Doxorubicin loading and in vitro release from poly(alkylcyanoacrylate) nanoparticles produced by redox radical emulsion polymerization

The aim of this work was to explore the capacity to load an anticancer agent Doxorubicin (Dox) on new poly(alkylcyanoacrylate) (PACA) nanoparticles prepared by redox radical emulsion polymerization (RREP). These nanoparticles present several advantages compared with the previously described PACA nanoparticles obtained by anionic emulsion polymerization (AEP). Their cytotoxicity was lower and because they do not activate the complement system, they are believed to behave like stealth nanoparticles after intravenous administration. Dox was incorporated during the preparation of the nanoparticles. However, the drug molecules were degraded by cerium IV, which is a strong oxidant agent. To avoid drug degradation, Dox must be loaded by adsorption on preformed nanoparticles. Optimal loading capacity was deduced from a Scatchard's analysis of the Dox adsorption pattern. The loading performance [Loading efficiency (LE) 74%, Loading content (LC) 3.7%], the Dox release and the amount of Dox retained by the new nanoparticles 75% were similar to those of the already well described PACA nanoparticles obtained by AEP (LE 79% and LC 4.2%, drug retention capacity 75%). It can be concluded that the loading and releasing properties make the new nanoparticles an interesting carrier candidate for the in vivo delivery of Dox. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Poly[N-(2-hydroxypropyl)methacrylamide]-Modified Magnetic γ-F2O3 Nanoparticles Conjugated with Doxorubicin for Glioblastoma Treatment

With the aim to develop a new anticancer agent, we prepared poly[N-(2-hydroxypropyl)methacrylamide-co-methyl 2-methacrylamidoacetate] [P(HP-MMAA)], which was reacted with hydrazine to poly[N-(2-hydroxypropyl)methacrylamide-co-N-(2-hydrazinyl-2-oxoethyl)methacrylamide] [P(HP-MAH)] to conjugate doxorubicin (Dox) via hydrazone bond. The resulting P(HP-MAH)-Dox conjugate was used as a coating of magnetic γ-Fe₂O₃ nanoparticles obtained by the coprecipitation method. In vitro toxicity of various concentrations of Dox, P(HP-MAH)-Dox, and γ-Fe₂O₃@P(HP-MAH)-Dox nanoparticles was determined on somatic healthy cells (human bone marrow stromal cells hMSC), human glioblastoma line (GaMG), and primary human glioblastoma (GBM) cells isolated from GBM patients both at a short and prolonged exposition time (up to 7 days). Due to hydrolysis of the hydrazone bond in acid milieu of tumor cells and Dox release, the γ-Fe₂O₃@P(HP-MAH)-Dox nanoparticles significantly decreased the GaMG and GBM cell growth compared to free Dox and P(HP-MAH)-Dox in low concentration (10 nM), whereas in hMSCs it remained without effect. γ-F₂O₃@PHP nanoparticles alone did not affect the viability of any of the tested cells.     

Smart therapeutic-polymer-loaded silica nanomaterials. Nanomedicine

ABSTRACT

Need for materials with high biocompatible properties have led to the development of porous silica nanoparticles. The structure of present nanostructures consists of a core and a silica shell or the silica core is coated with organic shell. The composite nanoparticles coated by organic shells with functional groups were considered to govern the covalent immobilization of biomolecules. The nanoparticles with unique chemical and physical properties may be useful as biosensors in living whole cells. The enhanced cellular drug delivery to cancer cell lines via nanoconjugates revealed that smart nanoparticles are an effective tool for transporting and delivering drugs.     

