RESUMO
A critical factor in developing an efficient photosensitizer-gold nanoparticle (PS-AuNP) hybrid system with improved plasmonic photosensitization is to allocate a suitable space between AuNPs and PS. Poly(amidoamine) (PAMAM) dendrimer is selected as a spacer between the PS and confeito-like gold nanoparticles (confeito-AuNPs), providing the required distance (≈2.5-22.5 nm) for plasmon-enhanced singlet oxygen generation and heat production upon 638-nm laser irradiation and increase the cellular internalization of the nanoconjugates. The loading of the PS, tetrakis(4-carboxyphenyl) porphyrin (TCPP), and modified zinc phthalocyanine (ZnPc1) onto PAMAM-confeito-AuNPs demonstrate better in vitro cancer cell-killing efficacy, as the combined photothermal-photodynamic therapies (PTT-PDTs) outperforms the single treatment modalities (PTT or PDT alone). These PS-PAMAM-confeito-AuNPs also demonstrate higher phototoxicity than photosensitizers directly conjugated to confeito-AuNPs (TCPP-confeito-AuNPs and ZnPc1-confeito-AuNPs) against all breast cancer cell lines tested (MDA-MB-231, MCF7, and 4T1). In the in vivo studies, TCPP-PAMAM-confeito-AuNPs are biocompatible and exhibit a selective tumor accumulation effect, resulting in higher antitumor efficacy than free TCPP, PAMAM-confeito-AuNPs, and TCPP-confeito-AuNPs. In vitro and in vivo evaluations confirm PAMAM effectiveness in facilitating cellular uptake, plasmon-enhanced singlet oxygen and heat generation. In summary, this study highlights the potential of integrating a PAMAM spacer in enhancing the plasmon effect-based photothermal-photodynamic anticancer treatment efficiency of PS-decorated confeito-AuNPs.
Assuntos
Dendrímeros , Nanopartículas Metálicas , Nanopartículas , Neoplasias , Fotoquimioterapia , Dendrímeros/farmacologia , Ouro/farmacologia , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Oxigênio Singlete/metabolismoRESUMO
BACKGROUND: Camptothecin is a naturally occurring alkaloid obtained from the stem wood of the Chinese tree, Camptotheca acuminata. It exerts pharmacological effects due to its ability to selectively inhibit the type-I topoisomerase DNA nuclear enzyme. Several semisynthetic analogs of camptothecin have been synthesized to date possessing antitumor activity. OBJECTIVE: Camptothecin (CPT) is one of the most promising anticancer drugs but it produces various side effects because of its non-selectivity towards cancer cells. To overcome these adverse effects, we synthesized biotin conjugate of camptothecin, which was linked via a self-immolative disulfide linker (CPT-SS-Biotin). METHODS: Biotin conjugated camptothecin linked through a disulfide bond was synthesized following schemes, and the structural characterization was carried out. The stability and drug release studies were performed in the presence of glutathione (GSH) while in vitro studies were performed on 4T1 tumor cell lines. In vivo pharmacological investigation was done using an antitumor Wistar rat model. RESULTS: The stability and drug release studies were performed in the presence of glutathione (GSH), and CPT-SSBiotin was found to be physiologically stable moiety and can only be cleaved in the presence of GSH to release free CPT. The CPT-SS-Biotin showed higher toxicity in the biotin-overexpressing 4T1 tumor cell line with a lower IC50 value (8.44 µM) compared to camptothecin alone (IC50 > 30 µM). CPT-SS-Biotin also showed 10.6% higher cellular uptake by cells in comparison to free camptothecin. The CPT-SS-Biotin was delivered to cells by binding to the biotin receptors on the cell surface, followed by energy-dependent endocytosis and internalization to cause cellular toxicity. CONCLUSION: In-vivo tumor suppression studies and in vitro cell line studies along with serological parameters and histopathological studies showed that conjugate produced a high therapeutic effect and remarkably reduced toxic effects in comparison to free CPT. The results suggested that biotinylation of camptothecin via disulfide linker can be a safe and efficacious method in cancer therapeutics.
