RESUMO
In recent years, the use of active substances as excipients or as substitutes for other excipients in the design of modern drug delivery systems has received widespread attention, which has promoted the development of the theory of unification of medicines and excipients in the design of traditional Chinese medicine(TCM) preparations. Adopting the theory of unification of medicines and excipients to design drug delivery systems can reduce the use of excipients and thus the cost of preparations, reduce drug toxicity, increase drug solubility and biocompatibility, enhance synergistic effect, and realize targeted delivery and simultaneous delivery of multiple components. However, the research on the application of this theory in the modern drug delivery system of TCM preparations is still insufficient, with few relevant articles. In addition, the TCM active substances that can be used as the excipients remain to be catalogued. In this paper, we review the types and applications of the drug delivery systems with TCM active substances as excipients and describe their common construction methods and mechanisms, aiming to provide references for the in-depth research on the modern drug delivery systems for TCM preparations.
Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Excipientes , Nanomedicina , Preparações FarmacêuticasRESUMO
Combining multiple drugs or biologically active substances for wound healing could not only resist the formation of multidrug resistant pathogens, but also achieve better therapeutic effects. Herein, the hydrophobic fluoroquinolone antibiotic ciprofloxacin (CIP) and the hydrophilic broad-spectrum antibiotic tetracycline hydrochloride (TH) were introduced into the coaxial polycaprolactone/gelatin (PCL/GEL) nanofiber mat with CIP loaded into the PCL (core layer) and TH loaded into the GEL (shell layer), developing antibacterial wound dressing with the co-delivering of the two antibiotics (PCL-CIP/GEL-TH). The nanostructure, physical properties, drug release, antibacterial property, and in vitro cytotoxicity were investigated accordingly. The results revealed that the CIP shows a long-lasting release of five days, reaching the releasing rate of 80.71%, while the cumulative drug release of TH reached 83.51% with a rapid release behavior of 12 h. The in vitro antibacterial activity demonstrated that the coaxial nanofiber mesh possesses strong antibacterial activity against E. coli and S. aureus. In addition, the coaxial mats showed superior biocompatibility toward human skin fibroblast cells (hSFCs). This study indicates that the developed PCL-CIP/GEL-TH nanofiber membranes hold enormous potential as wound dressing materials.
Assuntos
Ciprofloxacina/administração & dosagem , Escherichia coli/crescimento & desenvolvimento , Pele/citologia , Staphylococcus aureus/crescimento & desenvolvimento , Tetraciclina/administração & dosagem , Cicatrização , Animais , Bandagens , Linhagem Celular , Ciprofloxacina/química , Ciprofloxacina/farmacologia , Modelos Animais de Doenças , Composição de Medicamentos , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Gelatina/química , Humanos , Viabilidade Microbiana , Nanofibras , Poliésteres/química , Pele/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Tetraciclina/química , Tetraciclina/farmacologiaRESUMO
Graphene oxide (GO)-based theranostic nanohybrid is designed for tumor induced imaging and potential combinational tumor therapy. The anti-tumor drug, Doxorubicin (DOX) is chemically conjugated to the poly(ethylenimine)-co-poly(ethylene glycol) (PEI-PEG) grafted GO via a MMP2-cleavable PLGLAG peptide linkage. The therapeutic efficacy of DOX is chemically locked and its intrinsic fluorescence is quenched by GO under normal physiological condition. Once stimulated by the MMP2 enzyme over-expressed in tumor tissues, the resulting peptide cleavage permits the unloading of DOX for tumor therapy and concurrent fluorescence recovery of DOX for in situ tumor cell imaging. Attractively, this PEI-bearing nanohybrid can mediate efficient DNA transfection and shows great potential for combinational drug/gene therapy. This tumor induced imaging and potential combinational therapy will open a window for tumor treatment by offering a unique theranostic approach through merging the diagnostic capability and pathology-responsive therapeutic function.
