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1.
Purinergic Signal ; 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38436880

RESUMO

The development of ionizable lipid (IL) was necessary to enable the effective formulation of small interfering RNA (siRNA) to inhibit P2X7 receptors (P2X7R), a key player in tumor proliferation, apoptosis, and metastasis. In this way, the synthesis and utility of IL for enhancing cellular uptake of lipid nanoparticles (LNP) improve the proper delivery of siRNA-LNPs for knockdown overexpression of P2X7R. Therefore, to evaluate the impact of P2X7 knockdown on breast cancer (BC) migration and apoptosis, a branched and synthesized ionizable lipid (SIL) was performed for efficient transfection of LNP with siRNA for targeting P2X7 receptors (siP2X7) in mouse 4T-1 cells. Following synthesis and structural analysis of SIL, excellent characterization of the LNP was achieved (Z-average 126.8 nm, zeta-potential - 12.33, PDI 0.16, and encapsulation efficiency 85.35%). Afterward, the stability of the LNP was evaluated through an analysis of the leftover composition, and toxic concentration values for SIL and siP2X7 were determined. Furthermore, siP2X7-LNP cellular uptake in the formulation was assessed via confocal microscopy. Following determining the optimal dose (45 pmol), wound healing analysis was assessed using scratch assay microscopy, and apoptosis was evaluated using flow cytometry. The use of the innovative branched SIL in the formulation of siP2X7-LNP resulted in significant inhibition of migration and induction of apoptosis in 4T-1 cells due to improved cellular uptake. Subsequently, the innovative SIL represents a critical role in efficiently delivering siRNA against murine triple-negative breast cancer cells (TNBC) using LNP formulation, resulting in significant efficacy.

2.
Int J Pharm ; 649: 123635, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38000649

RESUMO

Asialoglycoprotein receptors (ASGPRs) are highly expressed on hepatocytes and have been used for liver-targeted delivery and hepatocellular carcinoma (HCC) therapy. However, targeted delivery of bortezomib (BTZ) to HCC has not been reported. In this study, N-stearyl lactobionamide (N-SALB) with galactose (Gal) moiety was synthesized as a targeting agent and its structure was confirmed by FT-IR and NMR analyses. N-SALB surface-modified solid lipid nanoparticles (SLNs) loaded with BTZ (Gal-SLNs/BTZ) were developed to target BTZ delivery into HCC cancer cells. The Gal-SLNs/BTZ had an average particle size of 116.3 nm, polydispersity index (PDI) of 0.210, and zeta potential of -13.8 mV. TEM analysis showed their nanometer-sized spherical morphology. The encapsulation efficiency (EE) and drug loading (DL) capacity were 84.5 % and 1.16 %, respectively. Release studies showed that BTZ loaded inside the SLNs was slowly released over a period of 72 h at pH 7.4. Flow cytometry analysis showed significantly higher intracellular uptake of N-SALB-targeted nanoparticles than non-targeted nanoparticles in HepG2 cells. All lipid formulations showed good biocompatibility in the cytotoxicity study using MTT assay. Concentration-dependent cytotoxicity was observed for all formulations, with N-SALB-targeted nanoparticles demonstrating more cytotoxicity against HepG2 cells. The highest percentage of apoptosis was obtained for N-SALB-targeted nanoparticles compared to non-targeted nanoparticles (42.2 % and 8.70 %, respectively). Finally, biodistribution studies in HepG2 bearing nude mice showed that the accumulation of targeted nanoparticles in the tumor was significantly higher than non-targeted nanoparticles.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Camundongos , Animais , Bortezomib , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Camundongos Nus , Distribuição Tecidual , Espectroscopia de Infravermelho com Transformada de Fourier , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/química , Tamanho da Partícula , Portadores de Fármacos/uso terapêutico
3.
Nanomedicine (Lond) ; 18(25): 1855-1873, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37991168

RESUMO

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, typically diagnosed in advanced stages. Chemotherapy is necessary for treating advanced liver cancer; however, several challenges affect its effectiveness. These challenges include low specificity, high dosage requirements, high systemic toxicity and severe side effects, which significantly limit the efficacy of chemotherapy. These limitations can hinder the treatment of HCC. This review focuses on the prevalence of HCC, different types of liver cancer and the staging of the disease, along with available treatment methods. Additionally, explores recent and relevant studies on smart drug- and gene-delivery systems specifically designed for HCC. These systems include targeted endogenous and exogenous stimuli-responsive platforms.


