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ACS Appl Mater Interfaces ; 13(14): 15959-15972, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33797220


Cancer stem cells (CSCs) are the tumor cell subpopulation responsible for resistance to chemotherapy, tumor recurrence, and metastasis. An efficient therapy must act on low proliferating quiescent-CSCs (q-CSCs). We here investigate the effect of magnetic hyperthermia (MHT) in combination with local chemotherapy as a dual therapy to inhibit patient-derived colorectal qCR-CSCs. We apply iron oxide nanocubes as MHT heat mediators, coated with a thermoresponsive polymer (TR-Cubes) and loaded with DOXO (TR-DOXO) as a chemotherapeutic agent. The thermoresponsive polymer releases DOXO only at a temperature above 44 °C. In colony-forming assays, the cells exposed to TR-Cubes with MHT reveal that qCR-CSCs struggle to survive the heat damage and, with a due delay, restart the division of dormant cells. The eradication of qCR-CSCs with a complete stop of the colony formation was achieved only with TR-DOXO when exposed to MHT. The in vivo tumor formation study confirms the combined effects of MHT with heat-mediated drug release: only the group of animals that received the CR-CSCs pretreated, in vitro, with TR-DOXO and MHT lacked the formation of tumor even after several months. For DOXO-resistant CR-CSCs cells, the same results were shown, in vitro, when choosing the drug oxaliplatin rather than DOXO and applying MHT. These findings emphasize the potential of our nanoplatforms as an effective patient-personalized cancer treatment against qCR-CSCs.

Antibióticos Antineoplásicos/administração & dosagem , Neoplasias Colorretais/patologia , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Hipertermia Induzida , Nanopartículas de Magnetita/química , Células-Tronco Neoplásicas/patologia , Terapia Combinada , Humanos
Nanomaterials (Basel) ; 10(1)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963449


In this study, we describe poly (lactic-co-glycolic) acid (PLGA)-based nanoparticles that combine photothermal therapy (PTT) with epigenetic therapy for melanoma. Specifically, we co-encapsulated indocyanine green (ICG), a PTT agent, and Nexturastat A (NextA), an epigenetic drug within PLGA nanoparticles (ICG-NextA-PLGA; INAPs). We hypothesized that combining PTT with epigenetic therapy elicits favorable cytotoxic and immunomodulatory responses that result in improved survival in melanoma-bearing mice. We utilized a nanoemulsion synthesis scheme to co-encapsulate ICG and NextA within stable and monodispersed INAPs. The INAPs exhibited concentration-dependent and near-infrared (NIR) laser power-dependent photothermal heating characteristics, and functioned as effective single-use agents for PTT of melanoma cells in vitro. The INAPs functioned as effective epigenetic therapy agents by inhibiting the expression of pan-histone deacetylase (HDAC) and HDAC6-specific activity in melanoma cells in vitro. When used for both PTT and epigenetic therapy in vitro, the INAPs increased the expression of co-stimulatory molecules and major histocompatibility complex (MHC) Class I in melanoma cells relative to controls. These advantages persisted in vivo in a syngeneic murine model of melanoma, where the combination therapy slowed tumor progression and improved median survival. These findings demonstrate the potential of INAPs as agents of PTT and epigenetic therapy for melanoma.

Int J Hyperthermia ; 37(3): 34-49, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33426992


Immune checkpoint blockade (ICB) comprising monoclonal antibodies (mAbs) against immune 'checkpoints', such as CTLA-4 and the PD1/PDL1 axis have dramatically improved clinical outcomes for patients with cancer. However, ICB by itself has failed to provide benefit in a wide range of solid tumors, where recurrence still occurs with high incidence. These poor response rates may be due to the therapeutic shortcomings of ICB; namely, a lack of cancer-specific cytotoxicity and ability to debulk tumors. To overcome these limitations, effective ICB therapy may require the combination with other complementary therapeutic platforms. Here, we propose that photothermal therapy (PTT) is an ideal therapeutic modality for combination with ICB because it can generate both tumor-specific cytotoxicity and immunogenicity. PTT elicits these specific effects because it is a localized thermal ablation technique that utilizes light-responsive nanoparticles activated by a wavelength-matched laser. While ICB immunotherapy alone improves cancer immunogenicity but does not generate robust antitumor cytotoxicity, nanoparticle-based PTT elicits targeted and controlled cytotoxicity but sub-optimal long-term immunogenicity. Thus, the two platforms offer complementary and potentially synergistic antitumor effects, which will be detailed in this review. We highlight three classes of nanoparticles used as agents of PTT (i.e., metallic inorganic nanoparticles, carbon-based nanoparticles and organic dyes), and illustrate the potential for nanoparticle-based PTT to potentiate the effects of ICB in preclinical models. Through this discussion, we aim to present PTT combined with ICB as a potent synergistic combination treatment for diverse cancer types currently refractory to ICB as well as PTT monotherapies.