Assuntos
Diagnóstico por Imagem/métodos , Grafite , Nanopartículas , Neoplasias/diagnóstico , Neoplasias/terapia , Óxidos , Animais , Linhagem Celular , Sobrevivência Celular , Terapia Combinada , Humanos , Luciferases/metabolismo , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Polietilenoimina/síntese química , Polietilenoimina/química , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , TermogravimetriaRESUMO
The present study investigated the concurrent delivery of antineoplastic drug, doxorubicin, and HER2 siRNA through a targeted theranostic metallic gold nanoparticle designed using polysaccharide, PSP001. The as-synthesized HsiRNA@PGD NPs were characterized in terms of structural, functional, physicochemical, and biological properties. HsiRNA@PGD NPs exposed adequate hydrodynamic size, considerable ζ potential, and excellent drug/siRNA loading and encapsulation efficiency. Meticulous exploration of the biocompatible dual-targeted nanoconjugate exhibited an appealing biocompatibility and pH-sensitive cargo release kinetics, indicating its safety for use in clinics. HsiRNA@PGD NPs deciphered competent cancer cell internalization, enhanced cytotoxicity mediated via the induction of apoptosis, and excellent downregulation of the overexpressing target HER2 gene. Further in vivo explorations in the SKBR3 xenograft breast tumor model revealed the appealing tumor reduction properties, selective accumulation in the tumor site followed by significant suppression of the HER2 gene which contributed to the exclusive abrogation of breast tumor mass by the HsiRNA@PGD NPs. Compared to free drugs or the monotherapy constructs, the dual delivery approach produced a synergistic suppression of breast tumors both in vitro and in vivo. Hence the drawings from these findings implicate that the as-synthesized HsiRNA@PGD NPs could offer a promising platform for chemo-RNAi combinational breast cancer therapy.
Assuntos
Neoplasias da Mama , Doxorrubicina , Inativação Gênica , RNA Interferente Pequeno , Receptor ErbB-2 , Animais , Feminino , Humanos , Camundongos , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacologiaRESUMO
Combination chemotherapy has been recognized as a more powerful strategy for tumor treatment rather than the single chemotherapy. However, the interactive mechanism of the two hydrophobic chemotherapeutic drugs has not been explored by now. Aiming for a better synergistic effect, such interactive mechanism was investigated in the present work, by designing CPT@DOX-DPUTEA-PEG nanomedicine with encapsulated camptothecin (CPT) and conjugated doxorubicin (DOX). The synergistic controlled drug release effect was found for the two drugs loaded on the different sites of the dendritic polyurethane core. Synergism was achieved on the HepG2 cells with a combination index (CI) of 0.58 in the in vitro cellular experiments. The results demonstrated the promising application of the unimolecular micelles-based nanomedicine with independently loading of two hydrophobic chemotherapeutic drugs.
Assuntos
Camptotecina , Doxorrubicina , Liberação Controlada de Fármacos , Micelas , Pró-Fármacos , Doxorrubicina/farmacologia , Doxorrubicina/química , Camptotecina/farmacologia , Camptotecina/química , Humanos , Concentração de Íons de Hidrogênio , Células Hep G2 , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Polímeros/química , Sobrevivência Celular/efeitos dos fármacos , Dendrímeros/química , Sistemas de Liberação de Medicamentos , Sinergismo Farmacológico , Polietilenoglicóis/químicaRESUMO
Combination therapy for cancer is expected for the synergetic effect of different treatments, and the development of promising carrier materials is demanded for new therapeutics. In this study, nanocomposites including functional nanoparticles (NPs) such as samarium oxide NP for radiotherapy and gadolinium oxide NP as a magnetic resonance imaging agent were synthesized and chemically combined with iron oxide NP-embedded or carbon dot-coating iron oxide NP-embedded carbon nanohorn carriers, where iron oxide NP is a hyperthermia reagent and carbon dot exerts effects on photodynamic/photothermal treatments. These nanocomposites exerted potential for delivery of anticancer drugs (doxorubicin, gemcitabine, and camptothecin) even after being coated with poly(ethylene glycol). The co-delivery of these anticancer drugs played better drug-release efficacy than the independent drug delivery, and the thermal and photothermal procedures enlarged the drug release. Thus, the prepared nanocomposites can be expected as materials to develop advanced medication for combination treatment.