Liver cancer is the third leading cause of cancer deaths in the world that is usually diagnosed in the last stages. Chemotherapy is commonly used to treat advanced liver cancer, but it faces several challenges that reduce its effectiveness. These challenges include low specificity (not targeting cancer cells specifically), high dosage requirements and side effects that can affect anywhere in the body. As a result, the efficacy of chemotherapy is significantly limited, making it difficult to treat liver cancer. This review discusses the prevalence of liver cancer, different types of liver cancer and how the disease is staged. It also explores various treatment methods available for liver cancer. Furthermore, the article explores recent and relevant studies on smart drug- and gene-delivery systems that are specifically designed to target liver cancer. These systems include platforms that respond to targeted and internal or external stimuli. They aim to improve the effectiveness of treatment for liver cancer.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Terapia de Alvo Molecular , Técnicas de Transferência de Genes
4.
Purinergic Signal ; 2023 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-37843749

RESUMO

Nucleosides and purine nucleotides serve as transmitter and modulator agents that extend their functions beyond the cell. In this context, purinergic signaling plays a crucial role in regulating energy homeostasis and modulating metabolic alterations in tumor cells. Therefore, it is essential to consider the pharmacological targeting of purinergic receptors (PUR), which encompass the expression and inhibition of P1 receptors (metabotropic adenosine receptors) as well as P2 receptors (extracellular ATP/ADP) comprising P2X and P2Y receptors. Thus, the pharmacological interaction between inhibitors (such as RNA, monoclonal antibodies, and small molecules) and PUR represents a key aspect in facilitating the development of therapeutic interventions. Moreover, this review explores recent advancements in pharmacological inhibitors and the regulation of innate and adaptive immunity of PUR, specifically in relation to immunological and inflammatory responses. These responses encompass the release of pro-inflammatory cytokines (PIC), the production of reactive oxygen and nitrogen species (ROS and RNS), the regulation of T cells, and the activation of inflammasomes in all human leukocytes.

5.
Int J Mol Sci ; 23(22)2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36430951

RESUMO

Aptamers are synthetic single-stranded oligonucleotides (such as RNA and DNA) evolved in vitro using Systematic Evolution of Ligands through Exponential enrichment (SELEX) techniques. Aptamers are evolved to have high affinity and specificity to targets; hence, they have a great potential for use in therapeutics as delivery agents and/or in treatment strategies. Aptamers can be chemically synthesized and modified in a cost-effective manner and are easy to hybridize to a variety of nano-particles and other agents which has paved a way for targeted therapy and diagnostics applications such as in breast tumors. In this review, we systematically explain different aptamer adoption approaches to therapeutic or diagnostic uses when addressing breast tumors. We summarize the current therapeutic techniques to address breast tumors including aptamer-base approaches. We discuss the next aptamer-based therapeutic and diagnostic approaches targeting breast tumors. Finally, we provide a perspective on the future of aptamer-based sensors for breast therapeutics and diagnostics. In this section, the therapeutic applications of aptamers will be discussed for the targeting therapy of breast cancer.


Assuntos
Aptâmeros de Nucleotídeos , Neoplasias da Mama , Humanos , Feminino , Técnica de Seleção de Aptâmeros , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Aptâmeros de Nucleotídeos/uso terapêutico , Sistemas de Liberação de Medicamentos , Ligantes
6.
Expert Opin Drug Discov ; 17(9): 1013-1027, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35996765

RESUMO

INTRODUCTION: The argument around cancer therapy is an old one. Using chemotherapeutic drugs, as one of the most effective strategies in treatment of malignancies, is restricted by various issues that progress during therapy and avoid achieving clinical endpoints. Multidrug resistance (MDR), frequently mediated by ATP-binding cassette (ABC) transporters, is one of the most recognized obstacles in the success of pharmacological anticancer approaches. These transporters efflux diverse drugs to extracellular environment, causing MDR and responsiveness of tumor cells to chemotherapy diminishes. AREAS COVERED: Several strategies have been used to overcome MDR phenomenon. Succession in this field requires complete knowledge about features and mechanism of ABC transporters. In this review, conventional synthetic and natural inhibitors are discussed first and then novel approaches including RNA, monoclonal antibodies, nanobiotechnology, and structural modification techniques are represented. EXPERT OPINION: With increasing frequency of MDR in cancer cells, it is essential to develop new drugs to inhibit MDR. Using knowledge acquired about ABC transporter's structure, rational design of inhibitors is possible. Also, some herbal products have shown to be potential lead compounds in drug discovery for reversal of MDR.


