Polyurethane/doxorubicin nanoparticles based on electrostatic interactions as pH‐sensitive drug delivery carriers

In order to obtain a pH‐sensitive delivery carrier for doxorubicin (DOX), DOX‐loaded polyurethane (PU·DOX) nanoparticles were readily prepared in water by electrostatic interactions between amphiphilic polyurethane with carboxyl pendent groups (PU‐COOH) and doxorubicin hydrochloride (DOX·HCl). The structures of the products obtained were characterized by Fourier transform infrared spectroscopy, ¹H NMR spectroscopy, gel permeation chromatography, UV–visible spectroscopy, dynamic light scattering and transmission electron microscopy. The average hydrodynamic size of the PU·DOX nanoparticles was around 182 nm with negative surface charge (?1.1 mV) and a spherical or rodlike shape. PU·DOX nanoparticles had a higher drug‐loading content of 14.1 wt%. The in vitro drug release properties of PU·DOX nanoparticles were investigated at pH 4.0, 5.0 and 7.4, respectively. PU·DOX nanoparticles exhibited a good pH‐sensitive drug release property, but there was almost no release of DOX from PU·DOX nanoparticles at pH 7.4. The in vitro cellular uptake assay and the Cell Counting Kit‐8 assay demonstrated that PU·DOX nanoparticles had a higher level of cellular internalization and higher inhibitory effects on the proliferation of human breast cancer (MCF‐7) cells than pure DOX. The enhancement of the inhibition effects resulted from increasing apoptosis‐inducing effects on MCF‐7 cells, which was related to the enhancement of Bax expression and the reduction of Bcl‐2 expression confirmed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay, real‐time polymerase chain reaction (PCR) assay and western blot assay. © 2018 Society of Chemical Industry     

Photo-Responsive Supramolecular Micelles for Controlled Drug Release and Improved Chemotherapy

Development of stimuli-responsive supramolecular micelles that enable high levels of well-controlled drug release in cancer cells remains a grand challenge. Here, we encapsulated the antitumor drug doxorubicin (DOX) and pro-photosensitizer 5-aminolevulinic acid (5-ALA) within adenine-functionalized supramolecular micelles (A-PPG), in order to achieve effective drug delivery combined with photo-chemotherapy. The resulting DOX/5-ALA-loaded micelles exhibited excellent light and pH-responsive behavior in aqueous solution and high drug-entrapment stability in serum-rich media. A short duration (1–2 min) of laser irradiation with visible light induced the dissociation of the DOX/5-ALA complexes within the micelles, which disrupted micellular stability and resulted in rapid, immediate release of the physically entrapped drug from the micelles. In addition, in vitro assays of cellular reactive oxygen species generation and cellular internalization confirmed the drug-loaded micelles exhibited significantly enhanced cellular uptake after visible light irradiation, and that the light-triggered disassembly of micellar structures rapidly increased the production of reactive oxygen species within the cells. Importantly, flow cytometric analysis demonstrated that laser irradiation of cancer cells incubated with DOX/5-ALA-loaded A-PPG micelles effectively induced apoptotic cell death via endocytosis. Thus, this newly developed supramolecular system may offer a potential route towards improving the efficacy of synergistic chemotherapeutic approaches for cancer.     

pH-responsive drug delivery system based on hollow silicon dioxide micropillars coated with polyelectrolyte multilayers

We report on the fabrication of polyelectrolyte multilayer-coated hollow silicon dioxide micropillars as pH-responsive drug delivery systems. Silicon dioxide micropillars are based on macroporous silicon formed by electrochemical etching. Due to their hollow core capable of being loaded with chemically active agents, silicon dioxide micropillars provide additional function such as drug delivery system. The polyelectrolyte multilayer was assembled by the layer-by-layer technique based on the alternative deposition of cationic and anionic polyelectrolytes. The polyelectrolyte pair poly(allylamine hydrochloride) and sodium poly(styrene sulfonate) exhibited pH-responsive properties for the loading and release of a positively charged drug doxorubicin. The drug release rate was observed to be higher at pH 5.2 compared to that at pH 7.4. Furthermore, we assessed the effect of the number of polyelectrolyte bilayers on the drug release loading and release rate. Thus, this hybrid composite could be potentially applicable as a pH-controlled system for localized drug release.     

