RESUMO
The current treatment protocols for breast cancer have shifted from single agent therapies to combinatorial approaches that offer synergistic efficacies and reduced side effects. Self-assembled nanogels comprising natural polysaccharides and functional proteins provide an intelligent platform for the targeted co-delivery of therapeutic molecules. Herein, we report the fabrication of self-assembled nanogels utilizing hydrophilic biocompatible proteins, lactoferrin (Lf), and polysaccharide carboxy methyl cellulose (CMC), for the combined delivery of the antimetabolite pemetrexed (PMT) and the herbal polyphenol honokiol (HK). PMT was conjugated to LF via an amide bond. The conjugate was then electrostatically assembled into CMC under optimized conditions to form nanogels (Lf-CMC NGs). An inclusion complex of HK with hydroxypropyl-ß-cyclodextrin was then encapsulated in the prepared Lf-CMC NGs with an entrapment efficiency of 66.67%. The dual drug-loaded cross-linked Lf-CMC NGs exhibited a particle size of 193.4 nm and zeta potential of - 34.5 mV and showed a sustained release profile for both drugs. PMT/HK-loaded Lf-CMC NGs were successfully taken up by MDA-MB-231 breast cancer cells and demonstrated superior in vitro cytotoxicity, as elucidated by a low combination index value (CI=0.17) and a higher dose reduction index (DRI) compared to those of the free drugs. An in vivo antitumor study using an Ehrlich ascites tumor (EAT) mouse model revealed the robust efficacy of PMT/HK-loaded Lf-CMC NGs in inhibiting tumor growth, which was ascribed to the reduced expression level of VEGF-1, elevated protein expression level of caspase-3, and suppressed Ki-67 protein level in the tumor tissue (P Ë0.05). In conclusion, our green fabricated self-assembled dual-loaded nanogels offer a promising biocompatible strategy for targeted combinatorial breast cancer therapy.
Assuntos
Carboximetilcelulose Sódica , Nanogéis , Fitoterapia , Animais , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/química , Química Verde , Lactoferrina/química , Camundongos , Tamanho da Partícula , PemetrexedeRESUMO
While cancer remains a significant global health problem, advances in cancer biology, deep understanding of its underlaying mechanism and identification of specific molecular targets allowed the development of new therapeutic options. Drug repurposing poses several advantages as reduced cost and better safety compared with new compounds development. COX-2 inhibitors are one of the most promising drug classes for repurposing in cancer therapy. In this review, we provide an overview of the detailed mechanism and rationale of COX-2 inhibitors as anticancer agents and we highlight the most promising research efforts on nanotechnological approaches to enhance COX-2 inhibitors delivery with special focus on celecoxib as the most widely studied agent for chemoprevention or combined with chemotherapeutic and herbal drugs for combating various cancers.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Celecoxib , Reposicionamento de Medicamentos , Humanos , Nanomedicina , Neoplasias/tratamento farmacológicoRESUMO
Introduction: The use of herbal compounds in cancer therapy has great potential to promote the efficacy of current cancer therapeutic strategies. Herbal compounds were successfully reported to enhance tumor cells sensitization to the action of chemo-, hormonal- and gene-therapeutic agents via different mechanisms. Herbal ingredients can affect different signaling pathways, reduce the toxic side effects or inhibit the efflux of anticancer drugs.Areas covered: This review will discuss the delivery of herbal compounds with other cancer treatments such as hormonal, small molecule inhibitors and inorganic hybrids to tumor cells. An overview of physicochemical properties of herbal components that require intelligent design of combo-nanomedicines for efficient co-delivery of those herbal-derived and other anticancer agents was discussed. Nanocarriers provide various benefits to overcome the shortcomings of the encapsulated herbal compounds including improved solubility, increased stability and enhanced tumor targeting. Different nanocarrier systems were the focus of this review.Expert opinion: Multifunctional nanocarrier systems encapsulating herbal and different anticancer drugs showed to be a wonderful approach in the treatment of cancer enabling the co-delivery of anticancer drugs with versatile modes of action in an accurate manner in an attempt to enhance the efficacy, benefit from the synergism between the drugs as well as to minimize the development of multi-drug resistance. The main challenge point is the early detection and management of any developed adverse effect.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Nanomedicina , Neoplasias/tratamento farmacológico , Resultado do TratamentoRESUMO