Assuntos
Antineoplásicos , Neoplasias , Transportadores de Cassetes de Ligação de ATP , Trifosfato de Adenosina/farmacologia , Trifosfato de Adenosina/uso terapêutico , Anticorpos Monoclonais/farmacologia , Descoberta de Drogas , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , RNA/farmacologia , RNA/uso terapêutico
7.
Stem Cell Res Ther ; 13(1): 344, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35883125

RESUMO

BACKGROUND: Mesenchymal-based therapy has been utilized as a practical approach in the treatment of renal ischemia/reperfusion (I/R) injury. However, low cell retention and survival in the ischemic site have remained challenging issues. To bridge this gap, the integrin receptor-binding RGD peptide-functionalized, s-nitroso-n-acetyl penicillamine (SNAP)-loaded hydrogel was used to transplant Wharton's jelly-mesenchymal stem cells (WJ-MSCs). METHODS: Apart from physicochemical and rheological characterizations that confirmed entangled interlocking ß-sheets with nanofibrous morphology, real-time RT-PCR, ROS production, serum biomarker concentrations, and histopathological alterations were explored in a mouse model to assess the therapeutic efficacy of formulations in the treatment of renal I/R injury. RESULTS: The RGD-functionalized Fmoc-diphenylalanine (Fmoc-FF + Fmoc-RGD) hydrogel supported the spread and proliferation of WJ-MSCs in vivo. Notably, intralesional injection of nitric oxide donor combined with the embedded WJ-MSCs caused superior recovery of renal I/R injury compared to free WJ-MSCs alone in terms of histopathological scores and renal function indices. Compared to the I/R control group, oxidative stress and inducible nitric oxide synthase (iNOS) expression biomarkers showed a significant decline, whereas endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) expression exhibited a significant increment, indicating regeneration of the injured endothelial tissue. CONCLUSION: The findings confirmed that the hydrogels containing WJ-MSCs and nitric oxide donors can promote the regeneration of renal I/R injuries by increasing angiogenic factors and cell engraftment.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Nanofibras , Traumatismo por Reperfusão , Geleia de Wharton , Animais , Hidrogéis , Integrinas/metabolismo , Isquemia/terapia , Rim/patologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Peptídeos/metabolismo , Fenilalanina , Traumatismo por Reperfusão/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
J Nanobiotechnology ; 20(1): 276, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35701851

RESUMO

In the last decade, the development of messenger RNA (mRNA) therapeutics by lipid nanoparticles (LNP) leads to facilitate clinical trial recruitment, which improves the efficacy of treatment modality to a large extent. Although mRNA-LNP vaccine platforms for the COVID-19 pandemic demonstrated high efficiency, safety and adverse effects challenges due to the uncontrolled immune responses and inappropriate pharmacological interventions could limit this tremendous efficacy. The current study reveals the interplay of immune responses with LNP compositions and characterization and clarifies the interaction of mRNA-LNP therapeutics with dendritic, macrophages, neutrophile cells, and complement. Then, pharmacological profiles for mRNA-LNP delivery, including pharmacokinetics and cellular trafficking, were discussed in detail in cancer types and infectious diseases. This review study opens a new and vital landscape to improve multidisciplinary therapeutics on mRNA-LNP through modulation of immunopharmacological responses in clinical trials.


Assuntos
Tratamento Farmacológico da COVID-19 , Nanopartículas , Humanos , Lipídeos , Lipossomos , Nanopartículas/uso terapêutico , Pandemias , RNA Mensageiro/genética
9.
Expert Opin Drug Deliv ; 19(6): 685-705, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35698794