Assuntos
Antineoplásicos , Camptotecina , Animais , Antineoplásicos/química , Biotina , Dissulfetos/química , Glutationa , Ratos , Ratos WistarRESUMO
Conventional cancer therapies such as chemotherapy are non-selective and induce immune system anergy, which lead to serious side effects and tumor relapse. It is a challenge to prime the body's immune system in the cancer-bearing subject to produce cancer antigen-targeting antibodies, as most tumor-associated antigens are expressed abundantly in cancer cells and some of normal cells. This study illustrates how hapten-based pre-immunization (for anti-hapten antibodies production) combined with cancer receptor labeling with hapten antigen constructs can elicit antibody-dependent cellular phagocytosis (ADCP). Thus, the hapten antigen 2,4-dinitrophenol (DNP) was covalently combined with a cancer receptor-binding dipeptide (IYIY) to form a dipeptide-hapten construct (IYIY-DNP, MW = 1322.33) that targets the tropomyosin receptor kinase C (TrkC)-expressed on the surface of metastatic cancer cells. IYIY-DNP facilitated selective association of RAW264.7 macrophages to the TrkC expressing 4T1 cancer cells in vitro, forming cell aggregates in the presence of anti-DNP antibodies, suggesting initiation of anti-DNP antibody-dependent cancer cell recognition of macrophages by the IYIY-DNP. In in vivo, IYIY-DNP at 10 mg/kg suppressed growth of 4T1 tumors in DNP-immunized BALB/c mice by 45% (p < 0.05), when comparing the area under the tumor growth curve to that of the saline-treated DNP-immunized mice. Meanwhile, IYIY-DNP at 10 mg/kg had no effect on TrkC-negative 67NR tumor-bearing mice immunized with DNP. Tumor growth suppression activity of IYIY-DNP in DNP-immunized mice was associated with an increase in the anti-DNP IgG (7.3 × 106 ± 1.6 U/mL) and IgM (0.9 × 106 ± 0.07 U/mL) antibodies after five cycles of DNP treatment, demonstrated potential for hapten-based pre-immunization then treatment with IYIY-DNP to elicit ADCP for improved immunotherapy of TrkC expressing cancers.
Assuntos
Recidiva Local de Neoplasia , Tropomiosina , Animais , Anticorpos , Formação de Anticorpos , Antígenos , Proteínas de Transporte , Dipeptídeos , Haptenos , Fatores Imunológicos , Imunoterapia , Camundongos , FagocitoseRESUMO
Toxicity testing relies heavily on animals, especially rodents as part of the non-clinical laboratory testing of substances. However, the use of mammalians and the number of animals employed in research has become a concern for institutional ethics committees. Toxicity testing involving rodents and other mammals is laborious and costly. Alternatively, non-rodent models are used as replacement, as they have less ethical considerations and are cost-effective. Of the many alternative models that can be used as replacement models, which ones can be used in predictive toxicology? What is the correlation between these models and rodents? Are there standardized protocols governing the toxicity testing of these commonly used predictive models? This review outlines the common alternative animal models for predictive toxicology to address the importance of these models, the challenges, and their standard testing protocols.
Assuntos
Alternativas aos Testes com Animais , Invertebrados/efeitos dos fármacos , Modelos Animais , Testes de Toxicidade , Toxicologia , Animais , Humanos , Medição de Risco , Especificidade da EspécieRESUMO
Active targeting compound, a non-iodinated derivative of IK-IK-I2-azaBODIPY (1a) was previously reported to preferentially bind melanoma over healthy cells. In this study, we evaluate the photodynamic therapy (PDT) efficiency on melanoma cells of 1a, together with its reversed sequence compound KI-KI-I2-azaBODIPY (1b) and a non-targeted control I2-azaBODIPY-NH2 (2). All three test compounds possess absorption wavelengths in the near-infrared (NIR) region (λmax between 678 and 687 nm) which alleviate melanin interference and allow deeper tissue penetration. In vitro studies revealed 1a and 1b are promising photosensitizers with enhanced singlet oxygen generation, have increased uptake by B16-F10 melanoma cells via clathrin-mediated endocytosis and good photocytotoxic efficacies. Ex vivo biodistribution assays showed both 1a and 1b accumulated in the tumour. In B16-F10 tumour bearing-C57BL/6 mice, 10 mg/kg of 1b and light irradiation was found to reduce tumour volume by up to 23% at day-3. Doubling the dosage of 1b (20 mg/kg) enhanced the antitumour effect, showing 96% maximum tumour volume reduction at day-7 and tumour growth suppression for up to 12 days.
