RESUMO
Breast cancer, specifically metastatic breast, is a leading cause of morbidity and mortality in women. This is mainly due to relapse and reoccurrence of tumor. The primary reason for cancer relapse is the development of multidrug resistance (MDR) hampering the treatment and prognosis. MDR can occur due to a multitude of molecular events, including increased expression of efflux transporters such as P-gp, BCRP, or MRP1; epithelial to mesenchymal transition; and resistance development in breast cancer stem cells. Excessive dose dumping in chemotherapy can cause intrinsic anti-cancer MDR to appear prior to chemotherapy and after the treatment. Hence, novel targeted nanomedicines encapsulating chemotherapeutics and gene therapy products may assist to overcome cancer drug resistance. Targeted nanomedicines offer innovative strategies to overcome the limitations of conventional chemotherapy while permitting enhanced selectivity to cancer cells. Targeted nanotheranostics permit targeted drug release, precise breast cancer diagnosis, and importantly, the ability to overcome MDR. The article discusses various nanomedicines designed to selectively target breast cancer, triple negative breast cancer, and breast cancer stem cells. In addition, the review discusses recent approaches, including combination nanoparticles (NPs), theranostic NPs, and stimuli sensitive or "smart" NPs. Recent innovations in microRNA NPs and personalized medicine NPs are also discussed. Future perspective research for complex targeted and multi-stage responsive nanomedicines for metastatic breast cancer is discussed.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Nanomedicina/métodos , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Terapia Genética/métodos , Humanos , Terapia de Alvo Molecular , Nanomedicina/tendências , Nanopartículas/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Células-Tronco Neoplásicas/metabolismo , Medicina de Precisão , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Lcn2 overexpression in metastatic breast cancer (MBC) can lead to cancer progression by inducing the epithelial-to-mesenchymal transition and enhancing tumor angiogenesis. In this study, we engineered a PEGylated liposomal system encapsulating lipocalin 2 (Lcn2) small interfering RNA (Lcn2 siRNA) for selective targeting MBC cell line MCF-7 and triple-negative breast cancer cell line MDA-MB-231. The PEGylated liposomes were decorated with octreotide (OCT) peptide. OCT is an octapeptide analog of somatostatin growth hormone, having affinity for somatostatin receptors, overexpressed on breast cancer cells. Optimized OCT-targeted Lcn2 siRNA encapsulated PEGylated liposomes (OCT-Lcn2-Lipo) had a mean size of 152.00 nm, PDI, 0.13, zeta potential 4.10 mV and entrapment and loading efficiencies of 69.5% and 7.8%, respectively. In vitro uptake and intracellular distribution of OCT-Lcn2-Lipo in MCF-7 and MDA-MB-231 and MCF-12A cells demonstrated higher uptake for the OCT-targeted liposomes at 6 h by flow cytometry and confocal microscopy. OCT-Lcn2-lipo could achieve approximately 55-60% silencing of Lcn2 mRNA in MCF-7 and MDA-MB-231 cells. OCT-Lcn2-Lipo also demonstrated in vitro anti-angiogenic effects in MCF-7 and MDA-MB-231 cells by reducing VEGF-A and reducing the endothelial cells (HUVEC) migration levels. This approach may be useful in inhibiting angiogenesis in MBC.
RESUMO
Active targeting and overcoming multi-drug resistance (MDR) can be some of the important attributes of targeted therapy for metastatic breast cancer (MBC) and triple-negative breast cancer (TNBC) treatment. In this study, we constructed a hyaluronic acid (HA)-decorated mixed nanomicelles-encapsulating chemotherapeutic agent paclitaxel (PTX) and P-glycoprotein inhibitor ritonavir (RTV). HA was conjugated to poly (lactide) co-(glycolide) (PLGA) polymer by disulfide bonds (HA-ss-PLGA). HA is a natural ligand for CD44 receptors overexpressed in breast cancer cells. Disulfide bonds undergo rapid reduction in the presence of glutathione, present in breast cancer cells. The addition of RTV can inhibit the P-gp and CYP3A4-mediated metabolism of PTX, thus aiding in reversing MDR and sensitizing the cells toward PTX. An in vitro uptake and cytotoxicity study in MBC MCF-7 and TNBC MDA-MB-231 cell lines demonstrated the effective uptake of the nanomicelles and drug PTX compared to non-neoplastic breast epithelium MCF-12A cells. Interestingly, in vitro potency determination showed a reduction in mitochondrial membrane potential and reactive oxygen species in breast cancer cell lines, indicating effective apoptosis of cancer cells. Thus, stimuli-sensitive nanomicelles along with HA targeting and RTV addition can effectively serve as a chemotherapeutic drug delivery agent for MBC and TNBC.