PURPOSE: Myricetin (MYR) flavonoid is well-recognized for its antioxidant, anti-inflammatory and anti-tumor potential. Introducing nanomedicine was the ultimate resort to solve the imperfections of this nutraceutical, namely solubility, stability and delivery issues. The study, thus, aims at developing inhalable microparticles comprising MYR solid lipid nanoparticles (SLNs) for lung cancer therapy. METHODS: A two-step preparation procedure starting with complexation of MYR with the phospholipid Lipoid-S100, followed by nanoencapsulation in Gelucire-based, surfactant-free SLNs was developed. SLNs were characterized in terms of physicochemical properties, MYR loading, release behavior as well as anti-tumor potential and cellular uptake. Respirable microparticles were then obtained by spray drying SLNs with carbohydrate carriers. Their size, flowability and pulmonary deposition pattern were assessed. RESULTS: Optimized SLNs were 75.98 nm in diameter with a zeta-potential of -22.5 mV, and an encapsulation efficiency of 84.5%. Attempts to ameliorate drug loading implicate MYR-phospholipid complexation (MYR-PH-CPX) prior to its entrapment in SLNs, which ensured 5-fold increase in drug loading. Viability assays were modified to guarantee MYR chemical stability. Superior antitumor activity of MYR-phospholipid-complex and 3-fold reduction in IC50 were accomplished with MYR-SLNs. This could be related to enhanced cellular uptake revealed by confocal imaging and doubled fluorescence intensity. SLNs entrapping MYR-PH-CPX were spray-dried with carbohydrate carriers to produce respirable microparticles. The latter ensured MMAD of 2.39 µm and span index of 1.84, in addition to good flowability and > 80% release over 8 h. Deposition experiments revealed MMAD of 2.77 µm, FPF of 81.23 and EF of 93% indicating particle deposition in the targeted bronchial region. CONCLUSIONS: The study highlights the ability of phospholipid-complex on the nanoencapsulation, cellular uptake and antitumor activity of MYR. Formulation of respirable microparticles gives promises of efficacious therapy of lung carcinoma.
Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Flavonoides/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Fosfolipídeos/química , Células A549 , Administração por Inalação , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Flavonoides/metabolismo , Flavonoides/farmacologia , Humanos , Tamanho da Partícula , Solubilidade , Propriedades de Superfície , Distribuição TecidualRESUMO
Despite the clinical approval of few nanomedicines for cancer therapy, some drawbacks still impede their improved efficiency including low drug loading, off-target toxicity and development of multi-drug resistance. Herein, lactoferrin (Lf)-coupled mesoporous silica nanoparticles (MSNPs) were developed for combined delivery of the cytotoxic drug pemetrexed (PMT) and the phytomedicine ellagic acid (EA) for synergistic breast cancer therapy. While the hydrophobic EA was physically encapsulated within the pores of MSNPs via the adsorptive properties of MSNPs and the electrostatic interactions between the negatively charged EA and positively charged amino modified MSNs, the highly water soluble PMT was chemically anchored to the Lf shell through chemical conjugation to the surface of lactoferrin coated MSNPs by carbodiimide reaction to avoid pre-mature drug release and systemic toxicity. The dual drug-loaded Lf-MSNPs (284â¯nm) demonstrated a sequential faster release of EA followed by a sustained release of PMT. The dual drug-loaded Lf-MSNPs exhibited highest cytotoxicity against MCF-7 (Michigan Cancer Foundation-7) breast cancer cells as revealed by the lowest combination index (CIâ¯=â¯0.885) compared to free drugs. The combination index value (< 1) revealed synergy between both loaded drugs. Furthermore, high cellular uptake of the nanocarriers into MCF-7 breast cancer cells was observed via Lf-receptor mediated endocytosis. Altogether, the dual drug-loaded Lf-targeted MSNPs showed to be a promising carrier for breast cancer therapy through triggering different signaling pathways, and hence overcoming the multi-drug resistance and minimizing the systemic toxicity.