Assuntos
Compostos de Boro/química , Compostos de Boro/uso terapêutico , Isoleucina/química , Lisina/química , Melanoma/metabolismo , Fotoquimioterapia/métodos , Animais , Compostos de Boro/farmacocinética , Linhagem Celular Tumoral , Endocitose , Humanos , Isoleucina/farmacocinética , Isoleucina/uso terapêutico , Lisina/farmacocinética , Lisina/uso terapêutico , Camundongos , Fármacos Fotossensibilizantes/uso terapêutico , Oxigênio Singlete/metabolismo , Distribuição Tecidual , Carga TumoralRESUMO
Photosensitizing nanogels were obtained through a surfactant-free single-step protocol by using a porphyrin-based cross-linker for stabilizing self-assembled nanosized aggregates of thermoresponsive copolymers. Nanogels with varying amounts of porphyrin retained the singlet oxygen generation ability of the porphyrin core and were also capable of inducing temperature increase upon irradiation at 635 nm. Photoinduced killing efficiency was tested against three cell lines: human breast adenocarcinoma (MDA-MB-231 and MCF7) and pancreatic adenocarcinoma (AsPC-1) cells, and a predominant photodynamic mechanism at 450 nm and a mixed photodynamic and photothermal effect at 635 nm was observed. This innovative access to photosensitizing nanogels is a proof of concept, and opens new perspectives toward the preparation of optimized nanophotosensitizers.
Assuntos
Géis/química , Nanoestruturas/química , Porfirinas/química , Tensoativos/química , Linhagem Celular Tumoral , Reagentes de Ligações Cruzadas/química , Humanos , Hipertermia Induzida/métodos , Fotoquimioterapia/métodosRESUMO
In this study, nanohybrid materials consisting of graphene oxide (GO), ßcyclodextrin (CD) and poly(amido amine) dendrimer (DEN) were successfully prepared by covalent bonding. GO-CD and GO-CD-DEN were found to be potential nanocarriers for anticancer drugs including chemotherapeutics (doxorubicin (DOX), camptothecin (CPT)) and photosensitizer (protoporphyrin IX (PpIX)). GO-CD possessed 1.2 times higher DOX-loading capacity than GO due to inclusion of additional DOX to the CD. The drug loading on GO-CD-DEN increased in the order: DOXâ¯<â¯PpIXâ¯<â¯CPT. Enhanced cytotoxicity of DOX and CPT and also the photocytotoxicity of PpIX were observed when the drugs were loaded in GO-CD and GO-CD-DEN. Functionalization of GO with CD and CD-DEN increased the uptake in cancer cells, and both GO-CD and GO-CD-DEN nanohybrids remained in the cytoplasm and were not uptaken into the nucleus, as shown in the flow cytometry and high-content screening study.
Assuntos
Antineoplásicos/química , Ciclodextrinas/química , Dendrímeros/química , Portadores de Fármacos/química , Grafite/química , Fármacos Fotossensibilizantes/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Camptotecina/química , Camptotecina/metabolismo , Camptotecina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Humanos , Luz , Microscopia de Força Atômica , Óxidos/química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Protoporfirinas/química , Protoporfirinas/metabolismo , Protoporfirinas/farmacologiaRESUMO
BODIPYs are photosensitizers activatable by light to generate highly reactive singlet oxygen (1O2) from molecular oxygen, leading to tissue damage in the photoirradiated region. Despite their extraordinary photophysical characteristics, they are not featured in clinical photodynamic therapy. This review discusses the recent advances in the design and/or modifications of BODIPYs since 2013, to improve their potential in photodynamic cancer therapy and related areas.