RESUMO
Recently, the stimulus-sensitive drug co-delivery system has gained increasing attentions in the clinic and exhibits improved efficiency rather than the mono-chemotherapy in anti-tumor therapy. Herein, the smart charge switchable nano-micelles (NMs) were fabricated for the endosomal escape mediated co-delivery of doxorubicin (DOX) and paclitaxel (PTX) in treatment of lung adenocarcinoma. The disulfide bonds were facilitated as the linker of the polymer backbone to achieve the redox-sensitive degradation by high intracellular GSH, and acid-liable DMMA was grafted onto DOX molecules for pH-triggered drug release under acidic tumoral microenvironment. Folic acid (FA) was utilized as targeting molecule for facilitating entry of the as prepared NMs into cancer cells. Remarkably, the as fabricated NMs exhibited surface charge-switch from negative to positive during transmitting from physiological pH to the tumor extracellular pH, which can improve the cellular internalization towards cancer cell. Subsequently, the "proton-sponge" effect mediated endosome escape of the NMs was facilitated in the acidic endo/lysosome environment. By the cell assay, the NMs possessed good biocompatibility, excellent cellular uptake, and improved inhibition rate against cancer cell. Moreover, the co-delivery of DOX/PTX exhibited synergistic and enhanced solid tumor inhibition efficiency comparing to mono-chemotherapy in A-549 tumor bearing mice model. Based on above experimental results, the as prepared drug co-delivery system showed promising biosafety and potentials for efficient lung adenocarcinoma treatment in clinic.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias , Adenocarcinoma de Pulmão/tratamento farmacológico , Animais , Doxorrubicina/química , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Endossomos , Concentração de Íons de Hidrogênio , Camundongos , Micelas , Neoplasias/tratamento farmacológico , Oxirredução , Paclitaxel , Microambiente TumoralRESUMO
Pancreatic cancer is a lethal malignancy and only around 4% of patients will live 5 years post-diagnosis. Photodynamic therapy (PDT) is a promising strategy for treating malignant tumors because of its high selectivity. Through the colocalization of light, oxygen and photosensitizer, a large number of reactive oxygen species (ROS) are generated under excitation at a specific wavelength of a laser, which can induce DNA damage and destroy cancer cells. However, the repair mechanism of cell will repair part of the damaged DNA, which could reduce the efficiency of PDT. The poly (ADP-Ribose) polymerase (PARP) plays a wide and multifaceted role in the cellular response to DNA damage, with growing evidence for participation in multiple pathways of DNA damage repair and genome maintenance. Cells require PARP to resolve single-strand DNA breaks (SSBs) induced by chemotherapy agents. Its inhibition is thought to result in the accumulation of damage in DNA, which may eventually lead to cell death. The combination therapy of PDT and PARP inhibitors may benefit patients. In this study, we design and synthesize a zeolitic imidazolate framework-8 (ZIF-8) to co-deliver DNA damaging agent Chlorin e6 (Ce6) and PARP inhibitor Olaparib (Ola). Ce6 and Ola demonstrate strong synergistic actions, providing a novel approach for the treatment of pancreatic cancer.
