an important cytokine considered as a product of T and natural killer cells. The remarkable ex vivo DC stimulation ability of this tumor cell supernatant is a result of an interleukin (IL)-12/IL-18 autocrine effect. These findings contribute to the understanding of how in situ light activation amplifies the host immune responses when NPs deliver the photosensitizer to the mitochondria and open up the possibility of using mitochondria-targeted-NP-treated, light-activated cancer cell supernatants as possible vaccines.Keywords: apoptosis; biodegradable polymer; dendritic cell therapy; photodynamic therapy; vaccine
Co-reporter:Sean Marrache
PNAS 2013 Volume 110 (Issue 23 ) pp:9445-9450
Publication Date(Web):2013-06-04
DOI:10.1073/pnas.1301929110
Atherosclerosis remains one of the most common causes of death in the United States and throughout the world because of the
lack of early detection. Macrophage apoptosis is a major contributor to the instability of atherosclerotic lesions. Development
of an apoptosis targeted high-density lipoprotein (HDL)-mimicking nanoparticle (NP) to carry contrast agents for early detection
of vulnerable plaques and the initiation of preventative therapies that exploit the vascular protective effects of HDL can
be attractive for atherosclerosis. Here, we report the construction of a synthetic, biodegradable HDL-NP platform for detection
of vulnerable plaques by targeting the collapse of mitochondrial membrane potential that occurs during apoptosis. This HDL
mimic contains a core of biodegradable poly(lactic-co-glycolic acid), cholesteryl oleate, and a phospholipid bilayer coat that is decorated with triphenylphosphonium (TPP) cations
for detection of mitochondrial membrane potential collapse. The lipid layer provides the surface for adsorption of apolipoprotein
(apo) A-I mimetic 4F peptide, and the core contains diagnostically active quantum dots (QDs) for optical imaging. In vitro
uptake, detection of apoptosis, and cholesterol binding studies indicated promising detection ability and therapeutic potential
of TPP-HDL-apoA-I-QD NPs. In vitro studies indicated the potential of these NPs in reverse cholesterol transport. In vivo
biodistribution and pharmacokinetics indicated favorable tissue distribution, controlled pharmacokinetic parameters, and significant
triglyceride reduction for i.v.-injected TPP-HDL-apoA-I-QD NPs in rats. These HDL NPs demonstrate excellent biocompatibility,
stability, nontoxic, and nonimmunogenic properties, which prove to be promising for future translation in early plaque diagnosis
and might find applications to prevent vulnerable plaque progression.
Co-reporter:Shanta Dhar;Sean Marrache
PNAS 2013 Volume 110 (Issue 38 ) pp:E3549
Publication Date(Web):2013-09-17
DOI:10.1073/pnas.1311060110
Co-reporter:Sean Marrache
PNAS 2012 Volume 109 (Issue 40 ) pp:16288-16293
Publication Date(Web):2012-10-02
DOI:10.1073/pnas.1210096109
Mitochondrial dysfunctions cause numerous human disorders. A platform technology based on biodegradable polymers for carrying
bioactive molecules to the mitochondrial matrix could be of enormous potential benefit in treating mitochondrial diseases.
Here we report a rationally designed mitochondria-targeted polymeric nanoparticle (NP) system and its optimization for efficient
delivery of various mitochondria-acting therapeutics by blending a targeted poly(d,l-lactic-co-glycolic acid)-block (PLGA-b)-poly(ethylene glycol) (PEG)-triphenylphosphonium (TPP) polymer (PLGA-b-PEG-TPP) with either nontargeted PLGA-b-PEG-OH or PLGA-COOH. An optimized formulation was identified through in vitro screening of a library of charge- and size-varied
NPs, and mitochondrial uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions
of cells treated with blended NPs composed of PLGA-b-PEG-TPP and a triblock copolymer containing a fluorescent quantum dot, PLGA-b-PEG-QD. The versatility of this platform was demonstrated by studying various mitochondria-acting therapeutics for different
applications, including the mitochondria-targeting chemotherapeutics lonidamine and α-tocopheryl succinate for cancer, the
mitochondrial antioxidant curcumin for Alzheimer’s disease, and the mitochondrial uncoupler 2,4-dinitrophenol for obesity.
These biomolecules were loaded into blended NPs with high loading efficiencies. Considering efficacy, the targeted PLGA-b-PEG-TPP NP provides a remarkable improvement in the drug therapeutic index for cancer, Alzheimer’s disease, and obesity compared
with the nontargeted construct or the therapeutics in their free form. This work represents the potential of a single, programmable
NP platform for the diagnosis and targeted delivery of therapeutics for mitochondrial dysfunction-related diseases.