Effect of graphene oxide on the pH-responsive drug release from supramolecular hydrogels

Polypseudorotaxane (PPR) hydrogels formed by inclusion complexes between poly(ethylene glycol) (PEG) and α-cyclodextrin (α-CD) are highlighted as promising biomaterial for drug delivery. Here, we report a novel injectable PPR hydrogel containing graphene oxide (GO) for pH-responsive controlled release of doxorubicin hydrochloride (DOX). Our results showed that the gelation rates of the PEG/α-CD supramolecular structures could be tailored depending on the reagent concentrations. The formation of PEG/α-CD inclusion complexes was confirmed by TEM and XRD, the latter further confirming that GO restricts their formation. The supramolecular hydrogels were easily loaded with DOX by simple addition into the PEG solution before the complex formation with the α-CD solution. Noteworthy, disruption of ionic interactions between DOX and GO in the nanocomposite at pH = 5.5 resulted in higher DOX release than under physiological conditions (pH = 7.4). This pH dependence was barely observed in pure PPR hydrogel. These findings introduce DOX-loaded supramolecular hydrogels nanocomposites as promising carriers for pH-responsive and therefore localized, drug delivery systems.     

ABC block copolymer as “smart” pH-responsive carrier for intracellular delivery of hydrophobic drugs

Amphiphilic triblock copolymer of poly(ethylene glycol)-block-poly(dimethylaminoethyl methacrylate)-block-poly(ε-caprolatone) (PEG-PDMA-PCL) was synthesized using a one-pot sequential oxyanionic polymerization of DMA and ε-CL, associated with a PEG-O⁻K⁺ macroinitiator. The pH-responsive micellization behavior of the copolymer was studied using dynamic light scattering (DLS), steady-state fluorescence and TEM techniques. The anti-cancer drug of doxorubicin (DOX) was chosen as a model drug to investigate the potential application of this triblock copolymer in drug controlled release. The results indicated the important roles of the PCL block for drug loading, the PDMA block for pH-responsive release, and PEG block for good bio-affinity. Cell cytotoxicity tests showed that the DOX-loaded PEG-PDMA-PCL micelles were pharmaceutically active to suppress the growth of SKOV-3 cells. This novel stimuli-responsive block copolymer is an attractive candidate as the “smart” pH-responsive carrier for intracellular delivery of hydrophobic drugs.     

Mechanism-Based Sonodynamic–Chemo Combinations against Triple-Negative Breast Cancer

Due to its noninvasive nature, site-confined irradiation, and high tissue penetrating capabilities, ultrasound (US)-driven sonodynamic treatment (SDT) has been proven to have broad application possibilities in neoplastic and non-neoplastic diseases. However, the inefficient buildup of sonosensitizers in the tumor site remarkably impairs SDT efficiency. The present work proposes a deep-penetrating sonochemistry nanoplatform (Pp18-lipos@SRA737&DOX, PSDL) comprising Pp18 liposomes (Pp18-lipos, Plipo), SRA737 (a CHK1 inhibitor), and doxorubicin (DOX) for the controlled formation of reactive oxygen species (ROS) and release of DOX and SRA737 upon US activation, therefore increasing chemotherapeutic effectiveness and boosting SDT efficacy. Therein, the antitumor activities of DOX have been attributed to its intercalation into the nucleus DNA and induction of cell apoptosis. CHK1 evolved to respond to DNA damage and repair the damage via cell cycle progression. SRA737 is a potent and orally bioavailable clinical drug candidate for inhibiting CHK1, demonstrating adjuvant anticancer effect in vitro and in vivo. It was interesting to find that SRA737 carried into Plipo@DOX could significantly alleviate G2/M cell cycle arrest and aggravate DNA double-strand injuries, resulting in significant cell death. The developed US-switchable nanosystem provides a promising strategy for augmenting sono-chemotherapy against breast cancer controllably and precisely.     

