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1.
Nanoscale ; 7(33): 13822-30, 2015 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-26234400

RESUMO

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.


Assuntos
Antineoplásicos/química , Cisplatino/química , Portadores de Fármacos/química , Nanopartículas/química , Alanina Transaminase/sangue , Animais , Antineoplásicos/toxicidade , Nitrogênio da Ureia Sanguínea , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Cisplatino/toxicidade , Creatinina/sangue , Cães , Feminino , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Platina/líquido cefalorraquidiano
2.
Chem Sci ; 6(3): 1832-1845, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25709804

RESUMO

A key hallmark of many aggressive cancers is accelerated glucose metabolism. The enzymes that catalyze the first step of glucose metabolism are hexokinases. High 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) that 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 higher Δψm in cancer cells compared to normal cells. In vitro studies demonstrated 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-AuNP 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 less toxic behavior of T-3-BPNPs in normal mesenchymal stem cells indicated that these NPs preferentially kill cancer cells. T-3-BP-AuNPs showed enhanced ability to modulate cancer cell metabolism by inhibiting glycolysis as well as demolishing mitochondrial oxidative phosphorylation. Our findings demonstrated 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.

3.
Cancer Lett ; 359(2): 233-40, 2015 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-25600708

RESUMO

Nucleoside analogs are used as chemotherapeutic options for the treatment of platinum-resistant ovarian cancers. Human concentrative nucleoside transporter 1 (hCNT1) is implicated in sensitizing solid tumors to nucleoside analogs although its role in determining drug efficacy in ovarian cancers remains unclear. Here we examined the functional expression of hCNT1 and compared its contributions toward gemcitabine efficacy in histological subtypes of ovarian cancer. Radioactivity analysis identified hCNT1-mediated (3)H-gemcitabine transport in ovarian cancer cells to be significantly reduced compared with that of normal ovarian surface epithelial cells. Biochemical and immunocytochemical analysis identified that unlike normal ovarian cells which expressed high levels of hCNT1 at the apical cell surface, the transporter was either diminished in expression and/or mislocalized in cell lines of various subtypes of ovarian cancer. Retroviral expression of hCNT1 selectively rescued gemcitabine transport in cell lines representing serous, teratocarcinoma, and endometrioid subtypes, but not clear cell carcinoma (CCC). In addition, exogenous hCNT1 predominantly accumulated in intracytoplasmic vesicles in CCC suggesting defective cellular trafficking of hCNT1 as a contributing factor to transport deficiency. Despite diminution of hCNT1 transport in the majority of ovarian cancers and apparent trafficking defects with CCC, the chemotherapeutic efficacy of gemcitabine was broadly enhanced in all subtypes when delivered via engineered nanoparticles (NPs). Additionally, by bypassing the transport requirement, the delivery of a gemcitabine-cisplatin combination in NP formulation increased their synergistic interactions. These findings uncover hCNT1 as a putative determinant for nucleoside analog chemoresistance in ovarian cancer and may help rationalize drug selection and delivery strategies for various histological subtypes of ovarian cancer.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Proteínas de Membrana Transportadoras/metabolismo , Antimetabólitos Antineoplásicos/química , Transporte Biológico , Linhagem Celular Tumoral , Cisplatino/química , Cisplatino/farmacologia , Desoxicitidina/química , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Concentração Inibidora 50 , Nanocápsulas/química , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Gencitabina
4.
Methods Mol Biol ; 1265: 113-22, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25634271

