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1.
Cancer Lett ; 589: 216810, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38494151

RESUMO

Pancreatic cancer is characterized by desmoplasia; crosstalk between pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) leads to the deposition of extracellular matrix proteins in the tumor environment resulting in poor vascularity. Targeting either PCCs or PSCs individually has produced mixed results, and there is currently no effective strategy to target both cell types simultaneously. Previously, we demonstrated, through in vitro cell culture experiments, that a specific gold nanoparticle-based nanoformulation containing the anti-EGFR antibody cetuximab (C225) as a targeting agent and gemcitabine as a chemotherapeutic agent effectively targets both PCCs and PSCs simultaneously. Herein, we extend our studies to test the ability of these in vitro tested nano formulations to inhibit tumor growth in an orthotopic co-implantation model of pancreatic cancer in vivo. Orthotopic tumors were established by co-implantation of equal numbers of PCCs and PSCs in the mouse pancreas. Among the various formulations tested, 5 nm gold nanoparticles coated with gemcitabine, cetuximab and poly-ethylene glycol (PEG) of molecular weight 1000 Da, which we named ACGP441000, demonstrated optimal efficacy in inhibiting tumor growth. The current study reveals an opportunity to target PCCs and PSCs simultaneously, by exploiting their overexpression of EGFR as a target, in order to inhibit pancreatic cancer growth.


Assuntos
Nanopartículas Metálicas , Neoplasias Pancreáticas , Animais , Camundongos , Gencitabina , Ouro , Cetuximab/farmacologia , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Distribuição Tecidual , Linhagem Celular Tumoral , Neoplasias Pancreáticas/patologia , Sistemas de Liberação de Medicamentos/métodos , Células Estreladas do Pâncreas/metabolismo
3.
ACS Nano ; 17(10): 9326-9337, 2023 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-37129853

RESUMO

The RAS-transformed cells utilize macropinocytosis to acquire amino acids to support their uncontrolled growth. However, targeting RAS to inhibit macropinocytosis remains a challenge. Here, we report that gold nanoparticles (GNP) inhibit macropinocytosis by decreasing KRAS activation. Using surface-modified and unmodified GNP, we showed that unmodified GNP specifically sequestered both wild-type and mutant KRAS and inhibited its activation, irrespective of growth factor stimulation, while surface-passivated GNP had no effect. Alteration of KRAS activation is reflected on downstream signaling cascades, macropinocytosis and tumor cell growth in vitro, and two independent preclinical human xenograft models of pancreatic cancer in vivo. The current study demonstrates NP-mediated inhibition of macropinocytosis and KRAS activation and provides translational opportunities to inhibit tumor growth in a number of cancers where activation of KRAS plays a major role.


Assuntos
Nanopartículas Metálicas , Neoplasias Pancreáticas , Humanos , Ouro/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Pinocitose , Neoplasias Pancreáticas/patologia , Proliferação de Células , Linhagem Celular Tumoral , Mutação
4.
Adv Sci (Weinh) ; 9(31): e2200491, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36104215

RESUMO

By exploiting the self-therapeutic properties of gold nanoparticles (GNPs) a molecular axis that promotes the growth of high-grade serous ovarian cancer (HGSOC), one of the deadliest gynecologic malignancies with poorly understood underlying molecular mechanisms, has been identified. The biodistribution and toxicity of GNPs administered by intravenous or intraperitoneal injection, both as a single dose or by repeated dosing over two weeks are first assessed; no biochemical or histological toxicity to vital organs is found. Using an orthotopic patient-derived xenograft (PDX) model of HGSOC, the authors then show that GNP treatment robustly inhibits tumor growth. Investigating the molecular mechanisms underlying the GNP efficacy reveals that GNPs downregulate insulin growth factor binding protein 2 (IGFBP2) by disrupting its autoregulation via the IGFBP2/mTOR/PTEN axis. This mechanism is validated by treating a cell line-based human xenograft tumor with GNPs and an mTOR dual-kinase inhibitor (PI-103), either individually or in combination with GNPs; GNP and PI-103 combination therapy inhibit ovarian tumor growth similarly to GNPs alone. This report illustrates how the self-therapeutic properties of GNPs can be exploited as a discovery tool to identify a critical signaling axis responsible for poor prognosis in ovarian cancer and provides an opportunity to interrogate the axis to improve patient outcomes.