Smart Lipid–Polysaccharide Nanoparticles for Targeted Delivery of Doxorubicin to Breast Cancer Cells

In this study, actively-targeted (CD44-receptors) and dual stimuli (pH/redox)-responsive lipid–polymer nanoparticles were proposed as a delivery vehicle of doxorubicin hydrochloride in triple negative breast cancer cell lines. A phosphatidylcholine lipid film was hydrated with a solution of oxidized hyaluronic acid and doxorubicin, chosen as model drug, followed by a crosslinking reaction with cystamine hydrochloride. The obtained spherical nanoparticles (mean diameter of 30 nm) were found to be efficiently internalized in cancer cells by a receptor-mediated endocytosis process, and to modulate the drug release depending on the pH and redox potential of the surrounding medium. In vitro cytotoxicity assays demonstrated the safety and efficacy of the nanoparticles in enhancing the cytotoxic effect of the free anticancer drug, with the IC₅₀ values being reduced by two and three times in MDA-MB-468 and MDA-MB-231, respectively. The combination of self-assembled phospholipid molecules with a polysaccharide counterpart acting as receptor ligand, and stimuli-responsive chemical moieties, was carried out on smart multifunctional nanoparticles able to actively target breast cancer cells and improve the in vitro anticancer activity of doxorubicin.     

Efficient CD44-targeted magnetic resonance imaging (MRI) of breast cancer cells using hyaluronic acid (HA)-modified MnFe2O4 nanocrystals

Targeted molecular imaging with hyaluronic acid (HA) has been highlighted in the diagnosis and treatment of CD44-overexpressing cancer. CD44, a receptor for HA, is closely related to the growth of cancer including proliferation, metastasis, invasion, and angiogenesis. For the efficient detection of CD44, we fabricated a few kinds of HA-modified MnFe₂O₄ nanocrystals (MNCs) to serve as specific magnetic resonance (MR) contrast agents (HA-MRCAs) and compared physicochemical properties, biocompatibility, and the CD44 targeting efficiency. Hydrophobic MNCs were efficiently phase-transferred using aminated polysorbate 80 (P80) synthesized by introducing spermine molecules on the hydroxyl groups of P80. Subsequently, a few kinds of HA-MRCAs were fabricated, conjugating different ratios of HA on the equal amount of phase-transferred MNCs. The optimized conjugation ratio of HA against magnetic content was identified to exhibit not only effective CD44 finding ability but also high cell viability through in vitro experiments. The results of this study demonstrate that the suggested HA-MRCA shows strong potential to be used for accurate tumor diagnosis.     

Acid‐sensitive magnetic nanoparticles as potential drug depots

Superparamagnetic magnetic nanoparticles were successfully functionalized with poly(methacrylic acid) via atom transfer radical polymerization, followed by conjugation to doxorubicin (Dox). Because of pH‐sensitive hydrazone linkages, the rate and extent of Dox release from the particles was higher at a lower pH and/or a higher temperature than at physiological conditions. Appropriate changes to the pH and temperature can increase the drug release from the particles. Because of the released drug, the particles were found to be cytotoxic to human breast cancer cells in vitro. Such magnetic nanoparticles, with the potential to retain drug under physiological conditions and release the drug in conditions where the pH is lower or temperature is higher, may be useful in magnetic drug targeting by reducing the side effects of the drug caused to healthy tissues. In addition, they may serve as hyperthermia agents where the high temperatures used in hyperthermia can trigger further drug release. © 2010 American Institute of Chemical Engineers AIChE J, 2011     

Preparation and functional study of pH-sensitive amorphous calcium phosphate nanocarriers

Recently, multifunctional nanoparticles have shown great prospects in cancer treatment, which have the ability to simultaneously deliver the drug, image and target tumor cells. In this paper, we designed a luminescent nanoparticles platform based on hydrothermal hyaluronic acid/amorphous calcium phosphate (HA-FCNs/ACP) with multifunctional properties for drug delivery, bio-imaging, and targeting treatment. HA-FCNs/ACP shows an ability to load curcumin (Cur) with pH-sensitive responsive drug release behavior and excellent biocompatibility. HA-FCNs/ACP dispersed in the cytoplasm through the overexpressed CD44 receptor that is actively targeted into human lung cancer cells (A549 cells). Meanwhile, the viability of A549 cells was significantly inhibited in vitro. The prepared HA-FCNs and HA-FCNs/ACP both exhibit excellent targeted bioimaging performance on cancer cells. Hence, the as-prepared nanoparticles have promising applications in treating tumor disease.     