RESUMO

Stimulating the immune system for potent immune therapy against cancer is potentially a revolutionary method to eradicate cancer. Tumors stimulated with photosensitizers (PSs) not only kill cancer cells but also help to boost the immune system. We recently reported that tumor-associated antigens (TAAs) generated by delivery of a mitochondria-acting PS zinc phthalocyanine (ZnPc) to MCF-7 breast cancer cells followed by laser irradiation can lead to ex vivo stimulation of mouse bone marrow-derived dendritic cells (BMDCs). The antigens generated from the breast cancer cells were also found to cause significant DC maturation and the activated DCs were able to stimulate T cells to cytotoxic CD8(+) T cells. In this protocol, we describe methods to engineer a mitochondria-targeted biodegradable nanoparticle (NP) formulation, T-ZnPc-NPs for delivery of ZnPc to the mitochondria of MCF-7 cells, subsequent photodynamic therapy (PDT) using a long wavelength laser irradiation to produce TAAs, DC stimulation by the TAAs to secrete interferon-gamma (IFN-γ), and matured DC-driven T-cell activation.


Assuntos
Células Dendríticas/metabolismo , Mitocôndrias/metabolismo , Nanoconjugados/química , Linfócitos T/metabolismo , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Camundongos , Mitocôndrias/efeitos da radiação , Fotoquimioterapia , Polietilenoglicóis/química , Poliglactina 910/química , Linfócitos T/imunologia
5.
Proc Natl Acad Sci U S A ; 111(29): 10444-9, 2014 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-25002500

RESUMO

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.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Genoma Mitocondrial/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Ácido Láctico/química , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nanopartículas/ultraestrutura , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Especificidade de Órgãos/efeitos dos fármacos , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Ratos , Distribuição Tecidual/efeitos dos fármacos
6.
ACS Chem Biol ; 9(5): 1178-87, 2014 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-24617941

RESUMO

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.


Assuntos
Antineoplásicos/administração & dosagem , Ácido Dicloroacético/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Mitocôndrias/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ácido Dicloroacético/farmacologia , Glucose/metabolismo , Humanos , Ácido Láctico/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Compostos Organofosforados/química , Inibidores de Proteínas Quinases/farmacologia
7.
Angew Chem Int Ed Engl ; 53(7): 1963-7, 2014 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-24453035

RESUMO

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.


Assuntos
Aspirina/administração & dosagem , Cisplatino/administração & dosagem , Pró-Fármacos/administração & dosagem , Administração Intravenosa , Aspirina/química , Aspirina/farmacocinética , Cisplatino/química , Cisplatino/farmacocinética , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Pró-Fármacos/química , Pró-Fármacos/farmacocinética
8.
ACS Nano ; 7(8): 7392-402, 2013 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-23899410

RESUMO

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.


Assuntos
Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Interferon gama/metabolismo , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Neoplasias/terapia , Animais , Antígenos de Neoplasias/química , Apoptose , Materiais Biocompatíveis/química , Vacinas Anticâncer/química , Linhagem Celular Tumoral , Células Dendríticas/citologia , Células HeLa , Humanos , Imunoterapia/métodos , Indóis/química , Isoindóis , Células MCF-7 , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/química , Polímeros/química , Compostos de Zinco
9.
PLoS One ; 8(8): e71196, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23940717

RESUMO

We evaluated the potential of an investigational histone methylation reversal agent, 3-deazaneplanocin A (DZNep), in improving the chemosensitivity of pancreatic cancer to nucleoside analogs (i.e., gemcitabine). DZNep brought delayed but selective cytotoxicity to pancreatic cancer cells without affecting normal human pancreatic ductal epithelial (HPDE) cells. Co-exposure of DZNep and gemcitabine induced cytotoxic additivity or synergism in both well- and poorly-differentiated pancreatic cell lines by increased apoptosis. In contrast, DZNep exerted antagonism with gemcitabine against HPDE cells with significant reduction in cytotoxicity compared with the gemcitabine-alone regimen. DZNep marginally depended on purine nucleoside transporters for its cytotoxicity, but the transport dependence was circumvented by acyl derivatization. Drug exposure studies revealed that a short priming with DZNep followed by gemcitabine treatment rather than co-treatment of both agents to produce a maximal chemosensitization response in both gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. DZNep rapidly and reversibly decreased trimethylation of histone H3 lysine 27 but increased trimethylation of lysine 9 in an EZH2- and JMJD1A/2C-dependent manner, respectively. However, DZNep potentiation of nucleoside analog chemosensitization was found to be temporally coupled to trimethylation changes in lysine 27 and not lysine 9. Polymeric nanoparticles engineered to chronologically release DZNep followed by gemcitabine produced pronounced chemosensitization and dose-lowering effects. Together, our results identify that an optimized DZNep exposure can presensitize pancreatic cancer cells to anticancer nucleoside analogs through the reversal of histone methylation, emphasizing the promising clinical utilities of epigenetic reversal agents in future pancreatic cancer combination therapies.