Assuntos
Nanopartículas Metálicas , Neoplasias Ovarianas , Feminino , Humanos , Ouro/química , Insulina , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , PTEN Fosfo-Hidrolase , Distribuição Tecidual , Serina-Treonina Quinases TOR , Animais
5.
Chembiochem ; 22(3): 523-531, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-32909670

RESUMO

Herein, we report effective, C-type lectin mannose receptor (MR)-selective, in vivo dendritic cell (DC)-targeting lipid nanoparticles (LNPs) of a novel lipid-containing mannose-mimicking di-shikimoyl- and guanidine head group and two n-hexadecyl hydrophobic tails (DSG). Subcutaneous administration of LNPs of the DSG/p-CMV-GFP complex showed a significant expression of green fluorescence protein in the CD11c+ DCs of the neighboring lymph nodes compared to the control LNPs of the BBG/p-CMV-GFP complex. Mannose receptor-facilitated in vivo DC-targeted vaccination (s.c.) with the electrostatic complex of LNPs of DSG/pCMV-MART1 stimulated long-lasting (270 days post B16F10 tumor challenge) antimelanoma immunity under prophylactic conditions. Remarkably, under therapeutic settings, vaccination (s.c.) with LNPs of the DSG/pCMV-MART1 complex significantly delayed melanoma growth and improved the survival of mice with melanoma. These findings demonstrate that this nonviral delivery system offers a resilient and potential approach to deliver DNA vaccines encoding tumor antigens to DCs in vivo with high efficacy.


Assuntos
Lectinas Tipo C/imunologia , Lipídeos/química , Lectinas de Ligação a Manose/imunologia , Melanoma Experimental/imunologia , Nanopartículas/química , Receptores de Superfície Celular/imunologia , Neoplasias Cutâneas/imunologia , Vacinas de DNA/imunologia , Animais , Células Dendríticas/imunologia , Receptor de Manose , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Neoplasias Cutâneas/terapia
6.
Biomater Sci ; 7(3): 773-788, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30601510

RESUMO

The clinical success of dendritic cell (DC)-based genetic immunization remains critically dependent on the availability of effective and safe nano-carriers for targeting antigen-encoded DNA vaccines to DCs, the most potent antigen-presenting cells in the human body in vivo. Recent studies revealed the efficacies of mannose receptor-mediated in vivo DC-targeted genetic immunization by liposomal DNA vaccine carriers containing both mannose-mimicking shikimoyl and transfection enhancing guanidinyl functionalities. However, to date, the efficacies of this approach have not been examined for metal-based nanoparticle DNA vaccine carriers. Herein, we report for the first time, the design, synthesis, physico-chemical characterization and bioactivities of gold nanoparticles covalently functionalized with a thiol ligand containing both shikimoyl and guanidinyl functionalities (Au-SGSH). We show that Au-SGSH nanoparticles can deliver DNA vaccines to mouse DCs under in vivo conditions. Subcutaneous administration of near infrared (NIR) dye-labeled Au-SGSH showed significant accumulation of the NIR dye in the DCs of the nearby lymph nodes compared to that for the non-targeting NIR-labeled Au-GSH nanoconjugate containing only a covalently tethered guanidinyl group, not the shikimoyl-functionality. Under prophylactic settings, in vivo immunization (s.c.) with the Au-SGSH-pCMV-MART1 nanoplex induced a long-lasting (180 days) immune response against murine melanoma. Notably, mannose receptor-mediated in vivo DC-targeted immunization (s.c.) with the Au-SGSH-MART1 nanoplex significantly inhibited established melanoma growth and increased the overall survivability of melanoma-bearing mice under therapeutic settings. The Au-SGSH nanoparticles reported herein have potential use for in vivo DC-targeted genetic immunization against cancer and infectious diseases.