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ácido Elágico/farmacologia , Lactoferrina/farmacologia , Nanopartículas/química , Pemetrexede/farmacologia , Dióxido de Silício/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Elágico/química , Humanos , Lactoferrina/química , Células MCF-7 , Estrutura Molecular , Tamanho da Partícula , Pemetrexede/química , Porosidade , Dióxido de Silício/química , Relação Estrutura-Atividade , Propriedades de Superfície , Células Tumorais CultivadasRESUMO
Multi-modality strategies of albumin-mediated drug accumulation in tumor, boronate-based active tumor targeting and synergistic cancer therapy were combined together for effective treatment of breast cancer. Herein we report the development of albumin-shell oily-core nanocapsules (NCs), loaded with novel combination of hydrophobic drugs, exemestane (EXE) and hesperetin (HES), for targeted breast cancer therapy. This protein-lipid nanohybrid carrier was successfully fabricated using a simple protein-coating method based on the electrostatic adsorption of negatively charged albumin shell onto the oily core containing cationic surfactant. While EXE was directly encapsulated into the oily core, HES was pre-formulated in the form of phospholipid complex before solubilization in oily phase. In addition to albumin-mediated binding to albondin and SPARC, phenylboronic acid was chemically coupled to the albumin shell to confer additional tumor targeting. The targeted nanocarrier (TNC) demonstrated enhanced internalization into MCF-7 breast cancer cells resulting in synergistic cytotoxic activity with a combination index (CI) of 0.662 and dose reduction index (DRI) of 8.22 and 1.84 for EXE and HES, respectively. In vivo, TNC displayed superior anti-cancer activity in tumor-bearing mice compared to their non-targeted counterparts and the free drug combination. A significant reduction of both tumor volume (7-folds) and Ki67 expression (3-folds) was obtained by the targeted nanocarriers compared to positive control. Overall, the boronic-targeted albumin NCs offer a promising platform for hydrophobic drug combination against cancer therapy.
Assuntos
Androstadienos , Antineoplásicos Fitogênicos , Inibidores da Aromatase , Neoplasias da Mama , Hesperidina , Nanocápsulas , Albuminas/química , Albuminas/farmacocinética , Albuminas/farmacologia , Androstadienos/química , Androstadienos/farmacocinética , Androstadienos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacocinética , Inibidores da Aromatase/farmacologia , Boro/química , Boro/farmacocinética , Boro/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Hesperidina/química , Hesperidina/farmacocinética , Hesperidina/farmacologia , Humanos , Células MCF-7 , Nanocápsulas/química , Nanocápsulas/uso terapêutico , Fosfolipídeos/química , Fosfolipídeos/farmacocinética , Fosfolipídeos/farmacologiaRESUMO
Aim: Multicompartmental lipid-protein nanohybrids (MLPNs) were developed for combined delivery of the anticancer drugs tretinoin (TRE) and genistein (GEN) as synergistic therapy of lung cancer. Materials & methods: The GEN-loaded lipid core was first prepared and then coated with TRE-loaded zein shell via nanoprecipitation. Results: TRE/GEN-MLPNs demonstrated a size of 154.5 nm. In situ ion pair formation between anionic TRE and the cationic stearyl amine improved the drug encapsulation with enhanced stability of MLPNs. TRE/GEN-coloaded MLPNs were more cytotoxic against A549 cancer cells compared with combined free GEN/TRE. In vivo, lung cancer bearing mice treated with TRE/GEN-MLPNs displayed higher apoptotic caspase activation compared with mice-treated free combined GEN/TRE. Conclusion: TRE/GEN-MLPNs might serve as a promising parenteral nanovehicles for lung cancer therapy.