Assuntos
Antineoplásicos , Neoplasias Pancreáticas , Fotoquimioterapia , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Fotoquimioterapia/métodos , Poli(ADP-Ribose) Polimerases , Dano ao DNA , Antineoplásicos/farmacologia , DNA , Neoplasias Pancreáticas/tratamento farmacológico , Linhagem Celular TumoralRESUMO
Chemotherapy drugs have been used for a long time in the treatment of cancer, but serious side effects are caused by the inability of the drug to be solely delivered to the tumor when treating cancer with chemotherapy. Natural products have attracted more and more attention due to the antitumor effect in multiple ways, abundant resources and less side effects. Therefore, the combination of natural active ingredients and chemotherapy drugs may be an effective antitumor strategy, which can inhibit the growth of tumor and multidrug resistance, reduce side effects of chemotherapy drugs. Nano-drug co-delivery system (NDCDS) can play an important role in the combination of natural active ingredients and chemotherapy drugs. This review provides a comprehensive summary of the research status and application prospect of nano-delivery strategies for the combination of natural active ingredients and chemotherapy drugs, aiming to provide a basis for the development of anti-tumor drugs.
Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Sistemas de Liberação de Medicamentos/métodos , Humanos , Sistemas de Liberação de Fármacos por Nanopartículas , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológicoRESUMO
Liver fibrosis is the hallmark of liver disease and occurs prior to the stages of cirrhosis and hepatocellular carcinoma. Any type of liver damage or inflammation can result in fibrosis. Fibrosis does not develop overnight, but rather as a result of the long-term action of injury factors. At present, however, there are no good treatment methods or specific drugs other than removing the pathogenic factors. Drug application is still limited, which means that drugs with good performance in vitro cannot achieve good therapeutic effects in vivo, owing to various factors such as poor drug targeting, large side effects and strong hydrophobicity. Hepatic stellate cells (HSCs) are the primary effector cells in liver fibrosis. The nano-drug delivery system is a new and safe drug delivery system that has many advantages which are widely used in the field of liver fibrosis. Drug resistance and side effects can be reduced when two or more drugs are used in combination drug delivery. Combination therapy of drugs with different targets has emerged as a novel approach to treating liver fibrosis, and the nano co-delivery system enhances the benefits of combination therapy. While nano co-delivery systems can maximise benefits while avoiding drug side effects, this is precisely the advantage of the nano co-delivery system. This review briefly described the pathogenesis and current treatment strategies, the different co-delivery systems of combination drugs in the nano delivery system, and targeting strategies for nano delivery systems on liver fibrosis therapy. Due to their superior performance, nano delivery systems and targeting drug delivery systems have received a lot of attention in the new drug delivery system. The new delivery systems offer a new pathway in the treatment of liver fibrosis, and it is believed that it can be a new treatment for fibrosis in the future. Nano co-delivery system of combination drugs and targeting strategies has proven the effectiveness of anti-fibrosis at the experimental level.
Assuntos
Neoplasias Hepáticas , Nanopartículas , Sistemas de Liberação de Medicamentos/métodos , Fibrose , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Neoplasias Hepáticas/tratamento farmacológico , Sistemas de Liberação de Fármacos por Nanopartículas , Nanopartículas/uso terapêuticoRESUMO
In this study, to improve the intestinal absorption of small molecule chemotherapeutic drug docetaxel (DTX) and macromolecular monoclonal antibody drug bevacizumab (BVZ), we designed and prepared a type of co-delivery nanoparticles for the oral administration of DTX and BVZ. Carboxymethyl chitosan (CMC) and poly(lactic-co-glycolic acid) (PLGA) were used as the carrier of DTX nanoparticles (CPNPDTX), and methoxy polyethylene glycol-poly (ß-amino ester) (mPEG-PAE) was used as the carrier of BVZ nanoparticles (PPNPBVZ). Then, the two nanoparticles were physically mixed in mass ratios to form mixed co-delivery nanoparticles, which was named as CPNPDTX&PPNPBVZ. The nanoparticles were characterized with pH-sensitive drug release property. CPNPDTX&PPNPBVZ could significantly increase the bioavailability of DTX and BVZ according to the more cellular uptake in Caco-2 cells and the higher absorption in the intestinal tissue. Compared with free DTX and BVZ, CPNPDTX&PPNPBVZ showed excellent cytotoxic effects on A549 cells. Our study revealed the potential of co-delivery nanoparticles of binary mixture of chemotherapeutic small molecule and macromolecular antibody drug as an oral administration therapeutic system.