Assuntos
Células Dendríticas/metabolismo , Ouro/química , Nanopartículas Metálicas/química , Nanoconjugados/química , Vacinas de DNA/imunologia , Animais , Células da Medula Óssea/citologia , Linhagem Celular Tumoral , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/imunologia , Feminino , Corantes Fluorescentes/química , Imunidade Ativa , Antígeno MART-1/química , Antígeno MART-1/imunologia , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/prevenção & controle , Nanopartículas Metálicas/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Plasmídeos/química , Plasmídeos/metabolismo , Compostos de Sulfidrila/química , Vacinas de DNA/química
7.
ACS Omega ; 3(8): 8663-8676, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31458997

RESUMO

Numerous prior studies on fighting cancer have been based on using inhibitors of JAK-STAT pathway (signal transducer and activator of transcription 3 (STAT3) inhibitor in particular), a signaling pathway responsible for progression of many types of cancer cells. However, recent studies have shown that STAT3 activation leads to upregulation of program death receptor-ligand 1 (PD-L1, an immune checkpoint protein that plays a major role behind evasion of immune systems by growing tumors) expression levels in tumor cells, leading to enhanced immune suppression. This is why global efforts are being witnessed in combating cancer through use of immune checkpoint inhibitors. Herein, we report on the design, synthesis, physicochemical characterizations, and bioactivity evaluation of novel tumor- and tumor-vasculature-targeting noncytotoxic Au-CGKRK nanoconjugates (17-80 nm) for combating tumor. Using a syngeneic mouse tumor model, we show that intraperitoneal (i.p.) administration of the Au-CGKRK nanoparticles (NPs) complexed with both PD-L1siRNA (the immune checkpoint inhibitor) and STAT3siRNA (the JAK-STAT pathway inhibitor) results in significant (>70%) enhancement in overall survivability (OS) in melanoma-bearing mice (n = 5) when compared to the OS in the untreated mice group. The expression levels of CD8 and CD4 proteins in the tumor lysates of differently treated mice groups (by Western blotting) are consistent with the observed OS enhancement being a T-cell-driven process. Biodistribution study using near-infrared dye-loaded Au-CGKRK nanoconjugates revealed selective accumulation of the dye in mouse tumor. Notably, the overall survival benefits were significantly less (∼35%) when melanoma-bearing mice were treated (i.p.) with Au-CGKRK NPs complexed with only PD-L1siRNA or with STAT3siRNA alone. The presently described Au-CGKRK nanoconjugates are expected to find future use in therapeutic RNA-interference-based cancer immunotherapy.

8.
Biomater Sci ; 4(4): 627-38, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26806172

RESUMO

Numerous prior studies have been reported on the use of pH-sensitive drug carriers such as micelles, liposomes, peptides, polymers, nanoparticles, etc. that are sensitive to the acidic (pH = ∼6.5) microenvironments of tumor tissues. Such systems have been primarily used in the past as effective drug/gene/microRNA carriers for releasing their anti-cancer payloads selectively to tumor cells/tissues. Herein, we report on the development of new liposomal drug carriers prepared from glutamic acid backbone-based cationic amphiphiles containing both endosomal pH-sensitive histidine as well as cellular uptake & solubility enhancing guanidine moieties in their polar head-group regions. The most efficient one among the four presently described endosomal pH-sensitive liposomal drug carriers not only effectively delivers potent anti-cancer drugs (curcumin & paclitaxel) to mouse tumor, but also significantly contributes to inhibiting mouse tumor growth. The findings in the in vitro mechanistic studies are consistent with apoptosis of tumor cells being mediated through increased cell cycle arrest in the G2/M phase. Findings in the FRET assay and in vitro drug release studies conducted with the liposomes of the most efficient pH-sensitive lipid demonstrated its pH dependent fusogenic and controlled curcumin release properties. Importantly, the presently described liposomal formulation of curcumin & paclitaxel enhanced overall survivability of tumor bearing mice. To the best of our knowledge, the presently described system (curcumin, paclitaxel and liposomal carrier itself) is the first of its kind pH-sensitive liposomal formulation of potent chemotherapeutics in which the liposomal drug itself exhibits significant mouse tumor growth inhibition properties.