Assuntos
Antineoplásicos/administração & dosagem , Genisteína/administração & dosagem , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Nanocápsulas/química , Tretinoína/administração & dosagem , Células A549 , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Sinergismo Farmacológico , Genisteína/farmacocinética , Genisteína/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Tretinoína/farmacocinética , Tretinoína/uso terapêutico , Zeína/químicaRESUMO
Herein, both strategies of synergistic drug combination together with dual active tumor targeting were combined for effective therapy of hepatocellular carcinoma (HCC). Therefore, based on the tumor sensitizing action, the herbal quercetin (QRC) was co-delivered with the targeted therapeutic drug sorafenib (SFB), preformulated as phospholipid complex, via protein shell-oily core nanocapsules (NCs). Inspired by the targeting action of lactoferrin (LF) via binding to LF receptors overexpressed by HCC cells, LF shell was electrostatically deposited onto the drug-loaded oily core to elaborate LF shell-oily core NCs. For dual tumor targeting, lactobionic acid (LA) or glycyrrhetinic acid (GA) was individually coupled to LF shell for binding to asialoglycoprotein and GA receptors on liver cancer cells, respectively. Compared to LF and GA/LF NCs, the dual-targeted LA/LF-NCs showed higher internalization into HepG2 cells with 2-fold reduction in half-maximal inhibitory concentration compared to free combination therapy after 48 h. Moreover, dual-targeted LF-NCs showed powerful in vivo antitumor efficacy. It was revealed as significant downregulation of the mRNA expression levels of nuclear factor-kappa B and tumor necrosis factor α as well as suppression of Ki-67 protein expression level in diethylnitrosamine (DEN)-induced HCC mice (P < 0.05). Furthermore, dual-targeted LF-NCs attenuated the liver toxicity induced by DEN in animal models. Overall, this study proposes dual-targeted LF-NCs for combined delivery of SFB and QRC as a potential therapeutic HCC strategy.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Lactoferrina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Nanocápsulas/química , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Dietilnitrosamina/química , Dietilnitrosamina/farmacologia , Dissacarídeos/química , Sistemas de Liberação de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ácido Glicirretínico/química , Células Hep G2 , Humanos , Antígeno Ki-67/genética , Lactoferrina/química , Lactoferrina/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , NF-kappa B/genética , FitoterapiaRESUMO
BACKGROUND: Lung cancer is the most common cancer and the leading cause of total deaths worldwide. Its classified into two major types including non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC) based on the origin of abnormal lung cells as well as the smoking status of the patient. NSCLC is the most common and aggressive type of lung cancer representing 80%-85% of all cases. PURPOSE: The aim of the study was to present lyotropic liquid crystalline nanoparticles (LCNPs) as promising carriers for co-delivery of the chemotherapeutic agent, pemetrexed (PMX) and the herbal drug, resveratrol (RSV) for effective lung cancer management. METHODS: The proposed PMX-RSV-LCNPs were prepared by hydrotrope method. Hydrophobic ion pairing with cetyl trimethyl ammonium bromide (CTAB) was implemented to increase the encapsulation efficiency of the hydrophilic PMX up to 95%±3.01%. RESULTS: The tailored PMX-RSV-LCNPs exhibited a particle size of 173±0.26 nm and biphasic release pattern with a relatively initial burst release within first 3-4 hour followed by sustained release up to 24 hours. Moreover, PMX-RSV-LCNPs manifested superior concentration and time dependent cytotoxicity profile against A549 lung cancer cells with IC50 4.0628 µg/mL. Besides, the enhanced cellular uptake profile based on bioadhesive properties of glyceryl monoolein (GMO) as well as energy independent (cholesterol dependent) pattern. In-vivo evaluations against urethane induced lung cancer bearing mice demonstrated the potentiality of PMX-RSV-LCNPs in tumor growth inhibition via inhibition of angiogenesis and induction of apoptosis. The results were supported by histopathological analysis and immunohistochemical Ki67 staining. Moreover, PMX-RSV-LCNPs displayed a promising safety profile via attenuating nephro- and hepatotoxicity. CONCLUSION: PMX-RSV-LCNPs elaborated in the current study hold a great promise for lung cancer treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistemas de Liberação de Medicamentos , Cristais Líquidos/química , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/administração & dosagem , Animais , Carcinógenos/toxicidade , Proliferação de Células , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Pemetrexede/administração & dosagem , Resveratrol/administração & dosagem , Células Tumorais Cultivadas , Uretana/toxicidadeRESUMO
BACKGROUND: The rationale of this study is to combine the merits of both albumin nanoparticles and quantum dots (QDs) in improved drug tumor accumulation and strong fluorescence imaging capability into one carrier. However, premature drug release from protein nanoparticles and high toxicity of QDs due to heavy metal leakage are among challenging hurdles. Following this platform, we developed cancer nano-theranostics by coupling biocompatible albumin backbone to CdTe QDs and mannose moieties to enhance tumor targeting and reduce QDs toxicity. The chemotherapeutic water soluble drug pemetrexed (PMT) was conjugated via tumor-cleavable bond to the albumin backbone for tumor site-specific release. In combination, the herbal hydrophobic drug resveratrol (RSV) was preformulated as phospholipid complex which enabled its physical encapsulation into albumin nanoparticles. RESULTS: Albumin-QDs theranostics showed enhanced cytotoxicity and internalization into breast cancer cells that could be traced by virtue of their high fluorescence quantum yield and excellent imaging capacity. In vivo, the nanocarriers demonstrated superior anti-tumor effects including reduced tumor volume, increased apoptosis, and inhibited angiogenesis in addition to non-immunogenic response. Moreover, in vivo bioimaging test demonstrated excellent tumor-specific accumulation of targeted nanocarriers via QDs-mediated fluorescence. CONCLUSION: Mannose-grafted strategy and QD-fluorescence capability were beneficial to deliver albumin nanocarriers to tumor tissues and then to release the anticancer drugs for killing cancer cells as well as enabling tumor imaging facility. Overall, we believe albumin-QDs nanoplatform could be a potential nano-theranostic for bioimaging and targeted breast cancer therapy.