Assuntos
Adenosina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nucleosídeos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Adenosina/farmacologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Células Cultivadas , Metilação de DNA/efeitos dos fármacos , Preparações de Ação Retardada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Humanos , Nanopartículas , Neoplasias Pancreáticas/patologia , Xenopus , Gencitabina
10.
Curr Med Chem ; 20(28): 3500-14, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23834187

RESUMO

Site directed drug delivery with high efficacy is the biggest challenge in the area of current pharmaceuticals. Biodegradable polymer-based controlled release nanoparticle platforms could be beneficial for targeted delivery of therapeutics and contrast agents for a myriad of important human diseases. Biodegradable nanoparticles, which can be engineered to load multiple drugs with varied physicochemical properties, contrast agents, and cellular or intracellular component targeting moieties, have emerged as potential alternatives for tracking and treating human diseases. In this review, we will highlight the current advances in the design and execution of such platforms for their potential application in the diagnosis and treatment of variety of diseases ranging from cancer to Alzheimer's and we will provide a critical analysis of the associated challenges for their possible clinical translation.


Assuntos
Portadores de Fármacos/química , Nanopartículas/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Materiais Biocompatíveis/química , Barreira Hematoencefálica/química , Barreira Hematoencefálica/metabolismo , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/tratamento farmacológico , Meios de Contraste/administração & dosagem , Meios de Contraste/química , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/tratamento farmacológico , Polímeros/química
11.
Proc Natl Acad Sci U S A ; 110(23): 9445-50, 2013 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-23671083

RESUMO

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.


Assuntos
Aterosclerose/diagnóstico , Lipoproteínas HDL , Modelos Moleculares , Nanopartículas , Pontos Quânticos , Animais , Apoptose/fisiologia , Linhagem Celular , Meios de Contraste/química , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Lipoproteínas HDL/química , Lipoproteínas HDL/farmacocinética , Espectrometria de Massas , Potencial da Membrana Mitocondrial/fisiologia , Células-Tronco Mesenquimais , Camundongos , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Nanopartículas/química
12.
Integr Biol (Camb) ; 5(1): 215-23, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22832596

RESUMO

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.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Neoplasias da Mama/secundário , Neoplasias da Mama/terapia , Indóis/uso terapêutico , Nanocápsulas/administração & dosagem , Oligodesoxirribonucleotídeos/administração & dosagem , Compostos Organometálicos/uso terapêutico , Fotoquimioterapia/métodos , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Isoindóis , Camundongos , Camundongos Endogâmicos BALB C , Nanocápsulas/ultraestrutura , Fármacos Fotossensibilizantes/uso terapêutico , Resultado do Tratamento , Compostos de Zinco
13.
Proc Natl Acad Sci U S A ; 109(40): 16288-93, 2012 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-22991470

RESUMO

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.


Assuntos
Bioengenharia/métodos , Sistemas de Liberação de Medicamentos/métodos , Doenças Mitocondriais/tratamento farmacológico , Nanopartículas/química , Polímeros/química , 2,4-Dinitrofenol , Adipogenia/fisiologia , Análise de Variância , Curcumina , Humanos , Indazóis , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Poliglactina 910/síntese química , Poliglactina 910/química , Polímeros/metabolismo , alfa-Tocoferol
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