Assuntos
Antineoplásicos , Nanopartículas , Administração Oral , Antineoplásicos/farmacologia , Bevacizumab/farmacologia , Células CACO-2 , Docetaxel/farmacologia , Portadores de Fármacos , Humanos , Absorção IntestinalRESUMO
In the treatment of malignant tumors, the combination of chemotherapy that can directly kill tumor cells and immunotherapy that can activate the body's immune system and regulate tumor microenvironments is becoming one of the most promising cancer treatments. However, to co-deliver agents with different physicochemical properties for immunochemotherapy is still facing a challenge. Here, nanoparticles are developed for the co-delivery of the hydrophobic chemotherapeutic drug paclitaxel (PTX) and biomacromolecule interleukin-12 (IL-12) through the acid-sensitive material mPEG-Dlinkm -PDLLA and low-temperature expansion effect of Pluronic F127. The nanoparticles encrich in the tumor site, significantly inhibit the growth and metastasis of breast cancer cells 4T1, and prolong the overall survival of tumor-bearing mice. The underlying immune mechanism is further explored. The combination of PTX and IL-12 activates T lymphocytes and NK cells to release IFN-γ, selectively inhibits regulatory T cells and induces M1-type differentiation of tumor-related macrophages, thereby improving tumor immunosuppressive microenvironments. This study may provide an effective strategy for cancer immunochemotherapy through co-delivery of chemotherapeutic drug and immune cytokine by the facile thermo-sponge nanoparticles.
Assuntos
Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Imunoterapia , Interleucina-12 , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel/farmacologia , Microambiente TumoralRESUMO
Although combined chemotherapy had achieved the ideal efficacy in clinical anti-cancer therapeutic, the issues that need to be addressed are non-targeting and toxic-side effects of small molecule chemical drug (SMCD). In this study, we designed and prepared a novel binary blended co-delivered nanoparticles (BBCD NPs) with pH-responsive feature on tumor microenvironment. The BBCD NPs consists of two kind of drug-loaded NPs, in one of which carboxymethyl chitosan (CMC) and Poly (lactic-co-glycolic acid) (PLGA) were chosen as delivery carrier to load anti-cancer drug vincristine (VCR), named CMC-PLGA-VCR NPs (or CPNPVCR); and in the other of which methoxy poly(ethylene glycol)-poly(ß-amino ester) (mPEG-PAE) were chosen as delivery carrier to load anti-fibrotic drug pirfenidone (PFD), named mPEG-PAE-PFD NPs (or PPNPPFD). Then, the two types of NPs (CPNPVCR and PPNPPFD) were physically mixed in mass ratios to form BBCD NPs, which was named CPNPVCR&PPNPPFD. CPNPVCR&PPNPPFD had good encapsulation efficiency and loading capacity, and the particle size distribution was uniform. In cytotoxicity experiments and non-contact co-culture studies in vitro, the model drugs loaded in CPNPVCR&PPNPPFD could respectively target cancer cell and cancer associated fibroblast (CAF) owing to the precise pH-sensitive drug release in the pharmacological targets and show stronger synergism than that of the combined treatment of two free drugs. As a modularity and assemble ability feature in design, BBCD NPs would have the advantages on the terms of concise on preparation process, controllable on quality standard, stable in natural environment storage. The research results can provide scientific evidence for the further development of a novel drug co-delivery system with multi-type cell targets.