Assuntos
Antineoplásicos/uso terapêutico , Compostos de Boro/uso terapêutico , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Humanos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/químicaRESUMO
We previously developed a new zinc(II) phthalocyanine (ZnPc) derivative (Pc 1) conjugated to poly-L-glutamic acid (PGA) (1-PG) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity, and nonselectivity in biodistribution and tumor targeting. During this study, we discovered that 1-PG possessed high near-infrared (NIR) light absorptivity (λmax = 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro. In the current study, we discovered that 1-PG accumulated in 4T1 mouse mammary tumors, with a retention time of up to 48 h. Furthermore, as part of an antitumor PDT, low dose 1-PG (2 mg of Pc 1 equivalent/kg) induced a greater tumor volume reduction (-74 ± 5%) when compared to high dose ZnPc (8 mg/kg, -50 ± 12%). At higher treatment doses (8 mg of Pc 1 equivalent/kg), 1-PG reduced tumor volume maximally (-91 ± 6%) and suppressed tumor size to a minimal level for up to 15 days. The kidney, liver, and lungs of the mice treated with 1-PG (both low and high doses) were free from 4T1 tumor metastasis at the end of the study. Telemetry-spectral-echocardiography studies also revealed that PGA (65 mg/kg) produced insignificant changes to the cardiovascular physiology of Wistar-Kyoto rats when administered in vivo. Results indicate that PGA displays an excellent cardiovascular safety profile, underlining its suitability for application as a nanodrug carrier in vivo. These current findings indicate the potential of 1-PG as a useful photosensitizer candidate for clinical PDT.
Assuntos
Indóis/administração & dosagem , Nanoconjugados/química , Neoplasias/tratamento farmacológico , Compostos Organometálicos/administração & dosagem , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Animais , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/etiologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Ecocardiografia , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/farmacocinética , Fotoquimioterapia/efeitos adversos , Fármacos Fotossensibilizantes/efeitos adversos , Fármacos Fotossensibilizantes/farmacocinética , Ácido Poliglutâmico/química , Ratos , Ratos Endogâmicos WKY , Distribuição TecidualRESUMO
Physiochemical changes, including size, are known to affect gold nanoparticle cellular internalization and treatment efficacy. Here, we report the effect of four sizes of cystine/citric acid-coated confeito-like gold nanoparticles (confeito-AuNPs) (30, 60, 80 and 100nm) on cellular uptake, intracellular localization and photothermal anticancer treatment efficiency in MDA-MB231 breast cancer cells. Cellular uptake is size dependent with the smallest size of confeito-AuNPs (30nm) having the highest cellular internalization via clathrin- and caveolae-mediated endocytosis. However, the other three sizes (60, 80 and 100nm) utilize clathrin-mediated endocytosis for cellular uptake. The intracellular localization of confeito-AuNPs is related to their endocytosis mechanism, where all sizes of confeito-AuNPs were localized highly in the lysosome and mitochondria, while confeito-AuNPs (30nm) gave the highest localization in the endoplasmic reticulum. Similarly, a size-dependent trend was also observed in in vitro photothermal treatment experiments, with the smallest confeito-AuNPs (30nm) giving the highest cell killing rate, whereas the largest size of confeito-AuNPs (100nm) displayed the lowest photothermal efficacy. Its desirable physicochemical characteristics, biocompatible nature and better photothermal efficacy will form the basis for further development of multifunctional confeito-AuNP-based nanotherapeutic applications.
Assuntos
Ácido Cítrico/química , Cistina/química , Ouro/química , Nanopartículas Metálicas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Endocitose , Humanos , Nanopartículas Metálicas/ultraestrutura , Microscopia Eletrônica , Neoplasias/patologia , Tamanho da Partícula , Fototerapia/métodosRESUMO
Previously reported amphiphilic diblock copolymer with pendant dendron moieties (P71D3) has been further evaluated in tumor-bearing mice as a potential drug carrier. This P71D3-based micelle of an average diameter of 100nm was found to be biocompatible, non-toxic and physically stable in colloidal system up to 15days. It enhanced the in vitro potency of doxorubicin (DOX) in 4T1 breast tumor cells by increasing its uptake, by 3-fold, compared to free DOX. In 4T1 tumor-bearing mice, the tumor growth rate of P71D3/DOX (2mg/kg DOX equivalent) treated group was significantly delayed and their tumor volume was significantly reduced by 1.5-fold compared to those treated with free DOX. The biodistribution studies indicated that P71D3/DOX enhanced accumulation of DOX in tumor by 5- and 2-fold higher than free DOX treated mice at 15min and 1h post-administration, respectively. These results suggest that P71D3 micelle is a promising nanocarrier for chemotherapeutic agents.
Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Polímeros/química , Animais , Antracenos/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Portadores de Fármacos/química , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Nanopartículas/química , Distribuição Tecidual/efeitos dos fármacosRESUMO
We synthesized a dextrin (DEX)-conjugated graphene oxide (GO) nanocarrier (GO100-DEX) as a potential drug delivery system to respond to a tumor-associated stimulus, α-amylase, that has high permeability through the fenestrated endothelial barrier to the tumor site. At acidic pH and in the presence of α-amylase to simulate tumor conditions, GO100-DEX released a 1.5-fold higher amount of doxorubicin (DOX) than of GO100. Under the same conditions, the cytotoxic effects of GO100-DEX/DOX were 2-fold greater than those of free DOX and 2.9-fold greater than those of GO100/DOX. Employing an in vitro biomimetic microfluidic blood vessel model lined with human umbilical vein endothelial cells, we evaluated the tumor vasculature endothelial permeation of GO100-DEX and GO100 using dextrans of 10 and 70kDa for comparison and as standards to validate the microfluidic blood vessel model. The results showed that the permeabilities of GO100-DEX and GO100 were 4.3- and 4.9-fold greater than that of 70kDa dextran and 2.7- and 3.1-fold higher than that of 10kDa dextran, thus demonstrating the good permeability of the GO-based nanocarrier through the fenestrated endothelial barrier.
Assuntos
Amilases/química , Antineoplásicos/química , Dextrinas/química , Portadores de Fármacos/química , Grafite/química , Nanopartículas/química , Óxidos/química , Antineoplásicos/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Células Cultivadas , Dextranos/química , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos , Células Endoteliais/metabolismo , Humanos , Microfluídica/métodosRESUMO
In photodynamic therapy (PDT), the low absorptivity of photosensitizers in an aqueous environment reduces singlet oxygen generation efficiency and thereby decreases photosensitizing efficacy in biological conditions. To circumvent this problem, we designed a phthalocyanine-poly-L-glutamic acid conjugate (1-PG) made from a new phthalocyanine (Pc 1) monofunctionalized to allow adequate conjugation to PGA. The resulting 1-PG conjugate retained high absorptivity in the near-infrared (NIR) region at its λmax 675nm in an aqueous environment. The 1-PG conjugate demonstrated good singlet oxygen generation efficiency, increased uptake by 4 T1 breast cancer cells via clathrin-mediated endocytosis, and enhanced photocytotoxic efficacy. The conjugate also displayed a high light-dark toxicity ratio, approximately 1.5-fold greater than zinc phthalocyanine at higher concentration (10 µM), an important feature for the reduction of dark toxicity and unwanted side effects. These results suggest that the 1-PG conjugate could be a useful alternative for deep tissue treatment with enhanced anti-cancer (PDT) efficacy.
Assuntos
Ácido Glutâmico/química , Indóis/química , Nanoconjugados/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Animais , Linhagem Celular Tumoral , Endocitose , Isoindóis , Luz , Camundongos , Estrutura Molecular , Oxigênio Singlete/químicaRESUMO
While nano-sized construct (NSC) use in medicine has grown significantly in recent years, reported unwanted side effects have raised safety concerns. However, the toxicity of NSCs to the cardiovascular system (CVS) and the relative merits of the associated evaluation methods have not been thoroughly studied. This review discusses the toxicological profiles of selected NSCs and provides an overview of the assessment methods, including in silico, in vitro, ex vivo and in vivo models and how they are related to CVS toxicity. We conclude the review by outlining the merits of telemetry coupled with spectral analysis, baroreceptor reflex sensitivity analysis and echocardiography as an appropriate integrated strategy for the assessment of the acute and chronic impact of NSCs on the CVS. Copyright © 2017 John Wiley & Sons, Ltd.