Fluorescent Silica Nanoparticles Targeting Mitochondria: Trafficking in Myeloid Cells and Application as Doxorubicin Delivery System in Breast Cancer Cells

Fluorescent silica nanoparticles (SiNPs) appear to be a promising imaging platform, showing a specific subcellular localization. In the present study, we first investigated their preferential mitochondrial targeting in myeloid cells, by flow cytometry, confocal microscopy and TEM on both cells and isolated mitochondria, to acquire knowledge in imaging combined with therapeutic applications. Then, we conjugated SiNPs to one of the most used anticancer drugs, doxorubicin (DOX). As an anticancer agent, DOX has high efficacy but also an elevated systemic toxicity, causing multiple side effects. Nanostructures are usually employed to increase the drug circulation time and accumulation in target tissues, reducing undesired cytotoxicity. We tested these functionalized SiNPs (DOX-NPs) on breast cancer cell line MCF-7. We evaluated DOX-NP cytotoxicity, the effect on the cell cycle and on the expression of CD44 antigen, a molecule involved in adhesion and in tumor invasion, comparing DOX-NP to free DOX and stand-alone SiNPs. We found a specific ability to release a minor amount of CD44+ extracellular vesicles (EVs), from both CD81 negative and CD81 positive pools. Modulating the levels of CD44 at the cell surface in cancer cells is thus of great importance for disrupting the signaling pathways that favor tumor progression.     

One-pot synthesis of sustained-released doxorubicin silica nanoparticles for aptamer targeted delivery to tumor cells

Site-specific delivery of drugs can significantly reduce drug toxicity and increase the therapeutic effect. Here, we report a one-pot synthesis of doxorubicin-doped silica nanoparticles (Dox/SiNPs) by using sodium fluoride (NaF) catalyzed hydrolysis of tetraethyl orthosilicate in a water-in-oil microemulsion. Through further surface chemical modification, carboxyl-terminated Dox/SiNPs (COOH-Dox/SiNPs) exhibiting high drug entrapment efficiency, strong fluorescence and long sustained release are obtained. Cell toxicity tests demonstrate that the COOH-Dox/SiNPs kill tumor cells effectively, while pure COOH-SiNPs are nontoxic. An aptamer is further conjugated to the nanoparticles for delivering loaded Dox to target cells. It is demonstrated that Dox/SiNPs modified with the aptamer sgc8c (sgc8c-Dox/SiNPs) could deliver loaded doxorubicin to CCRF-CEM cells with high specificity and excellent efficiency. Furthermore, ex vivo imaging studies show that the COOH-Dox/SiNPs are able to accumulate highly in the tumor areas, thanks to the enhanced permeability and retention (EPR) effects. Our data suggest that the sgc8c-Dox/SiNPs may be a useful new tumor therapy system.     

PrPC Aptamer Conjugated–Gold Nanoparticles for Targeted Delivery of Doxorubicin to Colorectal Cancer Cells

Anticancer drugs, such as fluorouracil (5-FU), oxaliplatin, and doxorubicin (Dox) are commonly used to treat colorectal cancer (CRC); however, owing to their low response rate and adverse effects, the development of efficient drug delivery systems (DDSs) is required. The cellular prion protein PrP^C, which is a cell surface glycoprotein, has been demonstrated to be overexpressed in CRC, however, there has been no research on the development of PrP^C-targeting DDSs for targeted drug delivery to CRC. In this study, PrP^C aptamer (Apt)-conjugated gold nanoparticles (AuNPs) were synthesized for targeted delivery of Dox to CRC. Thiol-terminated PrP^C-Apt was conjugated to AuNPs, followed by hybridization of its complementary DNA for drug loading. Finally, Dox was loaded onto the AuNPs to synthesize PrP^C-Apt-functionalized doxorubicin-oligomer-AuNPs (PrP^C-Apt DOA). The PrP^C-Apt DOA were spherical nanoparticles with an average diameter of 20 nm. Treatment of CRC cells with PrP^C-Apt DOA induced reactive oxygen species generation by decreasing catalase and superoxide dismutase activities. In addition, treatment with PrP^C-Apt DOA inhibited mitochondrial functions by decreasing the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, complex 4 activity, and oxygen consumption rates. Compared to free Dox, PrP^C-Apt DOA decreased proliferation and increased apoptosis of CRC cells to a greater degree. In this study, we demonstrated that PrP^C-Apt DOA targeting could effectively deliver Dox to CRC cells. PrP^C-Apt DOA can be used as a treatment for CRC, and have the potential to replace existing anticancer drugs, such as 5-FU, oxaliplatin, and Dox.     