RESUMO

INTRODUCTION: Compared to normal cells, malignant cancer cells require more iron for their growth and rapid proliferation, which can be supplied by a high expression level of transferrin receptor (TfR). It is well known that the expression of TfR on the tumor cells is considerably higher than that of normal cells, which makes TfR an attractive target in cancer therapy. AREAS COVERED: In this review, the primary focus is on the role of TfR as a valuable tool for cancer-targeted drug delivery, followed by the full coverage of available TfR ligands and their conjugation chemistry to the surface of liposomes. Finally, the most recent studies investigating the potential of TfR-targeted liposomes as promising drug delivery vehicles to different cancer cells are highlighted with emphasis on their improvement possibilities to become a part of future cancer medicines. EXPERT OPINION: Liposomes as a valuable class of nanocarriers have gained much attention toward cancer therapy. From all the studies that have exploited the therapeutic and diagnostic potential of TfR on cancer cells, it can be realized that the systematic assessment of TfR ligands applied for liposomal targeted delivery has yet to be entirely accomplished.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Ligantes , Lipossomos/metabolismo , Neoplasias/tratamento farmacológico , Receptores da Transferrina/metabolismo , Transferrina/metabolismo
10.
J Control Release ; 345: 371-384, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35301054

RESUMO

The effective treatment of glioma through conventional chemotherapy is proved to be a great challenge in clinics. The main reason is due to the existence of two physiological and pathological barriers respectively including the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) that prevent most of the chemotherapeutics from efficient delivery to the brain tumors. To address this challenge, an ideal drug delivery system would efficiently traverse the BBB and BBTB and deliver the therapeutics into the glioma cells with high selectivity. Herein, a targeted delivery system was developed based on nanostructured lipid carriers (NLCs) modified with two proteolytically stable D-peptides, D8 and RI-VAP (Dual NLCs). D8 possesses high affinity towards nicotine acetylcholine receptors (nAChRs), overexpressed on brain capillary endothelial cells (BCECs), and can penetrate through the BBB with high efficiency. RI-VAP is a specific ligand of cell surface GRP78 (csGRP78), a specific angiogenesis and cancer cell-surface marker, capable of circumventing the BBTB with superior glioma-homing property. Dual NLCs could internalize into BCECs, tumor neovascular endothelial cells, and glioma cells with high specificity and could penetrate through in vitro BBB and BBTB models with excellent efficiency compared to non-targeted or mono-targeted NLCs. In vivo whole-animal imaging and ex vivo imaging further confirmed the superior targeting capability of Dual NLCs towards intracranial glioma. When loaded with Bortezomib (BTZ), Dual NLCs attained the highest therapeutic efficiency by means of superior in vitro cytotoxicity and apoptosis and prolonged survival rate and efficient anti-glioma behavior in intracranial glioma bearing mice. Collectively, the designed targeting platform in this study could overcome multiple barriers and effectively deliver BTZ to glioma cells, which represent its potential for advanced brain cancer treatment with promising therapeutic outcomes.


Assuntos
Neoplasias Encefálicas , Glioma , Animais , Barreira Hematoencefálica/metabolismo , Bortezomib/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Células Endoteliais/metabolismo , Glioma/tratamento farmacológico , Lipídeos/uso terapêutico , Camundongos
11.
Arch Physiol Biochem ; 128(1): 59-68, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31496300

RESUMO

CONTEXT: Small peptides as multifunctional biomolecules can prevent the metabolic disorders such as diabetes. OBJECTIVE: The purpose of this study was to investigate the effects of small peptides on the enzymes and histopathology of the liver in mice exposed to diabetes. METHODS: Di- and tri-peptides containing proline, glycine, and leucine were produced by solid phase peptide synthesis (SPPS) protocol. The effects of produced peptides as well as carnosine (Ala-His) and glutathione (Glu-Cys-Gly) were evaluated on hepatic enzymes activity by enzymatic method and histopathology of liver using hematoxylin and eosin and TUNEL staining to assess histologic changes and apoptosis in diabetes induced by multiple low doses of streptozotocin (MLDS). RESULTS: The Ala-His, Leu-Gly and Pro-Gly-Pro peptides had the higher protective effects against the effects of diabetes on the enzymes and histologic changes of liver in mice. CONCLUSION: These peptides can be raised as considerable pharmaceutical preventive agent against diabetes development.