构建pH响应性中空介孔硅纳米复合材料用于肿瘤联合治疗

以正硅酸四乙酯为原料,合成直径约为100 nm的中空介孔二氧化硅纳米颗粒(HMSN)作为药物载体,采用物理包埋法和原位还原KMnO4生成二氧化锰的方法实现对化疗药物阿霉素(DOX)和MnO2的有效负载.此外,利用肿瘤靶向性功能肽(PEG-R7-RGDS)末端的氨基与醛基修饰的HMSN(HMSN-CHO)形成席夫碱,合成pH响应性纳米载药系统(DOX/MnO2@HMSN-imide-PEG-R7-RGDS).通过TEM、激光粒度仪、FTIR和XRD对合成材料形貌、粒径、结构和组成等进行表征.结果表明,合成的HMSN呈球形中空结构.DOX/MnO2@HMSN-imide-PEG-R7-RGDS在模拟的肿瘤酸性环境(pH 5.0)中具有明显快于在模拟生理环境(pH 7.4)下的药物释放行为.此外,体外细胞实验结果表明,DOX/MnO2@HMSN-imide-PEG-R7-RGDS可以靶向进入宫颈癌细胞(HeLa)并快速释放DOX.与此同时,纳米载药颗粒中的MnO2和肿瘤细胞中高浓度谷胱甘肽(GSH)反应产生具有类芬顿反应效果的Mn2+.Mn2+与肿瘤细胞内过表达的H2O2反应生成?OH,发挥增强的化学动力学治疗.细胞毒性实验证明,化学动力学治疗与化疗相结合能对HeLa细胞产生很高的细胞毒性.     

Self-assembled polymeric micelles based on THP and THF linkage for pH-responsive drug delivery

Developing smart nanocarriers for drug delivery system is advantageous for many kinds of successful biomedicinal therapy. In this study, we designed an amphiphilic block copolymers containing pH-responsive tetrahydropyran (THP) and tetrahydrofuran (THF) linkage. Their structures were confirmed by ¹H NMR and gel permeation chromatography (GPC). The release rate of encapsulated drugs depends upon the pH value and pH sensitive linkage in the backbone of copolymers. For PLA–THP–PEG micelles the cumulative release amount of doxorubicin (DOX) was 62% at pH 5.0, which is about four times higher than that at pH 7.4. Under the same conditions the release rate for PLA–THF–PEG micelles is a little faster than that of the PLA–THP–PEG micelles. Cellular uptake study demonstrates that DOX-loaded micelles can easily enter the cells and produce the desired pharmacological action and minimizing the side effect of free DOX. These findings indicate that THP and THF linked diblock copolymer micelles is a promising candidate for drug carrier.     

Synthesis of chitosan‐graft‐β‐cyclodextrin for improving the loading and release of doxorubicin in the nanopaticles

Chitosan‐graft‐β‐cyclodextrin (CS‐g‐β‐CD) copolymer was synthesized by conjugating β‐cyclodextrins to chitosan molecules through click chemistry. The copolymer structure was characterized by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). CS‐g‐β‐CD/CMC nanoparticles were prepared by a polyelectrolyte complexation process in aqueous solution between CS‐g‐β‐CD copolymer and carboxymethyl chitosan (CMC), which was used to load anticancer drug (Doxorubicin hydrochloride, DOX·HCl) with hydrophobic group. The particle size, surface charge, zeta potential, and morphology of the nanoparticles were characterized with dynamic light scattering. The drug loading efficiency and in vitro release of DOX·HCl of the nanoparticles were measured by ultraviolet spectrophotometer. The results demonstrated that the size, surface charge and drug loading efficiency of the nanoparticles could be modulated by the fabrication conditions. The drug loading efficiency of CS‐g‐β‐CD/CMC nanoparticles was improved from 52.7% to 88.1% because of the presence of β‐CD moieties with hydrophobic cavities, which can form inclusion complexes with the drug molecules. The in vitro release results showed that the CS‐g‐β‐CD/CMC nanoparticles released DOX·HCl in a controlled manner, importantly overcoming the initial burst effect. These nanoparticles possess much potential to be developed as anticancer drug delivery systems, especially those drugs with hydrophobic group. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 41034.     