A Dual‐Targeting Octaguanidine–Doxorubicin Conjugate Transporter for Inducing Caspase‐Mediated Apoptosis on Folate‐Expressing Cancer Cells

An efficient synthetic framework was assembled (G8‐FKE‐FA‐Dox), consisting of a lysosome‐targeting octaguanidine molecular transporter with a cathepsin B (cath B)‐specific peptide substrate, folic acid, and the potent chemotherapeutic drug doxorubicin (Dox). Because the folate receptor (FR) and cath B are overexpressed in malignant cells, this transporter conjugate successfully executed lysosome‐mediated transport of Dox to FR‐positive tumor cells, illustrating this framework as an excellent targeted drug delivery system (TDDS). G8‐FKE‐FA‐Dox was shown to exhibit selective toxicity toward FR‐overexpressing cancer cells, with an IC₅₀ value superior to that of the USFDA‐approved Lipodox^TM and proportional to that of free Dox via selective induction of apoptosis by the activation of caspases 8, 9, and 3. This TDDS was observed to be nontoxic to red blood cells and lymphocytes at neutral pH. Furthermore the tumor‐targeting dissemination pattern of this system was revealed by monitoring the in vivo biodistribution of the carrier (G8‐FKE‐FA‐FL) in normal and FR‐overexpressing tumor‐bearing mice.     

SI-ATRP Decoration of Magnetic Nanoparticles with PHEMA and Post-Polymerization Modification with Folic Acid for Tumor Cells’ Specific Targeting

Targeted nanocarriers could reach new levels of drug delivery, bringing new tools for personalized medicine. It is known that cancer cells overexpress folate receptors on the cell surface compared to healthy cells, which could be used to create new nanocarriers with specific targeting moiety. In addition, magnetic nanoparticles can be guided under the influence of an external magnetic field in different areas of the body, allowing their precise localization. The main purpose of this paper was to decorate the surface of magnetic nanoparticles with poly(2-hydroxyethyl methacrylate) (PHEMA) by surface-initiated atomic transfer radical polymerization (SI-ATRP) followed by covalent bonding of folic acid to side groups of the polymer to create a high specificity magnetic nanocarrier with increased internalization capacity in tumor cells. The biocompatibility of the nanocarriers was demonstrated by testing them on the NHDF cell line and folate-dependent internalization capacity was tested on three tumor cell lines: MCF-7, HeLa and HepG2. It has also been shown that a higher concentration of folic acid covalently bound to the polymer leads to a higher internalization in tumor cells compared to healthy cells. Last but not least, magnetic resonance imaging was used to highlight the magnetic properties of the functionalized nanoparticles obtained.     

Exploiting the Lactose–GM3 Interaction for Drug Delivery

Protein–protein and protein–carbohydrate interactions as a means to target the cell surface for therapeutic applications have been extensively investigated. However, carbohydrate–carbohydrate interactions (CCIs) have largely been overlooked. Here, we investigate the concept of CCI‐mediated drug delivery. Lactose‐functionalized β‐cyclodextrin (L‐β‐CD) hosting doxorubicin (Dox) was evaluated for site‐specific delivery to cancer cells via interaction with GM₃, a cell‐surface carbohydrate. The host–guest complex was evaluated in B16 melanoma cells, which express exceptionally high levels of GM₃, and acute monocytic leukemia (THP‐1) and mouse fibroblast (NIH‐3T3) cells, which lack GM₃ on the cell surface. Doxorubicin (Dox) was delivered more efficiently into B16 cells compared with NIH‐3T3 and THP‐1 cells. In B16 cells pretreated with sialidase or sodium periodate, thus preventing CCI formation, drug uptake was significantly decreased. Taken together, the results of these studies strongly support CCI‐mediated uptake via the GM₃–lactose interaction as the mechanism of controlled drug delivery.     