Co-reporter:Ru Wen, Bhabatosh Banik, Rakesh K. Pathak, Anil Kumar, ... Shanta Dhar
Advanced Drug Delivery Reviews (1 April 2016) Volume 99(Part A) pp:52-69
Publication Date(Web):1 April 2016
DOI:10.1016/j.addr.2015.12.024
Mitochondrial dysfunctions are recognized as major factors for various diseases including cancer, cardiovascular diseases, diabetes, neurological disorders, and a group of diseases so called “mitochondrial dysfunction related diseases”. One of the major hurdles to gain therapeutic efficiency in diseases where the targets are located in the mitochondria is the accessibility of the targets in this compartmentalized organelle that imposes barriers toward internalization of ions and molecules. Over the time, different tools and techniques were developed to improve therapeutic index for mitochondria acting drugs. Nanotechnology has unfolded as one of the logical and encouraging tools for delivery of therapeutics in controlled and targeted manner simultaneously reducing side effects from drug overdose. Tailor-made nanomedicine based therapeutics can be an excellent tool in the toolbox for diseases associated with mitochondrial dysfunctions. In this review, we present an extensive coverage of possible therapeutic targets in different compartments of mitochondria for cancer, cardiovascular, and mitochondrial dysfunction related diseases.Download high-res image (99KB)Download full-size image
Co-reporter:Sean Marrache and Shanta Dhar
Chemical Science (2010-Present) 2015 - vol. 6(Issue 3) pp:NaN1845-1845
Publication Date(Web):2014/10/27
DOI:10.1039/C4SC01963F
A key hallmark of many aggressive cancers is accelerated glucose metabolism. The enzymes that catalyze the first step of glucose metabolism are hexokinases. Elevated levels of hexokinase 2 (HK2) are found in cancer cells, but only in a limited number of normal tissues. Metabolic reprogramming of cancer cells using the energy blocker 3-bromopyruvate (3-BP), which inhibits HK2, has the potential to provide tumor-specific anticancer agents. However, the unique structural and functional characteristics of mitochondria prohibit selective subcellular targeting of 3-BP to modulate the function of this organelle for therapeutic gain. A mitochondria-targeted gold nanoparticle (T-3-BP-AuNP), decorated with 3-BP and delocalized lipophilic triphenylphosphonium cations to target the mitochondrial membrane potential (Δψm), was developed for delivery of 3-BP to cancer cell mitochondria by taking advantage of the higher Δψm in cancer cells compared to normal cells. In vitro studies demonstrated an enhanced anticancer activity of T-3-BP-AuNPs compared to the non-targeted construct NT-3-BP-AuNP or free 3-BP. The anticancer activity of T-3-BP-AuNPs was further enhanced upon laser irradiation by exciting the surface plasmon resonance band of AuNP and thereby utilizing a combination of 3-BP chemotherapeutic and AuNP photothermal effects. The lower toxicity of T-3-BP-NPs in normal mesenchymal stem cells indicated that these NPs preferentially kill cancer cells. T-3-BP-AuNPs showed an enhanced ability to modulate cancer cell metabolism by inhibiting glycolysis as well as demolishing mitochondrial oxidative phosphorylation. Our findings demonstrate that concerted chemo-photothermal treatment of glycolytic cancer cells with a single NP capable of targeting mitochondria, mediating simultaneous release of a glycolytic inhibitor and photothermal ablation, may have promise as a new anticancer therapy.
Co-reporter:Ru Wen and Shanta Dhar
Chemical Science (2010-Present) 2016 - vol. 7(Issue 8) pp:NaN5567-5567
Publication Date(Web):2016/05/09
DOI:10.1039/C6SC00481D
The down regulation of the cellular power generator, adenosine triphosphate (ATP) synthase, in various cancer cells plays an obstructive role in mitochondria-mediated cell death. Cancer cells up-regulate ATPase inhibitory factor 1 (IF1) and down-regulate β-F1-ATPase of ATP synthase to enhance aerobic glycolysis for tumor growth via inhibiting total ATP synthase activity in the oxidative phosphorylation (OXPHOS) pathway. Alpha-tocopheryl succinate (α-TOS), one of the most bioactive derivatives of vitamin E, can selectively induce apoptosis in numerous cancer cells. The cancer cell selective apoptosis inducing property of α-TOS is correlated to: mitochondrial destabilization, inhibition of anti-apoptotic B cell lymphoma 2 (Bcl2) and protein kinase C (PKC), caspase 3 activation, production of mitochondrial reactive oxygen species (ROS), and inhibition of succinate dehydrogenase activity of mitochondrial complex II, and interaction with complex I to some extent. There is no report which elucidates the effects of α-TOS on the cellular power generator, complex V or ATP synthase. Here, we report the activation of mitochondrial ATP synthase using a suitably designed chemical formulation of α-TOS for the first time. A mitochondria targeted α-TOS nanoparticle formulation demonstrated enhanced cytotoxicity and mitochondrial activities in cancer cells by inhibiting Bcl2 protein and activating ATP synthase. The modulation of ATP synthase in cancer cells by the engineered formulation of α-TOS can be promising for solid cancers with compromised ATP synthase.
Co-reporter:Akil A. Kalathil, Anil Kumar, Bhabatosh Banik, Timothy A. Ruiter, Rakesh K. Pathak and Shanta Dhar
Chemical Communications 2016 - vol. 52(Issue 1) pp:NaN143-143
Publication Date(Web):2015/10/16
DOI:10.1039/C5CC07316B
For better use of cyclooxygenase dependent anti-inflammatory properties and mitochondrial activities of aspirin, new hydrophobic analogues of aspirin were developed and successfully encapsulated in polymeric nanoparticles (NPs). In vivo anti-inflammatory effects of these NPs using a mouse model demonstrated unique properties of an optimized aspirin analogue to inhibit production of pro-inflammatory and enrichment of anti-inflammatory cytokines.
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