Gd(¿)-DOTA-modified sonosensitive liposomes for ultrasound-triggered release and MR imaging

ABSTRACT: Ultrasound-sensitive (sonosensitive) liposomes for tumor targeting have been studied in order to increase the antitumor efficacy of drugs and decrease the associated severe side effects. Liposomal contrast agents having Gd(III) are known as a nano-contrast agent system for the efficient and selective delivery of contrast agents into pathological sites. The objective of this study was to prepare Gd(III)-DOTA-modified sonosensitive liposomes (GdSL), which could deliver a model drug, doxorubicin (DOX), to a specific site and, at the same time, be capable of magnetic resonance (MR) imaging. The GdSL was prepared using synthesized Gd(III)-DOTA-1,2-distearoyl-sn-glycero-3-phosphoethanolamine lipid. Sonosensitivity of GdSL to 20-kHz ultrasound induced 33% to 40% of DOX release. The relaxivities (r1) of GdSL were 6.6 to 7.8 mM[MINUS SIGN]1 s[MINUS SIGN]1, which were higher than that of MR-bester[REGISTERED SIGN]. Intracellular uptake properties of GdSL were evaluated according to the intensity of ultrasound. Intracellular uptake of DOX for ultrasound-triggered GdSL was higher than that for non-ultrasound-triggered GdSL. The results of our study suggest that the paramagnetic and sonosensitive liposomes, GdSL, may provide a versatile platform for molecular imaging and targeted drug delivery.     

Synthesis,Characterization, and Viscoelastic Behavior of Thermothickening Poly (N-Isopropylacrylamide-Methacrylicacide-Vinylpyrrolidone) Nanogels as an Injectable Biocompatible Drug Carrier

In the present work, the preparation of dual thermo-/pH-responsive nanogels composed poly (NIPAAm-MAA-VP) was investigated as an injectable carrier in which doxorubicin hydrochloride (DOX) was opted as an anticancer agent. The SEM photomicrographs showed that copolymer was almost spherical in shape with the mean diameter below 30 nm. Using dynamic oscillatory the gel-like behavior was observed at 37°C for the crosslinked polymer. Biocompatibility of the synthesized nanoparticles and superior antitumor activity of DOX-loaded nanoparticles were proved by in vitro cytotoxicity assay. The system is expected to be valuable for the delivery of chemotherapeutic agents in the treatment of solid tumors.     

疏水修饰磁性壳聚糖载药纳米粒子的制备与表征

利用O-羧甲基壳聚糖(O-CMC)的表面多种官能团(如-NH_2,-OH,-COOH等)与胆酸(CA)进行化学修饰得到两亲性共聚物,再以反溶剂法将Fe_3O_4和阿霉素(DOX)包埋在两亲性共聚物疏水的核中,制备两亲性的磁性壳聚糖载药纳米粒子,并对磁性载药纳米粒子的形貌、粒径大小、磁性、药物控释等进行了研究。结果表明:磁性壳聚糖纳米粒子有较高的药物包埋效率(92.3%),与自由阿霉素相比,磁性复合物具有明显的缓释作用和pH响应性;同时,有较好的超顺磁性。这些说明制备的疏水修饰磁性壳聚糖载药纳米粒子具有双重响应性,有望作为药物输送载体对肿瘤进行实时跟踪、诊断和治疗。     

Hollow luminescent carbon dots for drug delivery

Carbon dots (CDs) are luminescent nanomaterials with unique properties that show great potential in many applications. Herein, hollow CDs (HCDs) are prepared from bovine serum albumin by solvothermal reaction. The obtained HCDs are ca. 6.8 nm in diameter and have a quantum yield of 7%. Their bright photoluminescence means they can be used for cellular imaging. Structure and composition analyses indicate that the HCDs possess a hollow structure with a pore size of ca. 2 nm. The HCDs are used as a delivery system for doxorubicin (DOX). The DOX-HCD drug delivery system exhibits pH-controlled release, and is rapidly taken up by cells. Because of their specific nanostructure and photoluminescence properties, the multifunctional HCDs prepared here show potential for application in both cell imaging and cancer therapy.     