Assuntos
Barorreflexo/efeitos dos fármacos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/diagnóstico , Sistema Cardiovascular/efeitos dos fármacos , Nanomedicina/métodos , Nanopartículas/toxicidade , Telemetria , Algoritmos , Animais , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Nanopartículas/química , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Processamento de Sinais Assistido por ComputadorRESUMO
Conjugation of Doxorubicin (DOX) to N-(2-hydroxypropyl) methylacrylamide copolymer (HPMA) has significantly reduced the DOX-associated cardiotoxicity. However, the reports on the impact of HPMA-DOX conjugates on the cardiovascular system such as blood pressure (BP) and heart rate (HR) were in restrained animals using tail cuff and/or other methods that lacked the resolution and sensitivity. Herein, we employed radiotelemetric-spectral-echocardiography approach to further understand the in vivo cardiovascular hemodynamics and variability post administration of free DOX and HPMA-DOX. Rats implanted with radio-telemetry device were administered intravenously with DOX (5 mg/kg), HPMA-DOX (5 mg DOX equivalent/kg) and HPMA copolymer and subjected to continuous cardiovascular monitoring and echocardiography for 140 days. We found that DOX-treated rats had ruffled fur, reduced body weight (BW) and a low survival rate. Although BP and HR were normal, spectral analysis indicated that their BP and HR variabilities were reduced. All rats exhibited typical signs of cardiotoxicity at histopathology. In contrast, HPMA-DOX rats gained weight over time and survived. Although BP, HR and related variabilities were unaffected, the left ventricular end diastolic volume (EDV) of these rats, as well as of the HPMA copolymer-treated rats, was found increased at the end of observation period. Additionally, HPMA copolymer caused microscopic injury of the heart tissue. All of these suggest the necessity of caution when employing HPMA as carrier for prolonged drug delivery. The current study also indicates the potential of radiotelemetric-spectral-echocardiography approach for improved preclinical cardiovascular risk assessment of polymer-drug conjugate and other nano-sized-drug constructs.
Assuntos
Acrilamidas/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Doxorrubicina/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Coração/efeitos dos fármacos , Acrilamidas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade , Doxorrubicina/administração & dosagem , Ecocardiografia , Injeções Intravenosas , Estimativa de Kaplan-Meier , Masculino , Camundongos , Miocárdio/patologia , Distribuição Aleatória , Ratos , Ratos Wistar , Análise de Sobrevida , TelemetriaRESUMO
Tropomyosin receptor kinase C (TrkC) targeted ligand-photosensitizer construct, IYIY-diiodo-boron-dipyrromethene (IYIY-I2-BODIPY) and its scrambled counterpart YIYI-I2-BODIPY have been prepared. IYIY-I2-BODIPY binds TrkC similar to neurotrophin-3 (NT-3), and NT-3 has been reported to modulate immune responses. Moreover, it could be shown that photodynamic therapy (PDT) elevates antitumor immune responses. This prompted us to investigate the immunological impacts mediated by IYIY-I2-BODIPY in pre- and post-PDT conditions. We demonstrated that IYIY-I2-BODIPY (strong response) and YIYI-I2-BODIPY (weak response) at 10 mg/kg, but not I2-BODIPY control, increased the levels of IL-2, IL-4, IL-6 and IL-17, but decreased the levels of systemic immunoregulatory mediators TGF-ß, myeloid-derived suppressor cells and regulatory T-cells. Only IYIY-I2-BODIPY enhanced the IFN-γ+ and IL-17+ T-lymphocytes, and delayed tumor growth (~20% smaller size) in mice when administrated daily for 5 days. All those effects were observed without irradiation; when irradiated (520 nm, 100 J/cm2, 160 mW/cm2) to produce PDT effects (drug-light interval 1 h), IYIY-I2-BODIPY induced stronger responses. Moreover, photoirradiated IYIY-I2-BODIPY treated mice had high levels of effector T-cells compared to controls. Adoptive transfer of immune cells from IYIY-I2-BODIPY-treated survivor mice that were photoirradiated gave significantly delayed tumor growth (~40-50% smaller size) in recipient mice. IYIY-I2-BODIPY alone and in combination with PDT modulates the immune response in such a way that tumor growth is suppressed. Unlike immunosuppressive conventional chemotherapy, IYIY-I2-BODIPY can act as an immune-stimulatory chemotherapeutic agent with potential applications in clinical cancer treatment.