Assuntos
Antineoplásicos/farmacologia , Curcumina/química , Portadores de Fármacos/química , Endossomos/química , Lipossomos/química , Lipossomos/farmacologia , Paclitaxel/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Curcumina/farmacologia , Sistemas de Liberação de Medicamentos , Endossomos/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Micelas , Paclitaxel/farmacologia , Polímeros/química
9.
Mol Ther ; 24(2): 385-397, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26666450

RESUMO

A major limiting factor retarding the clinical success of dendritic cell (DC)-based genetic immunizations (DNA vaccination) is the scarcity of biologically safe and effective carrier systems for targeting the antigen-encoded DNA vaccines to DCs under in vivo settings. Herein, we report on a potent, mannose receptor selective in vivo DC-targeting liposomes of a novel cationic amphiphile with mannose-mimicking shikimoyl head-group. Flow cytometric experiments with cells isolated from draining lymph nodes of mice s.c. immunized with lipoplexes of pGFP plasmid (model DNA vaccine) using anti-CD11c antibody-labeled magnetic beads revealed in vivo DC-targeting properties of the presently described liposomal DNA vaccine carrier. Importantly, s.c. immunizations of mice with electrostatic complex of the in vivo DC-targeting liposome and melanoma antigen-encoded DNA vaccine (p-CMV-MART1) induced long-lasting antimelanoma immune response (100 days post melanoma tumor challenge) with remarkable memory response (more than 6 months after the second tumor challenge). The presently described direct in vivo DC-targeting liposomal DNA vaccine carrier is expected to find future exploitations toward designing effective vaccines for various infectious diseases and cancers.


Assuntos
Vacinas Anticâncer/administração & dosagem , Células Dendríticas/imunologia , Neoplasias/tratamento farmacológico , Vacinas de DNA/administração & dosagem , Animais , Biomimética , Antígeno CD11c/genética , Vacinas Anticâncer/imunologia , Feminino , Imunoterapia Ativa , Lipossomos , Camundongos , Neoplasias/imunologia , Vacinas de DNA/imunologia
10.
ACS Biomater Sci Eng ; 1(8): 646-655, 2015 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-33435088

RESUMO

Herein we report on the unexpected cancer cell selective cytotoxicities of the liposomal formulations of aspartic and glutamic acid backbone-based four novel lipids with endosomal pH-sensitive head-groups and aliphatic n-hexadecyl & n-octadecyl hydrophobic tails. Surprisingly, although the formulations killed cancer cells efficiently, they were significantly less cytotoxic in non-cancerous healthy cells. Importantly, intratumoral administration of the liposomal formulations efficiently inhibited growth of melanoma in a syngeneic C57BL/6J mouse tumor model. Western Blotting experiments with the lysates of liposomes treated cancer cells revealed that liposomes of lipids 1-4 induce apoptosis selectively in cancer cells presumably by releasing cytochrome c from depolarized mitochondria and subsequent activation of caspases 3 & 9, upregulation of Bax and down regulation of Bcl-2. In summary, the present report describes for the first time tumor growth inhibition properties of the liposomal formulations of endosomal pH-sensitive histidinylated cationic lipids under both in vitro and systemic settings.

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