Assuntos
Nanopartículas , Microambiente Tumoral , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Tamanho da Partícula , Polietilenoglicóis , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
In this work, paclitaxel (Ptx) combined with tanshinone IIA (TanIIA) was found to show synergistic effect on inducing apoptosis of human acute promyelocytic leukemia (APL) cell line NB4, and the anti-tumor effect was strongest when its molar ratio was 1:1. To enhance the efficacy and reduce side effects, an active targeting drug delivery system with mesoporous silica nanoparticles (MSNs) coated with folic acid (FA) modified PEGylated lipid-bilayer (LB) membrane (FA-LB-MSNs) was established for co-loading drugs. The drug loadings of Ptx and TanIIA in FA-LB-MSNs were 5.5% and 1.8%, respectively. Compared with the uncoated MSNs, the FA-LB-MSNs showed a sustained drug release, and Ptx and TanIIA released synchronously from the carriers. By means of biological adhesion between FA and its receptors, the uptake of FA-LB-MSNs by NB4 cells was significantly higher than that of uncoated preparations, and Ptx combined with TanIIA had strong synergistic effect to enhance the apoptosis and differentiation of NB4 cells. The results of pharmacodynamics in vivo showed that the FA-LB-MSNs targeted tumor in nude mice more effectively than the compared formulations without FA modification. The Ptx and TanIIA-loaded FA-LB-MSNs group showed significantly better effects on inducing apoptosis and inhibiting tumor growth than the reference groups, which agreed with the results of anti-tumor experiments in vitro. Furthermore, no toxicity was observed to the heart, liver, spleen, lung and kidney of the tumor-bearing animals, indicating good biocompatibility of the prepared novel nanocarriers. This study confirmed the synergistic therapeutic effect of Ptx and TanIIA on APL, and the superior of FA-LB-MSNs as co-loaded nanocarriers for active targeted therapy of tumors.
Assuntos
Abietanos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Promielocítica Aguda/tratamento farmacológico , Paclitaxel/administração & dosagem , Abietanos/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Preparações de Ação Retardada , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Ácido Fólico/química , Humanos , Leucemia Promielocítica Aguda/patologia , Bicamadas Lipídicas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas , Paclitaxel/farmacologia , Dióxido de Silício/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A combination of chemotherapeutic drugs and siRNA is emerging as a new modality for cancer therapy. A safe and effective carrier platform is needed for combination drug delivery. Here, a functionalized mixed micelle-based delivery system was developed for targeted co-delivery of methotrexate (MTX) and survivin siRNA. Linolenic acid (LA) was separately conjugated to branched polyethlenimine (b-PEI) and methoxy-polyethyleneglycol (mPEG). MTX was then conjugated to LA-modified b-PEI (MTX-bPEI-LA) to form a functionalized polymer-drug conjugate. Functionalized mixed micelles (M-MTX) were obtained by the self-assembly of MTX-bPEI-LA and LA-modified mPEG (mPEG-LA). M-MTX had a narrow particle size distribution and could successfully condense siRNA at an N/P ratio of 16/1. M-MTX/siRNA was selectively taken up by HeLa cells overexpressing the folate receptor (FR) and facilitated the release of the siRNA into the cytoplasm. In vitro, M-MTX/siRNA produced a synergy between MTX and survivin siRNA and markedly suppressed survivin protein expression. In tumor-bearing mice, M-MTX/Cy5-siRNA showed an elevated tumor uptake. In addition, M-MTX/siRNA inhibited tumor growth. Immunohistochemistry and a western blot analysis showed a significant target gene downregulation. In conclusion, M-MTX/siRNA was highly effective as a delivery system and may serve as a model for the targeted co-delivery of therapeutic agents.
RESUMO
Different strategies of chemotherapeutics-based combination cancer therapy have presented enhanced antitumor efficiency and are widely used in clinical cancer treatments. However, several drawbacks of the systems for systemic administration, including low drug accumulation at tumor sites and significant systemic side effects limit their efficacy and application in the clinic. Local drug co-delivery systems based on injectable hydrogels may have considerable advantages, such as a facile drug-delivery procedure, targeted delivery of antitumor agents to tumor sites in a sustained manner, and markedly reduced systemic toxicities. Thus, in recent years, these systems have received increasing attention and consequently various injectable hydrogels have been tested as platforms for local chemotherapeutics-based combination antitumor therapy. In this review, the focus is on recent advances in injectable hydrogel-based drug co-delivery systems for local combination antitumor therapy, including multiple chemotherapeutics combination therapy, chemo-immunotherapy, chemo-radiotherapy, and hyperthermia-chemotherapy. Moreover, the rationale and preparation of local co-delivery systems are summarized and discussed.
Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Hidrogéis/química , Neoplasias/terapia , Animais , Antineoplásicos/farmacocinética , Terapia Combinada , Reagentes de Ligações Cruzadas/química , Raios gama/uso terapêutico , Humanos , Hipertermia Induzida/métodos , Imunoterapia/métodos , Injeções , Camundongos , Neoplasias/metabolismo , Neoplasias/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Combinations of therapeutic agents could synergistically enhance the response of lung cancer cells. Co-delivery systems capable of transporting chemotherapeutics with different physicochemical properties and with the simultaneous release of drugs remain elusive. Here, we assess the ability of nanoparticles of 30-nm diameter obtained from the self-assembly of hyaluronan-based copolymer targeting CD44 receptors to encapsulate both gefitinib and vorinostat for effective combinational lung cancer treatment. Drug loading was performed by nanoprecipitation. Drug release experiments showed a slow release of both drugs after 5â¯days. Using two- and three-dimensional lung adenocarcinoma cell cultures, we observed that the nanoparticles were mostly found at the periphery of the CD44-expressing spheroids. These drug-loaded nanoparticles were as cytotoxic as free drugs in the two- and three-dimensional systems and toxicity was due to apoptosis induction. In mouse models, intravenous injection of hyaluronan-based nanoparticles showed a selective delivery to subcutaneous CD44-overexpressing tumors, despite a significant liver capture. In addition, the systemic toxicity of the free drugs was reduced by their co-delivery using the nanoparticles. Finally, intrapulmonary administration of drug-loaded nanoparticles, to avoid a possible hepatic toxicity due to their accumulation in the liver, showed a stronger inhibition of orthotopic lung tumor growth compared to free drugs. In conclusion, hyaluronan-based nanoparticles provide active targeting partially mediated by CD44, less-toxic drug release and improved antitumor efficiency.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Gefitinibe/administração & dosagem , Ácido Hialurônico/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/administração & dosagem , Vorinostat/administração & dosagem , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Feminino , Gefitinibe/química , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Neoplasias Pulmonares/metabolismo , Camundongos Nus , Nanopartículas/química , Vorinostat/químicaRESUMO
Polymeric prodrugs are of immense interest as anticancer drug-delivery system owing to their superior drug stability during circulation and satisfactory drug loading capacity. However, they are usually less effective than free drugs due to imperfect degradable characteristics or active sites blockage. A polymeric prodrug (HPAA-MTX) with chemotherapeutic self-sensibilization effect consisting of glutathione (GSH)-triggered hyperbranched poly(amido amine) (HPAA) and methotrexate (MTX) was designed and synthesized in this work. This prodrug not only showed better inhibition effect on the tumor cells proliferation compared with free MTX, but also displayed selective sensibilization to tumor cells rather than normal cells. Meanwhile, HPAA-MTX was also explored as a MMP-9 shRNA plasmid delivery vector due to their rich amino group of HPAA, accompanying with MTX for simultaneous inhibiting tumor cells proliferation and migration. As expected, HPAA-MTX possessed excellent gene delivery capacity with significant down-regulation expression of MMP-9 protein and further inhibition of MCF-7 cells migration. Benefiting from the self-sensibilization effect and MTX/MMP-9 co-delivery strategy, this HPAA-MTX/MMP-9 co-delivery system exhibited significantly improved therapeutic efficacy to breast cancer in a combined manner which was confirmed through in vitro and in vivo assays. The strategy established in this study provided a facile "all-in-one" platform to integrate the drug/gene co-delivery strategy and self-sensibilization effect into one single nanocomposite for potential cancer treatment. STATEMENT OF SIGNIFICANCE: A cationic polymeric prodrug with chemotherapeutic self-sensibilization effect was designed and showed better inhibition effect on tumor cells proliferation compared with its free drug, as well displayed the selective sensibilization effect to tumor cells rather than normal cells. Moreover, the prodrug could also deliver MMP-9 shRNA plasmid for a combined therapy. As expected, the prodrug possessed excellent gene delivery capacity with significant down-regulation expression of MMP-9 protein and further inhibition of MCF-7 cells migration. Benefiting from the self-sensibilization effect and the drug/gene co-delivery strategy, this prodrug exhibited significantly improved therapeutic efficacy to breast cancer in a combined manner.