Assuntos
Compostos de Boro/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Imunidade Celular/efeitos dos fármacos , Neoplasias Mamárias Animais , Peptidomiméticos/farmacologia , Fotoquimioterapia/métodos , Receptor trkC/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Citocinas/imunologia , Feminino , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/imunologia , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Reguladores/patologia , Células Th17/patologiaAssuntos
Sobrevivência Celular/efeitos dos fármacos , Iodo/química , Fotoquimioterapia/métodos , Porfirinas/administração & dosagem , Porfirinas/síntese química , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Sinergismo Farmacológico , Humanos , Iodo/administração & dosagem , Células MCF-7 , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/síntese química , Tensoativos/administração & dosagem , Tensoativos/síntese químicaRESUMO
A novel BODIPY derivative was designed for biomedical applications. Its mono-quaternized structure ensured its water-solubility and suitable amphiphilicity. Showing no singlet oxygen generation to avoid damage to healthy cells, this new derivative proved to be an extremely promising antimicrobial agent, with activity equal or superior to ampicillin against MRS Staphylococcus strains with no short-term resistance issue. Its activity against MSS Staphylococcus strains was largely superior to those of ampicillin and reached the activity of vancomycin against MSS S. epidermidis. This latter result is in particular extremely promising for the treatment of hospital-acquired infections. Also the fluorescence properties of BODIPY allowed imaging of the uptake.
Assuntos
Antibacterianos/farmacologia , Compostos de Boro/química , Compostos de Boro/farmacologia , Staphylococcus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Compostos de Boro/síntese química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Staphylococcus/classificação , Relação Estrutura-AtividadeRESUMO
Graphene oxide (GO)-based nanocarriers have been frequently studied due to their high drug loading capacity. However, the unsatisfactory biocompatibility of these GO-based nanocarriers hampers their use in clinical settings. This review discusses how each of the physicochemical characteristics (e.g., size, surface area, surface properties, number of layers and particulate states) and surface coatings on GO affect its in vitro and in vivo nanotoxicity. We provide an overview on the effect of GO properties on interactions with cells such as red blood cells, macrophages and cell lines, and experimental organisms including rodents, rabbits and Zebrafish, offering some guidelines for development of safe GO-based nanocarriers. We conclude the paper by outlining the challenges involving GO-based formulations and future perspectives of this research in the biomedical field.
Assuntos
Materiais Biocompatíveis/metabolismo , Portadores de Fármacos/metabolismo , Grafite/metabolismo , Óxidos/metabolismo , Preparações Farmacêuticas/administração & dosagem , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Grafite/química , Grafite/toxicidade , Humanos , Óxidos/química , Óxidos/toxicidadeRESUMO
Previously synthesized amphiphilic diblock copolymers with pendant dendron moieties have been investigated for their potential use as drug carriers to improve the delivery of an anticancer drug to human breast cancer cells. Diblock copolymer (P71 D3 )-based micelles effectively encapsulate the doxorubicin (DOX) with a high drug-loading capacity (≈95%, 104 DOX molecules per micelle), which is approximately double the amount of drug loaded into the diblock copolymer (P296 D1 ) vesicles. DOX released from the resultant P71 D3 /DOX micelles is approximately 1.3-fold more abundant, at a tumoral acidic pH of 5.5 compared with a pH of 7.4. The P71 D3 /DOX micelles also enhance drug potency in breast cancer MDA-MB-231 cells due to their higher intracellular uptake, by approximately twofold, compared with the vesicular nanocarrier, and free DOX. Micellar nanocarriers are taken up by lysosomes via energy-dependent processes, followed by the release of DOX into the cytoplasm and subsequent translocation into the nucleus, where it exert its cytotoxic effect.