Assuntos
Diabetes Mellitus Experimental , Glicina , Sequência de Aminoácidos , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Leucina , Fígado , Camundongos , Peptídeos , Prolina
12.
Int J Pharm ; 613: 121395, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34933080

RESUMO

The existence of the blood-brain barrier (BBB) makes the clinical chemotherapy of glioma a formidable challenge, because it hinders the passage of different chemotherapeutics into the brain and reduces the overall therapeutic efficiency. Therefore, it is necessary to design a drug delivery system in way that would favor the transportation of anti-cancer agents across the BBB and increase their selective accumulation within the tumor cells without affecting the normal tissues. Transferrin receptor (TfR) that shows an elevated level of expression on the BBB and glioma cells emerges as a promising tool for brain targeted delivery and glioma therapy. However, only a limited number of studies have comparatively evaluated the functionally of TfR targeting ligands. Herein, a series of liposomal formulations modified with the most well-known TfR targeting peptides including T12 (also known as THR), B6, and T7 was developed and their brain targeting capability and selective glioma accumulation was comparatively evaluated in vitro and in vivo. Among all TfR targeting or non-targeting groups, T7-modified liposomes (T7-LS) showed the highest BBB penetration capacity and brain distribution and displayed an enhanced accumulation in glioma cells. When loaded with vincristine (VCR), as a model chemotherapeutic, T7-LS/VCR could achieve the best anti-glioma outcome by means of targeted cytotoxicity and apoptosis in vitro. The obtained results suggested T7-LS as a potential platform for effective brain targeted delivery and glioma therapy in clinic.


Assuntos
Neoplasias Encefálicas , Glioma , Barreira Hematoencefálica , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Humanos , Lipossomos , Peptídeos , Transferrina , Vincristina
13.
Iran J Pharm Res ; 20(3): 506-515, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34904004

RESUMO

Methotrexate (MTX) is one of the most effective therapeutics to treat different types of solid tumors; however, it suffers low permeability limiting its bioavailability and cellular uptake. To tackle this, we aim to design and fabricate different types of cell-penetrating peptides (CPPs) to improve the intracellular uptake of MTX without causing any immunogenic response. CPPs were synthesized by the solid-phase peptide synthesis method. Peptide-MTX conjugates were prepared via covalent binding of peptide and drug molecule. CPPs and peptide-E8 nanoparticles were characterized using zeta-sizer and scanning electron microscopy. Cytotoxicity of CPPs and peptide-MTX conjugates was evaluated by MTT assay. An enzyme-linked immunosorbent assay was employed to assess the IL-6 and TNF-α cytokine release profile. Amongst all sequences, W4R4-MTX possessed the highest loading efficiency (97%) and drug to peptide percentage (24.02%). The lowest loading efficiency (36%) and drug to peptide percentage (8.76%) were seen for NGRWK-MTX conjugates. The NGRWR peptide and NGRWR-E8 nanoparticles had acceptable size (~100 nm) with spherical and rod-like structures, respectively. The selected CPPs and peptide-MTX conjugates did not show any cytotoxicity or immunogenicity. The fabricated peptides are represented as promising carriers to improve the intracellular delivery of MTX to cancer cells with low immunogenic and cytotoxic effects on normal cells.

14.
Int J Pharm ; 609: 121148, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34600054

RESUMO

The present study aimed to synthesize cholesteryl acetyl carnitine (CAC), and surface modify the PEGylated liposomes with the intention of enhanced cancer cell uptake. For this, CAC synthesis was performed in amine-free esterification conditions and then four liposomal formulations of unmodified, CAC/PEG, and CAC + PEG-modified were prepared by ethanol injection method. Cytotoxicity of the liposomes was investigated in A549 cells, followed by cellular uptake assessments of coumarin 6 (C6)-loaded liposomes. The results of ATR-FTIR, 1HNMR, and 13CNMR demonstrated successful formation of CAC. A molecular docking study showed efficient binding affinities rather than carnitine to the active site of four carnitine transporters. Liposomal formulations possessed spherical morphology with a mean particle size range of 112-138 nm, narrow size distribution, and negative surface charge. All formulations had low cytotoxicity at 0.5 mg/ml, but high cytotoxicity at around 2.5 mg/ml. The lowest IC50 was obtained for CAC modified liposomes. CAC + PEG-modified liposomes had the highest cellular uptake. In conclusion, CAC + PEG modification of liposomes is an effective approach for increasing A549 cellular uptake, with low cytotoxicity at commonly applied liposome concentrations. The elevated uptake may be due to the involvement of the organic cation transporter, cationic structure, and the metabolic preference of CAC in cancer cells.