Assuntos
Albuminas , Antineoplásicos , Neoplasias da Mama/terapia , Pontos Quânticos , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Linhagem Celular Tumoral , Terapia Combinada , Quimioterapia Combinada , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Imagem Óptica , FitoterapiaRESUMO
AIM: Herein, tumor-targeted quantum dots (QDs)-based theranostic nanocapsules (NCs) coloaded with celecoxib and honokiol were developed. Materials & methodology: The anionic CD44-targeting chondroitin sulfate and cationic low density lipoprotein (LDL)-targeting lactoferrin (LF) were sequentially assembled onto the surface of the positively charged oily core. As an imaging probe, highly fluorescent mercaptopropionic acid-capped cadmium telluride QDs were coupled to LF. RESULTS: In vitro, fluorescence of QDs was quenched (OFF state) due to combined electron/energy transfer-mediated processes involving LF. After intracellular uptake of NCs, fluorescence was restored (ON state), thus enabled tracing their internalization. The NCs demonstrated enhanced cytotoxicity against breast cancer cells as well as superior in vivo antitumor efficacy. CONCLUSION: We propose these multifunctional nanotheranostics for imaging and targeted therapy of breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Lactoferrina/genética , Nanocápsulas/administração & dosagem , Nanomedicina Teranóstica , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Celecoxib/administração & dosagem , Celecoxib/química , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/química , Feminino , Humanos , Receptores de Hialuronatos/genética , Lipoproteínas LDL/genética , Nanocápsulas/química , Fitoterapia , Pontos Quânticos/químicaRESUMO
AIM: Lactoferrin (LF)-targeted gliadin nanoparticles (GL-NPs) were developed for targeted oral therapy of hepatocellular carcinoma. MATERIALS & METHODS: Celecoxib and diosmin were incorporated in the hydrophobic matrix of GL-NPs whose surface was decorated with LF by electrostatic interaction for binding to asialoglycoprotein receptors overexpressed by liver cancer cells. RESULTS: Targeted GL-NPs showed enhanced cytotoxic activity and increased cellular uptake in liver tumor cells compared with nontargeted NPs. Moreover, they demonstrated superior in vivo antitumor effects including reduction in the expression levels of tumor biomarkers and induction of caspase-mediated apoptosis. Ex vivo imaging of isolated organs exhibited extensive accumulation of NPs in livers more than other organs. CONCLUSION: LF-targeted GL-NPs could be considered as an efficient nanoplatform for targeted oral drug delivery for liver cancer therapy.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/administração & dosagem , Fitoterapia , Administração Oral , Animais , Carcinoma Hepatocelular/patologia , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Células Hep G2 , Humanos , Lactoferrina/química , Neoplasias Hepáticas/patologia , Camundongos , Nanopartículas/química , Nanosferas/administração & dosagem , Nanosferas/efeitos adversos , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIM: A Nano-in-Nano approach was exploited to facilitate incorporation of the chemotherapeutic drug etoposide (ETP) as nanosuspension, synergistically with berberine (BER) into hydrophilic albumin nanoparticles (HSA NPs). METHODS: For maximal tumor targeting, HSA was modified with mannose and phenyl-boronic acid. Furthermore, different crosslinkers were investigated for sustained release of water soluble BER from HSA NPs. RESULTS: The elaborated dual-targeted HSA NPs (216.2 nm) were spherical with high BER and ETP entrapment efficiency (69.5 and 87.6%, respectively) and loading (10.52 and 14.04%, respectively). The NPs exhibited sequential release pattern for both ETP and BER (51.55 and 34.33% over 72 h, respectively). Phenyl-boronic acid/mannose-HSA NPs demonstrated powerful cytotoxicity against A549 lung cancer cells (IC50: 12.4 µg/ml) correlated to enhanced cellular internalization. Dual-targeted NPs displayed 9.77-fold higher caspase-3 level and 3.5-fold lower VEGF level than positive control mice. CONCLUSION: Dual-targeted Nano-in-Nano albumin carriers could be beneficial for parenteral ETP/BER delivery to lung cancer.
Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Extratos Vegetais/química , Albumina Sérica Humana/química , Células A549 , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Berberina/química , Berberina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Etoposídeo/química , Etoposídeo/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lectinas/metabolismo , Camundongos , Terapia de Alvo Molecular , Tamanho da Partícula , Extratos Vegetais/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
In recent years, green nanomedicines have made transformative difference in cancer therapy researches. Herein, we propose dual-functionalized spray-dried casein micelles (CAS-MCs) for combined delivery of two phytochemicals; berberine (BRB) and diosmin (DSN) as targeted therapy of hepatocellular carcinoma (HCC). The nanomicelles enabled parenteral delivery of the poorly soluble DSN via its encapsulation within their hydrophobic core. Moreover, sustained release of the water soluble BRB was attained by hydrophobic ion pairing with sodium deoxycholate followed by genipin crosslinking of CAS-MCs. Dual-active targeting of MCs, via conjugating both lactobionic acid (LA) and folic acid (FA), resulted in superior cytotoxicity and higher cellular uptake against HepG2 cells compared to single-targeted and non-targeted CAS-MCs. The dual-targeted DSN/BRB-loaded CAS-MCs demonstrated superior in vivo anti-tumor efficacy in HCC bearing mice as revealed by down regulation of cell necrosis markers (NF-κB and TNF-α), inflammatory marker COX2, inhibition of angiogenesis and induction of apoptosis. Histopathological analysis and immunohistochemical Ki67 staining confirmed the superiority of the dual-targeted micelles. Ex-vivo imaging showed preferential liver-specific accumulation of dual-targeted CAS-MCs. Overall, this approach combined the benefits of traditional herbal medicine with nanotechnology via LA/FA-CAS-MCs loaded with BRB and DSN as a promising nanoplatform for targeted HCC therapy.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Berberina/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Caseínas/química , Preparações de Ação Retardada/química , Diosmina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Berberina/uso terapêutico , Carcinoma Hepatocelular/patologia , Diosmina/uso terapêutico , Sistemas de Liberação de Medicamentos , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Camundongos , MicelasRESUMO
OBJECTIVES: Herein, we propose combined aromatase inhibitor and herbal therapy of breast cancer as a synergistic therapeutic modality. METHODS: Zein nanospheres were prepared by phase separation for co-delivery of exemestane and luteolin. To enhance their tumor-targeting capability, the nanospheres were coated with PEGylated phospholipids and lactoferrin for passive and active targeting, respectively. RESULTS: The developed nanospheres demonstrated a small particle size and controlled drug release. In addition, the nanospheres revealed high serum stability, acceptable hemocompatibility, and good physical stability. Moreover, a 5-fold scale-up of zein nanospheres could be enabled followed by spray-drying using 2.5% mannitol as a drying adjuvant. PEGylated and lactoferrin-targeted nanospheres showed enhanced cytotoxicity against MCF-7 and 4T1 breast cancer cells with higher selectivity to cancer cells rather than normal fibroblasts. The in-vivo pharmacokinetics and anti-tumor efficacy confirmed the superiority of zein nanospheres particularly after PEGylation compared to free drug(s). The enhanced anti-cancer activity of nanocarriers was revealed as prolonged circulation half-life, lower % change in tumor volume, reduced expression of aromatase, Cyclin D1 and VEGF markers as well as amplified apoptosis and necrosis. CONCLUSION: Overall, combined delivery of aromatase inhibitors and herbal drugs via tumor-targeted zein nanospheres could serve as a promising strategy for breast cancer therapy.