Assuntos
Técnicas de Transferência de Genes , Metaloproteinase 9 da Matriz , Metotrexato/farmacologia , Proteínas de Neoplasias , Neoplasias Experimentais , Plasmídeos , Pró-Fármacos/farmacologia , RNA Interferente Pequeno , Células 3T3 , Animais , Células Hep G2 , Humanos , Células MCF-7 , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Plasmídeos/genética , Plasmídeos/metabolismo , Plasmídeos/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Pancreatic cancer (PCa) is one of the most lethal malignancies, with a 5 year survival rate of less than 8%. Current treatment regiments have a low response rate in unselected patients. However, the subgroup of PCa patients with BRCA mutations may benefit from poly-ADP-ribose polymerase inhibitors (PARPi) due to their biological properties in DNA repair. Dose-limiting toxicity in normal tissues is frequently observed when PARPi are combined with other chemotherapies, and the co-delivery of two drugs to tumor sites at an adequate concentration is challenging. To address this issue, we have engineered an epidermal growth factor receptor (EGFR) targeting (with GE11 peptide) self-assembly amphiphilic peptide nanoparticle (GENP) to co-deliver gemcitabine and the PARPi olaparib to treat BRCA mutant PCa. The GENP was relatively stable, exhibited high encapsulation efficiency, and could coordinately release the two drugs in tumor milieu. Gemcitabine and olaparib showed strong synergistic actions in optimized conditions in vitro. The nanoparticle prolonged the half-life of both drugs and resulted in their tumor accumulation at the optimal therapeutic ratio in vivo. The drug-loaded nanoparticles were able to significantly suppress tumor growth in a murine PCa model with minimal side effects. Drug co-delivery of DNA damaging agents and PARP inhibitors via the GENP represents a promising approach for treatment of pancreatic cancers with molecular defects in the DNA repair pathway.
Assuntos
Proteína BRCA2/genética , Desoxicitidina/análogos & derivados , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias Pancreáticas/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA2/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Receptores ErbB/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mutação , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Peptídeos/química , Ftalazinas/farmacocinética , Ftalazinas/uso terapêutico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , GencitabinaRESUMO
Triple negative breast cancer (TNBC) is the most aggressive and lethal subtype of breast cancer. It is associated with a very poor prognosis and intrinsically resistant to several conventional and targeted chemotherapy agents and has a 5-year survival rate of less than 25%. Because the treatment options for TNBC are very limited and not efficient enough for achieving minimum desired goals, shifting toward a new generation of anti-cancer agents appears to be very critical. Among recent alternative approaches being proposed, small interfering RNA (siRNA) gene therapy can potently suppress Bcl-2 proto-oncogene and p-glycoprotein gene expression, the most important chemotherapy resistance inducers in TNBC. When resensitized, primarily ineffective chemotherapy drugs turn back into valuable sources for further intensive chemotherapy. Regrettably, siRNA's poor stability, rapid clearance in the circulatory system, and poor cellular uptake mostly hampers the beneficial outcomes of siRNA therapy. Considering these drawbacks, dual siRNA/chemotherapy drug encapsulation in targeted delivery vehicles, especially mesoporous silica nanoparticles (MSNs) appears to be the most reasonable solution. The literature is full of reports of successful treatments of multi-drug-resistant cancer cells by administration of dual drug/siRNA-loaded MSNs. Here we tried to answer the question of whether application of a similar approach with identical delivery devices in TNBC is rational.