Synthesis of mesoporous CuFe2O4@SiO2 core-shell nanocomposite for simultaneous drug release and hyperthermia applications

In the present work, magnetic CuFe₂O₄ nanoparticles were synthesized through a sol-gel combustion. The synthesized CuFe₂O₄ were coated with mesoporous SiO₂. The synthesized CuFe₂O₄@SiO₂ nanocomposite was investigated for drug release and hyperthermia applications. The products were studied by X-ray diffraction analysis, Fourier-transform infrared spectroscopy, simultaneous thermal analysis, Brunauer-Emmett-Teller surface area, scanning electron microscopy, transmission electron microscopy, and vibrating sample magnetometer. TEM images showed the formation of silica coating with a thickness of 14 nm around copper ferrite. The surface area of the samples increases from 2.59 to 199.2 m²/g after the surface modification of ferrites nanoparticles with silica. The CuFe₂O₄@SiO₂ exhibited high ibuprofen loading and controlled drug release. These improvements resulted from the nanocomposite's mesoporous structure and high surface area. Coating CuFe₂O₄ nanoparticles with mesoporous silica reduced the cytotoxicity and improved drug release properties. However, this coating reduced the hyperthermia ability. The formed CuFe₂O₄@SiO₂ nanocomposites show high potential for simultaneous drug release and hyperthermia applications with prospective use for biomedical applications.     

Mortality response of folate receptor-activated,PEG–functionalized TiO2 nanoparticles for doxorubicin loading with and without ultraviolet irradiation

TiO₂ nanoparticles (NPs) were synthesized by hydrothermal assisted sol–gel technique. In the next step, as-synthesized NPs were modified by poly ethylene glycol (PEG). Then, folic acid (FA) was conjugated to TiO₂–PEG. Finally, Doxorubicin (Dox) as an anticancer drug was loaded on as-prepared TiO₂–PEG–FA nanocarrier. The optimization of TiO₂ and FA concentration and the influence of ultraviolet (UV) irradiation on photocatalytic activity of nanocarrier and Dox loaded carrier were assessed by utilizing the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT)-assay method.     

Mesoporous silica nanoparticles functionalized with a redox-responsive biopolymer

A redox-responsive delivery system has been formulated for cancer therapy using mesoporous silica nanoparticles (MSNs). The silica surface is modified with carboxylic acid groups prior to loading with 5-fluorouracil (5-FU). Subsequently, the pores of the MSNs are sealed by reacting cystamine-modified carboxymethyl cellulose (CMC), which contains disulfide bonds, with the surface of the MSNs via carbodiimide chemistry. Because these bonds are the sites of cleavage, cells overexpressing reducing agents should be able to cleave Cystamine-modified CMC and release the encapsulated drug. Characterization of the resulting nanoparticles shows a decrease in surface area and pore volume, which suggests that the pores of MSNs has been sealed by the attachment of Cystamine-modified CMC. Transmission electron microscopy confirms these results and shows a coating of Cystamine-modified CMC on the surface of the MSNs. The release of 5-FU can be triggered in the presence of dithiothreitol (DDT), a reducing agent. The breast cancer cells (MCF-7) show the positive uptake of Redox-responsive MSNs Moreover, these nanoparticles exhibit higher cytotoxicity when the breast cancer cells are preincubated with DTT compared to the control nanoparticles or 5-FU loaded MSNs in the absence of DTT. These results show that MSNs crosslinked with Cystamine-modified CMC are redox-responsive and can be developed further for cancer therapy.     