Assuntos
Androstadienos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Lactoferrina/química , Zeína/química , Animais , Inibidores da Aromatase/administração & dosagem , Portadores de Fármacos/química , Feminino , Humanos , Luteolina/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Nanosferas , Tamanho da Partícula , Fosfolipídeos/química , Polietilenoglicóis/química , Ratos , Ratos Sprague-DawleyRESUMO
Etoposide (ETP), as a potential treatment for lung cancer, has limited application due to its poor solubility, and systemic side effects. In the current study, we propose inhalable boronate-targeted HSA nanocomposites for combined delivery of ETP and the herbal drug, berberine (BER) for localized therapy of lung cancer. First, ETP was pre-formulated as phospholipid complex (EPC) to enhance drug solubility and facilitate its encapsulation within the hydrophilic albumin nanoparticles (NPs). Second, EPC and BER were then co-loaded with high efficiency into HSA NPs as a synergistic therapy for lung cancer. The NPs displayed suitable size around 200â¯nm and sequential drug release pattern. Moreover, conjugation of aminophenylboronic acid (APBA) to HSA NPs resulted in enhanced cytotoxicity and internalization into A549 lung cancer cells, compared to non-targeted NPs or free drugs via binding to sialic acid residues over-expressed by cancer cells. Using mannitol as a spray-drying carrier, the developed inhalable nanocomposites demonstrated deep pulmonary deposition, confirmed by small MMAD (2.112⯵m) and high FPF (77.86%). In vivo investigations in lung cancer animal models revealed the superior anti-tumor efficacy of the inhalable nanocomposites. Overall, the inhalable APBA-HSA nanocomposites offered an alternative strategy for systemic delivery of ETP and BER in lung cancer therapy.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Berberina/administração & dosagem , Ácidos Borônicos/metabolismo , Portadores de Fármacos/metabolismo , Etoposídeo/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Albumina Sérica Humana/metabolismo , Células A549 , Administração por Inalação , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Berberina/farmacocinética , Berberina/uso terapêutico , Ácidos Borônicos/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Etoposídeo/farmacocinética , Etoposídeo/uso terapêutico , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Ácido N-Acetilneuramínico/metabolismo , Nanocompostos/química , Albumina Sérica Humana/químicaRESUMO
Pulmonary delivery of drug nanocarriers can overcome the shortcomings of systemic cancer therapy via the enhanced permeability and retention (EPR) based-nanomedicine. Herein, inhalable multi-compartmental nanocomposites with the capability for both localized and modulated release of the hydrophobic mTOR inhibitor, rapamycin (RAP) and the hydrophilic herbal drug, berberine (BER) have been developed for lung cancer therapy. Two types of multi-compartmental nanocarriers were fabricated by enveloping BER hydrophobic ion pair-lipid nanocore within a shell of RAP-phospholipid complex bilayer to reduce the delivery gap between the two drugs. To further enhance their tumor targeting, the nanocarriers were layer-by-layer coated by cationic lactoferrin and anionic hyaluronate resulting in enhanced internalization and cytotoxicity against lung cancer cells. The inhalable nanocomposites fabricated by spray-drying of multi-compartmental nanocarriers exhibited favorable aerosolization efficiency (MMAD of 3.28⯵m and FPF of 55.5%). The powerful anti-cancer efficacy of inhalable nanocomposites in lung cancer bearing mice compared to the inhaled free drugs was revealed by remarkable decrease in lung weight, and reduction in both number and diameters of lung adenomatous foci and angiogenic markers compared to positive control. Overall, localized delivery of RAP and BER to tumor cells via inhalable multi-compartmental nanocomposites holds great promise in management of lung cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Berberina/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Sirolimo/administração & dosagem , Células A549 , Adenocarcinoma/tratamento farmacológico , Administração por Inalação , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Química Farmacêutica/métodos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Ácido Hialurônico/química , Interações Hidrofóbicas e Hidrofílicas , Lactoferrina/química , Masculino , Camundongos , Nanocompostos , Fosfolipídeos/químicaRESUMO
AIM: Monascin and ankaflavin, the major fractions of the fungal-derived monascus yellow pigments, were incorporated with the herbal drug, resveratrol (RSV) within the core of folate-conjugated casein micelles (FA-CAS MCs, F1) for active targeting. PEGylated RSV-phospholipid complex bilayer enveloping casein-loaded micelles (PEGPC-CAS MCs) were also developed as passive-targeted nanosystem. RESULTS: FA- and PEGPC-CAS MCs demonstrated a proper size with monomodal distribution, sustained drug release profiles and good hemocompatibility. The coloaded MCs showed superior cytotoxicity to MCF-7 breast cancer cells compared with free drugs. Both nanosystems exerted excellent in vivo antitumor efficacy in breast cancer bearing mice with PEGylated MCs showing comparable tumor regression to folate-conjugated MCs. CONCLUSION: Evergreen nanoplatforms coloaded with monascus yellow pigments and RSV were effective for breast cancer treatment.