N‐(2‐hydroxypropyl)methacrylamide‐based polymer conjugates with pH‐controlled activation of doxorubicin. I. New synthesis,physicochemical characterization and preliminary biological evaluation

New method of synthesis of water‐soluble polymer‐drug conjugates, exhibiting remarkable anticancer activity in mice models, has been developed. In the conjugates, an anticancer drug doxorubicin (DOX) is attached to a polymer carrier based on N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymer via a hydrolytically labile hydrazone bond. New methacrylamide‐type comonomers, containing either hydrazide group or hydrazon of DOX, were used for copolymerization with HPMA. In contrast to the synthetic procedure described earlier the new method is simpler, cheaper, and results in a better‐defined conjugate structure. The conjugates are fairly stable in buffer at pH 7.4 (model of blood stream) but release DOX under mild acid conditions modeling the tumor microenvironment. The conjugates showed significant in vivo antitumor activity in treatment of T‐cell lymphoma EL‐4 bearing mice with up to 100% long‐term survivors. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Biocompatible Polymer Coated Paramagnetic Nanoparticles for Doxorubicin Delivery: Synthesis and Anticancer Effects Against Human Breast Cancer Cells

To increase the efficacy of doxorubicin in induction of apoptosis, pH-responsive nanocarriers with an average particle size of 20 nm by using chitosan-polymethacrylic acid (CTS-PMAA) shells and Fe₃O₄ cores via in situ polymerization approach were synthesized. Doxorubicin hydrochloride (DOX) was loaded effectively to nanocarrier through electrostatic interactions and strong hydrogen banding. The cumulative release of DOX-loaded nanoparticles was pH dependent with a maximum release rate at pH 5.8. In vitro cytotoxicity assay revealed the biocompatibility of blank nanocarrier and superior anticancer performance of DOX-loaded nanoparticles verified by DAPI staining and MTT assay tests.     

F3-functionalized nanoscale metal–organic frameworks for tumor-targeting combined chemotherapy and chemodynamic therapy

Nanoscale metal–organic frameworks (nMOFs) have attracted much attention as emerging porous materials as drug delivery carriers. Appropriate surface modification of them can greatly improve stability and introduce biocompatibility and cancer targeting functionality into drug delivery systems. Herein, we prepared nano-sized MIL-101(Fe)-N₃ and loaded anticancer drug doxorubicin (DOX) into it. The synthetic polymer layer Alkyne-PLA-PEG was then attached to the F3 peptide (labeled as Alkyne-PLA-PEG-F3), and the surface of DOX/MIL-101(Fe)-N₃ was covalently modified with it to obtain DOX/MIL-101-PLA-PEG-F3. Nano-sized MIL-101(Fe)-N₃ has high drug loading capacity and the modification of MIL-101(Fe)-N₃ by polymer Alkyne-PLA-PEG not only improved the dispersion, but also avoided the sudden release of the drugs and increased the biocompatibility of nanocarriers. The F3 peptide introduced into the nanocarriers also enabled it to specifically target tumor tissues and achieved active targeted drug delivery. As a nucleolin-mediated endocytosis drug delivery system, DOX/MIL-101-PLA-PEG-F3 can not only deliver anticancer drugs to tumors accurately, but also participate in Fenton-like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy (CDT), thus enabling combination therapy. It holds great promise as drug candidates to reduce systemic toxicity and improve the efficacy of cancer treatment.     

pH-responsive magnetic mesoporous silica nanospheres for magnetic resonance imaging and drug delivery

Multi-functional magnetic mesoporous silica nanospheres (MMSNs), which were coated with poly(acrylic acid) (PAA), have been synthesized using the atom transfer radical polymerization of tert-butyl acrylate on the surface of MMSNs followed by the hydrolysis of the grafted poly(tert-butyl acrylate) chains. The resulting MMSN-PAA nanocomposites exhibit negligible cytotoxicity toward HeLa and L02 cells. Magnetic resonance imaging (MRI) studies reveal that the nanocomposites can be effectively taken-up by the cancer cells. The anticancer drug doxorubicin hydrochloride (DOX) can be loaded into the nanocomposites and subsequently released in a sustained and pH-responsive way because of the presence of pH-sensitive polymer shells. The DOX-loaded nanocomposites exhibit notable cytotoxicity to HeLa cancer cells. These results demonstrate that the pH-responsive MMSN-PAA nanocomposites can be applied to biological systems for MRI and drug delivery.     