Assuntos
Sistemas de Liberação de Medicamentos , Ácido Hialurônico/química , Paclitaxel/farmacologia , Ritonavir/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Ácido Hialurônico/farmacologia , Células MCF-7 , Micelas , Nanopartículas/química , Metástase Neoplásica , Paclitaxel/química , Ritonavir/química , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
AIM: To prepare and characterise lutein-loaded polylactide-co-glycolide-polyethylene glycol-folate (PLGA-PEG-FOLATE) nanoparticles and evaluate enhanced uptake in SK-N-BE(2) cells. METHODS: Nanoparticles were prepared using O/W emulsion solvent evaporation and characterised using DLS, SEM, DSC, FTIR and in-vitro release. Lutein-uptake in SK-N-BE(2) cells was determined using flow-cytometry, confocal-microscopy and HPLC. Control was lutein PLGA nanoparticles. RESULTS: The size of lutein-loaded PLGA and PLGA-PEG-FOLATE nanoparticles were 189.6 ± 18.79 nm and 188.0 ± 4.06 nm, respectively. Lutein entrapment was â¼61%(w/w) and â¼73%(w/w) for PLGA and PLGA-PEG-FOLATE nanoparticles, respectively. DSC and FTIR confirmed encapsulation of lutein into nanoparticles. Cellular uptake studies showed â¼1.6 and â¼2-fold enhanced uptake of lutein from PLGA-PEG-FOLATE nanoparticles compared to PLGA nanoparticles and lutein, respectively. Cumulative release of lutein was higher in PLGA nanoparticles (100% (w/w) within 24 h) compared to PLGA-PEG-FOLATE nanoparticles (â¼80% (w/w) in 48 h). CONCLUSION: Lutein-loaded PLGA-PEG-FOLATE nanoparticles could be a potential treatment for hypoxic ischaemic encephalopathy.
Assuntos
Portadores de Fármacos/química , Ácido Fólico/análogos & derivados , Luteína/administração & dosagem , Poliésteres/química , Polietilenoglicóis/química , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Humanos , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Luteína/farmacocinéticaRESUMO
Introduction: Proteins and peptides are prominent therapeutic agents, which are effective in number of ailments. Long-term delivery of protein and peptide therapeutics requires polymeric encapsulation to protect from degradation and for its sustained release. However, results from encapsulation of protein macromolecules in dynamic delivery systems report unreliable clinical outcome, indicating ease of degradation, low permeability, and serious immune responses. A specifically targeted delivery system as tumor or cancer theranostics may surpass these limitations. Areas covered: This review covers recent advancements in approaches involving conjugated protein nano-formulations as targeting delivery technology for various ailments encompassing mostly cancer treatment options. Progressions in targeted chemotherapeutics, protein nanoparticles, peptide nanoparticles, lipidation, and antibody drug-conjugates are discussed. Expert opinion: Significant expansions have been made in forming new generation of antitumor-recombinant proteins, which proves a milestone of advancements for more potent and explicit cancer therapies. However, transformation of biologics from laboratory to clinical trials is an immense challenge, because of drop in efficiency of drug-loading, poor reproducibility of nanoparticles, inadequate information regarding long-term toxicity and insufficient pharmacokinetics data. Hence, early stage tumor diagnosis with précised drug delivery to tumor site is crucial for protein- and peptide- based therapeutics for cancer.