Antineoplásicos Imunológicos , Neoplasias , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias/tratamento farmacológico , Terapia Fototérmica
Nano Res ; 13(3): 736-744, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34079616


Natural killer (NK) cells are attractive effector cells of the innate immune system against human immunodeficiency virus (HIV) and cancer. However, NK cell therapies are limited by the fact that target cells evade NK cells, for example, in latent reservoirs (in HIV) or through upregulation of inhibitory signals (in cancer). To address this limitation, we describe a biodegradable nanoparticle-based "priming" approach to enhance the cytotoxic efficacy of peripheral blood mononuclear cell-derived NK cells. We present poly(lactic-co-glycolic acid) (PLGA) nanodepots (NDs) that co-encapsulate prostratin, a latency-reversing agent, and anti-CD25 (aCD25), a cell surface binding antibody, to enhance primary NK cell function against HIV and cancer. We utilize a nanoemulsion synthesis scheme to encapsulate both prostratin and aCD25 within the PLGA NDs (termed Pro-aCD25-NDs). Physicochemical characterization studies of the NDs demonstrated that our synthesis scheme resulted in stable and monodisperse Pro-aCD25-NDs. The NDs successfully released both active prostratin and anti-CD25, and with controllable release kinetics. When Pro-aCD25-NDs were administered in an in vitro model of latent HIV and acute T cell leukemia using J-Lat 10.6 cells, the NDs were observed to prime J-Lat cells resulting in significantly increased NK cell-mediated cytotoxicity compared to free prostratin plus anti-CD25, and other controls. These findings demonstrate the feasibility of using our Pro-aCD25-NDs to prime target cells for enhancing the cytotoxicity of NK cells as antiviral or antitumor agents.

ACS Appl Mater Interfaces ; 11(6): 5727-5739, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30624889


The use of magnetic nanoparticles in oncothermia has been investigated for decades, but an effective combination of magnetic nanoparticles and localized chemotherapy under clinical magnetic hyperthermia (MH) conditions calls for novel platforms. In this study, we have engineered magnetic thermoresponsive iron oxide nanocubes (TR-cubes) to merge MH treatment with heat-mediated drug delivery, having in mind the clinical translation of the nanoplatform. We have chosen iron oxide based nanoparticles with a cubic shape because of their outstanding heat performance under MH clinical conditions, which makes them benchmark agents for MH. Accomplishing a surface-initiated polymerization of strongly interactive nanoparticles such as our iron oxide nanocubes, however, remains the main challenge to overcome. Here, we demonstrate that it is possible to accelerate the growth of a polymer shell on each nanocube by simple irradiation of a copper-mediated polymerization with a ultraviolet light (UV) light, which both speeds up the polymerization and prevents nanocube aggregation. Moreover, we demonstrate herein that these TR-cubes can carry chemotherapeutic doxorubicin (DOXO-loaded-TR-cubes) without compromising their thermoresponsiveness both in vitro and in vivo. In vivo efficacy studies showed complete tumor suppression and the highest survival rate for animals that had been treated with DOXO-loaded-TR-cubes, only when they were exposed to MH. The biodistribution of intravenously injected TR-cubes showed signs of renal clearance within 1 week and complete clearance after 5 months. This biomedical platform works under clinical MH conditions and at a low iron dosage, which will enable the translation of dual MH/heat-mediated chemotherapy, thus overcoming the clinical limitation of MH: i.e., being able to monitor tumor progression post-MH-treatment by magnetic resonance imaging (MRI).

Portadores de Fármacos/química , Compostos Férricos/química , Nanoestruturas/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Humanos , Hipertermia Induzida , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita/química , Camundongos , Camundongos Nus , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Neoplasias/patologia , Polímeros/química , Distribuição Tecidual , Transplante Heterólogo , Raios Ultravioleta
Acc Chem Res ; 51(5): 999-1013, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29733199


Combining hard matter, like inorganic nanocrystals, and soft materials, like polymers, can generate multipurpose materials with a broader range of applications with respect to the individual building blocks. Given their unique properties at the nanoscale, magnetic nanoparticles (MNPs) have drawn a great deal of interest due to their potential use in the biomedical field, targeting several applications such as heat hubs in magnetic hyperthermia (MHT, a heat-damage based therapy), contrast agents in magnetic resonance imaging (MRI), and nanocarriers for targeted drug delivery. At the same time, polymers, with their versatile macromolecular structure, can serve as flexible platforms with regard to constructing advanced functional materials. Advances in the development of novel polymerization techniques has enabled the preparation of a large portfolio of polymers that have intriguing physicochemical properties; in particular, those polymers that can undergo conformational and structural changes in response to their surrounding environmental stimuli. Therefore, merging the unique features of MNPs with polymer responsive properties, such as pH and thermal stimuli activation, enables smart control of polymer properties operated by the MNPs and vice versa at an unprecedented level of sophistication. These magnetic-stimuli-responsive nanosystems will impact the cancer field by combining magnetic hyperthermia with stimuli-dependent controlled drug delivery toward multimodal therapies. In this approach, a malignant tumor may be destroyed by a combination of the synergic effects of thermal energy generated by MNPs and the controlled release of antitumoral agents, activated by means of either heat or pH changes, finally leading to a much more effective cancer treatment than those available today. Also, taking advantage of such a triggered chemotherapy will overcome the notorious drawbacks of classic chemotherapy. Nevertheless, tracking the changes in the magnetic properties of such pH-responsive magnetic nanoparticles, which are provided by changes in relaxation signals of water molecules surrounding the nanoplatform, is a novel approach to the detection of pathological conditions (such as pH-changes at the ischemic and tumor sites). Despite great efforts by chemists to fabricate different featured materials, there have been few successful preclinical studies to date. A clinical translation of magnetic stimuli-responsive systems would require overcoming the actual nanosystem limitations and the joint efforts of an interdisciplinary scientific community. In this Account, we have framed state of the art magnetic stimuli-responsive systems, focusing on thermo- and pH-responsive behavior, following an organization based on the response mechanisms of polymers. By evaluating the features of the most representative and advanced nanosystems that already exist in literature, we present the challenges to overcome, the future directions to undertake for the development of magnetic stimuli-responsive nanoplatforms that will work under clinical operating conditions and have biodegradable and biocompatible features, and a consideration of the technical aspects.