A magnetic polypeptide nanocomposite with pH and near-infrared dual responsiveness for cancer therapy

A magnetic polypeptide nanocomposite with pH and near-infrared (NIR) dual responsiveness was developed as a drug carrier for cancer therapy, which was prepared through the self-assembly of Fe₃O₄ superparamagnetic nanoparticles, poly(aspartic acid) derivative (mPEG-g-PDAEAIM) and doxorubicin (DOX) in water. Fe₃O₄ nanoparticles were prepared to provide the superparamagnetic core of nanocomposites for tumor targeting via chemical co-precipitation. The protonable imidazole groups of mPEG-g-PDAEAIM with a pKa of ~7 were accountable for the pH-responsiveness of nanocomposites. The photothermal effect of nanocomposites under the irradiation of NIR laser was induced via the interactions between dopamine groups of mPEG-g-PDAEAIM and Fe₃O₄ superparamagnetic nanoparticles to trigger the drug release. NMR, FT-IR, TEM, hysteresis loop analysis and MRI were utilized to characterize the materials. The DOX loaded nanocomposites exhibited pH-responsive and NIR dependent on/off switchable release profiles. The nanocomposites without drug loading (Fe₃O₄@mPEG-g-PDAEAIM) showed excellent biocompatibility while DOX loaded nanocomposites caused MCF-7 cells’ apoptosis due to the photothermal/chemotherapy combination effects. Overall, the pH and near-infrared dual responsive magnetic nanocomposite had a great potential for cancer therapy.     

Antitumor efficacy of doxorubicin encapsulated within PEGylated poly(amidoamine) dendrimers

We report here a general approach to using poly(amidoamine) (PAMAM) dendrimers modified with polyethylene glycol (PEG) as a platform to encapsulate an anticancer drug doxorubicin (DOX) for in vitro cancer therapy applications. In this approach, PEGylated PAMAM dendrimers were synthesized by conjugating monomethoxypolyethylene glycol with carboxylic acid end group (mPEG‐COOH) onto the surface of generation 5 amine‐terminated PAMAM dendrimer (G5.NH₂), followed by acetylation of the remaining dendrimer terminal amines. By varying the molar ratios of mPEG‐COOH/G5.NH₂, G5.NHAc‐mPEG_n (n = 5, 10, 20, and 40, respectively) with different PEGylation degrees were obtained. We show that the PEGylated dendrimers are able to encapsulate DOX with approximately similar loading capacity regardless of the PEGylation degree. The formed dendrimer/DOX complexes are water soluble and stable. In vitro release studies show that DOX complexed with the PEGylated dendrimers can be released in a sustained manner. Further cell viability assay in conjunction with cell morphology observation demonstrates that the G5.NHAc‐mPEG_n/DOX complexes display effective antitumor activity, and the DOX molecules encapsulated within complexes can be internalized into the cell nucleus, similar to the free DOX drug. Findings from this study suggest that PEGylated dendrimers may be used as a general drug carrier to encapsulate various hydrophobic drugs for different therapeutic applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40358.     

淀粉微球(CSM)的制备优化及其缓释性能

为了优化反相悬浮法合成交联淀粉微球(CSM)的工艺,采用响应曲面法分析了交联剂质量分数(X1)、反应温度(X2)和引发剂浓度(X3)对于CSM溶胀度和平均粒径的影响,建立预测模型。方差分析表明,X1、X2和X3对于CSM品质具有极显著的影响。较优工艺参数为:X1为0.5%,X2为48℃,X3为3.7 mmol/L,对应的CMS溶胀度及平均粒径的预测值分别为246%和16.5μm,与实验值接近,表明应用响应曲面法所得到的CMS合成工艺参数是可行的,将CSM用于盐酸阿霉素(DOX.HCl)的包载,显示良好的缓释效果。