Assuntos
Acetilcarnitina , Lipossomos , Neoplasias , Polietilenoglicóis , Cátions , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Tamanho da Partícula
15.
J Control Release ; 338: 367-393, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34461174

RESUMO

The two major challenges in cancer treatment include lack of early detection and ineffective therapies with various side effects. Angiogenesis is the key process in the growth, survival, invasiveness, and metastasis of many of cancerous tumors. Imaging of the angiogenesis could lead to diagnosis of tumors in the early stage and evaluation of the therapeutic responses. Angiogenic blood vessels express specific molecular markers different from normal blood vessels (in level or kind). This fact would make the tumor vasculature a suitable site to target therapeutics and imaging agents within the tumor. Surface modified nanoparticles using peptide ligands with high binding affinity to the vasculature markers, provide efficient delivery of therapeutic and imaging agents, while avoiding undesirable side effects. In this review, we discuss discoveries of various tumor targeting peptides useful for tumor angiogenesis imaging and targeted therapy with emphasis on surface modified nanomedicines using vasculature targeting peptides.


Assuntos
Nanopartículas , Neoplasias , Humanos , Nanomedicina , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/tratamento farmacológico , Peptídeos
16.
Iran J Basic Med Sci ; 24(3): 383-390, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33995950

RESUMO

OBJECTIVES: Doxorubicin (Dox) is one of the most well-known chemotherapeutics that are commonly applied for a wide range of cancer treatments. However, in most cases, efflux pumps like P-glycoprotein (P-gp), expel the taken drugs out of the cell and decrease the Dox bioavailability. Expression of P-gp is associated with elevated mRNA expression of the ATP-binding cassette B1 (ABCB1) gene. MATERIALS AND METHODS: In the current study, different sequences of cell-penetrating peptides (CPPs) containing tryptophan, lysine, and arginine and their nano-complexes were synthesized and their impact on the expression and activity of the ABCB1 gene was evaluated in the A549 lung carcinoma cell line. Furthermore, the cellular uptake of designed CPPs in the A549 cell line was assessed. RESULTS: The designed peptides, including [W4K4], [WR]3-QGR, R10, and K10 increased Dox cytotoxicity after 48 hr. Furthermore, arginine-rich peptides showed higher cellular uptake. Rhodamin123 accumulation studies illustrated that all the obtained peptides could successfully inhibit the P-gp pump. The designed peptides inhibited the ABCB1 gene expression, of which, [W4K4] resulted in the lowest expression ratio. CONCLUSION: [W4K4], [WR]3-QGR, R10, and K10 could successfully increase the Dox cytotoxicity by decreasing the efflux pump gene expression.

17.
Int J Pharm ; 602: 120645, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915182

RESUMO

High-grade glioma is one of the most aggressive types of cancer with a low survival rate ranging from 12 to 15 months after the first diagnosis. Though being the most common strategy for glioma therapy, conventional chemotherapy suffers providing the therapeutic dosage of common therapeutics mostly because of limited permeability of blood-brain barrier (BBB), and blood-brain tumor barrier (BBTB) to anticancer agents. Among various nanoformulations, liposomes are considered as the most popular carriers aimed for glioma therapy. However, non-targeted liposomes which passively accumulate in most of the cancer tissues mainly through the enhanced permeation and retention effect (EPR), may not be applicable for glioma therapy due to BBB tight junctions. In the recent decade, the surface modification of liposomes with different active targeting ligands has shown promising results by getting different chemotherapeutics across the BBB and BBTB and leading them into the glioma cells. The present review discusses the major barriers for drug delivery systems to glioma, elaborates the existing mechanisms for liposomes to traverse across the BBB, and explores the main strategies for incorporation of targeting ligands onto the liposomes. It subsequently investigates the most recent and relevant studies of actively targeted liposomes modified with antibodies, aptamers, monosaccharides, polysaccharides, proteins, and peptides applied for effective glioma therapy, and highlights the common challenges facing this area. Finally, the actively targeted liposomes undergoing preclinical and clinical studies for delivery of different anticancer agents to glioma cells will be reviewed.