Combined TiO2/SiO2 mesoporous photocatalysts with location and phase controllable TiO2 nanoparticles

Combined TiO₂/SiO₂ mesoporous materials were prepared by deposition of TiO₂ nanoparticles synthesised via the acid-catalysed sol–gel method. In the first synthesis step a titania solution is prepared, by dissolving titaniumtetraisopropoxide in nitric acid. The influences of the initial titaniumtetraisopropoxide concentration and the temperature of dissolving on the final structural properties were investigated. In the second step of the synthesis, the titania nanoparticles were deposited on a silica support. Here, the influence of the temperature during deposition was studied. The depositions were carried out on two different mesoporous silica supports, SBA-15 and MCF, leading to substantial differences in the catalytic and structural properties. The samples were analysed with N₂-sorption, X-ray diffraction (XRD), electron probe microanalysis (EPMA) and transmission electron microscopy (TEM) to obtain structural information, determining the amount of titania, the crystal phase and the location of the titania particles on the mesoporous material (inside or outside the mesoporous channels). The structural differences of the support strongly determine the location of the nanoparticles and the subsequent photocatalytic activity towards the degradation of rhodamine 6G in aqueous solution under UV irradiation.     

GSH-responsive polyglutamic acid nanocarriers for dual targeted cancer therapy

In order to reduce the toxic side effects of chemotherapeutic drugs and improve the targeting and efficiency of cancer treatment, the development of drug delivery system has received great attention. In this study, second generation polyglutamic acid dendrimers (G₂) are used as basic materials to produce porous nanoparticles through cross link by crosslinkers containing disulfide bonds. The crosslinked products (G₂)_n have negative electricity and abundant voids, which enable them to adsorb the electronegative anticancer drug DOX. At the same time, in order to transport DOX to the tumor site, we modified FA on DOX and encapsulated it in magnetic mesoporous silica (FA-DOX-MSNs). Therefore, the final nanoparticles (FA-DOX-MSNs/(G₂)_n) not only have dual targeting ability to transport DOX to the tumor site, but also have reductive responsiveness that can release drugs responsively in the tumor cells. In addition, it has good biocompatibility and endocytosis ability.     

Preparation and evaluation of chitosan/β‐cyclodextrin magnetic nanoparticles as a photodegradable and hydrophobic drug delivery carrier

In this study, novel tumor targeting nanocarriers comprised of chitosan (CS)/β‐cyclodextrin (β‐CD) magnetic nanoparticles were prepared to improve the photodegradable stability and bioavailability of hydrophobic drug. Resveratrol (Res) with photodegradable and hydrophobic properties was selected as a model drug. The photodegradation rate of Res in Fe₃O₄ nanoparticles solution was 7.8 times lower than that in the ethanol solution_. In addition, the value of the saturation magnetization of CS/β‐CD nanoparticles was found to be 19.56 emu/g with characteristic of superparamagnetism. Approximately 90% Res was entrapped into the CS/β‐CD magnetic nanoparticles with the size distribution ranging from 200 to 359 nm, and the nanoparticles were spherical in shape with high zeta potentials. Furthermore, the formation of CS/β‐CD nanoparticles showed a sustained release in vitro. These results indicated that the obtained CS/β‐CD magnetic nanoparticles were a promising magnetic targeting carrier for photodegradable and hydrophobic drugs. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45076.     

pH响应的二氧化硅纳米粒子载运阿霉素进行癌症化疗

对所制备的二氧化硅纳米粒子(MS NPs)的载药性能、生物相容性和pH响应的药物释放性能进行了系统研究。实验结果显示,该MS NPs对化疗药物阿霉素(Dox)的负载量可达30μg·mg~(-1),具有很好的药物载运能力。此外,这种MS NPs具有pH响应性,能够对肿瘤微环境发生响应并精准释放药物对肿瘤细胞进行治疗。细胞MTT实验结果表明,所制得的MS NPs具有良好的生物相容性以及载药后很好的抗肿瘤能力,72h后可杀灭约82%的肿瘤细胞。因此,所制备的MS NPs在抗肿瘤领域有着巨大的应用潜力。