Assuntos
Neoplasias Encefálicas , Glioma , Barreira Hematoencefálica , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Humanos , Lipossomos
18.
J Microencapsul ; 38(3): 192-202, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33530812

RESUMO

AIM: Nano drug delivery systems can provide the opportunity to reduce side effects and improve the therapeutic aspect of a variety of drugs. Bortezomib (BTZ) is a proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma. Severe side effects of BTZ are the major dose-limiting factor. Particulate drug delivery systems for BTZ are polymeric and lipidic drug delivery systems. This review focussed on lipidic-nano drug delivery systems (LNDDSs) for the delivery of BTZ. RESULTS: LNDDSs including liposomes, solid lipid nanoparticles, and self-nanoemulsifying drug delivery systems showed reduce systemic side effects, improved therapeutic efficacy, and increased intestinal absorption. Besides LNDDSs were used to target-delivery of BTZ to cancer. CONCLUSION: Overall, LNDDSs can be considered as a novel delivery system for BTZ to resolve the treatment-associated restrictions.


Assuntos
Bortezomib/administração & dosagem , Sistemas de Liberação de Medicamentos , Lipídeos/química , Nanopartículas , Inibidores de Proteassoma/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Bortezomib/farmacocinética , Bortezomib/uso terapêutico , Composição de Medicamentos , Emulsões , Humanos , Lipossomos , Tamanho da Partícula , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/uso terapêutico , Ratos
19.
J Control Release ; 328: 932-941, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33129921

RESUMO

As one of the deadliest diseases, cancer frequently resists existing therapeutics because they do not target all cells within a progressing tumor, for example both tumor stem and proliferating cells. This frequently results in enrichment of invasive and metastatic drug-resistant tumor cells subpopulations, cancer recurrence and eventually, patient mortality. Thus, there is an urgent need to identify specific markers, by which the targeted imaging and/or therapeutic "guided missile"-like agents can specifically detect and/or eradicate all cancer cells within a heterogeneous tumor, while leaving the normal cells intact. As a member of heat shock protein 70 (HSP70) superfamily, glucose regulated protein 78 (GRP78) has been documented as a molecular chaperone in the endoplasmic reticulum (ER) which mainly responds to ER stresses in normal cells. There is over-expression of GRP78 on the surface of cancer cells and angiogenic endothelial cells, which makes it a promising target for different types of peptides and antibodies that can be employed for targeted cancer therapy or imaging. In this review, we discuss the biological processes, functional importance and translocation mechanisms of cell surface GRP78 (csGRP78) in tumor cells. As a cancer biomarker, we also review the potential applications of csGRP78 targeted therapy and imaging and finally we suggest a brief roadmap ahead of csGRP78 targeting for targeted theranostic implications.


Assuntos
Proteínas de Membrana , Neoplasias , Chaperona BiP do Retículo Endoplasmático , Células Endoteliais , Glucose , Proteínas de Choque Térmico , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico
20.
ACS Omega ; 5(38): 24628-24638, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33015480

RESUMO

This study aims to engineer a new type of ultrahigh quantum yield carbon dots (CDs) from methotrexate (MTX-CDs) with self-targeting, imaging, and therapeutic effects on MDA-MB 231 breast cancer cells. CDs were synthesized via a straightforward thermal method using a methotrexate (MTX) drug source. The physicochemical characteristics of the prepared MTX-CDs were studied using Fourier transform infrared (FT-IR) spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray powder diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). TEM and DLS revealed which MTX-CDs have homogeneous spherical morphology with a smaller average size of 5.4 ± 2.2 nm, polydispersity index (PDI) of 0.533, and positive surface charge of around +3.93 mV. Results of FT-IR spectroscopy and high-resolution XPS indicated the presence of residues of MTX on CDs. Therefore, the synthesized MTX-CDs could be targeted and be taken up by FR-positive cell lines without the aid of additional targeting molecules. In vitro epifluorescence images demonstrated high-contrast cytoplasm biodistribution of MTX-CDs after 2 h of treatment. A much stronger fluorescent signal was detected in MDA-MB 231 compared to MCF 7, indicating their ability to precisely target FR. The highest cytotoxic and apoptotic effects were observed in MTX-CDs compared to free MTX obtained by the MTT assay, cell cycle arrest, and annexin V-FITC apoptosis techniques. Results revealed that the novel engineered MTX-CDs were capable of inducing apoptosis (70.2% apoptosis) at a lower concentration (3.2 µM) compared to free MTX, which was proved by annexin V and cell cycle. This work highlights the potential application of CDs for constructing an intelligent nanomedicine with integration of diagnostic, targeting, and therapeutic functions.

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