Synthesis and characterization of biodegradable pH and reduction dual‐sensitive polymeric micelles for doxorubicin delivery

Novel pH and reduction dual‐sensitive biodegradable polymeric micelles for efficient intracellular delivery of anticancer drugs were prepared based on a block copolymer of methyloxy‐poly(ethylene glycol)‐b‐poly[(benzyl‐l ‐aspartate)‐co‐(N‐(3‐aminopropyl) imidazole‐l ‐aspartamide)] [mPEG‐SS‐P(BLA‐co‐APILA), MPBA] synthesized by a combination of ring‐opening polymerization and side‐chain reaction. The pH/reduction‐responsive behavior of MPBA was observed by both dynamic light scattering and UV–vis experiments. The polymeric micelles and DOX‐loaded micelles could be prepared simply by adjusting the pH of the polymer solution without the use of any organic solvents. The drug release study indicated that the DOX‐loaded micelles showed retarded drug release in phosphate‐buffered saline at pH 7.4 and a rapid release after exposure to weakly acidic or reductive environment. The empty micelles were nontoxic and the DOX‐loaded micelles displayed obvious anticancer activity similar to free DOX against HeLa cells. Confocal microscopy observation demonstrated that the DOX‐loaded MPBA micelles can be quickly internalized into the cells, and effectively deliver the drugs into nuclei. Thus, the pH and reduction dual‐responsive MPBA polymeric micelles are an attractive platform to achieve the fast intracellular release of anticancer drugs. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1771–1780     

Copolymers: efficient carriers for intelligent nanoparticulate drug targeting and gene therapy

Copolymers are among the most promising substances used in the preparation of drug/gene delivery systems. Different categories of copolymers, including block copolymers, graft copolymers, star copolymers and crosslinked copolymers, are of interest in drug delivery. A variety of nanostructures, including polymeric micelles, polymersomes and hydrogels, have been prepared from copolymers and tested successfully for their drug delivery potential. The most recent area of interest in this field is smart nanostructures, which benefit from the stimuli-responsive properties of copolymeric moieties to achieve novel targeted drug delivery systems. Different copolymer applications in drug/gene delivery using nanotechnology-based approaches with particular emphasis on smart nanoparticles are reviewed.     

Tamoxifen-loaded polymeric micelles: preparation, physico-chemical characterization and in vitro evaluation studies

Several samples of polymeric micelles, formed by amphiphilic derivatives of PHEA, obtained by grafting into polymeric backbone of PEGs and/or hexadecylamine groups (PHEA-PEG-C(16) and PHEA-C(16)) and containing different amount of Tamoxifen, were prepared. All Tamoxifen-loaded polymeric micelles showed to increase drug water solubility. TEM studies provided evidence of the formation of supramolecular core/shell architectures containing drug, in the nanoscopic range and with spherical shape. Samples with different amount of encapsulated Tamoxifen were subjected to in vitro cytotoxic studies in order to evaluate the effect of Tamoxifen micellization on cell growth inhibition. All samples of Tamoxifen-loaded polymeric micelles showed a significantly higher antiproliferative activity in comparison with free drug, probably attributable to fluidification of cellular membranes, caused by amphiphilic copolymers, that allows a higher penetration of the drug into tumoral cells. To gain preliminary information about the potential use of prepared micelles as Tamoxifen drug delivery systems, studies evaluating drug release ability of micelle systems in media mimicking biological fluids (buffer solutions at pH 7.4 and 5.5) and in human plasma were carried out. These studies, performed evaluating the amount of Tamoxifen that remains in solution as a function of time, showed that at pH 7.4, as well as in plasma, PHEA-C(16) polymeric micelles were able to release lower drug amounts than PHEA-PEG(5000)-C(16) ones, while at pH 5.5, the behavior difference between two kind of micelles was less pronounced.     

Synthesis and characterization of biodegradable amphiphilic ABC Y‐shaped miktoarm terpolymer by click chemistry for drug delivery

Biodegradable amphiphilic ABC Y‐shaped triblock copolymer (MPBC) containing PEG, PBLA, and PCL segments was synthesized via the combination of enzymatic ring‐opening polymerization (ROP) of epsilon‐caprolactone, ROP of BLA‐N‐carboxyanhydride and click chemistry, where PEG, PBLA, and PCL are poly(ethylene glycol), poly(benzyl‐l ‐aspartate), and polycaprolactone, respectively. Propynylamine was employed as ROP initiator for the preparation of alkynyl‐terminated PBLA and methyloxy‐PEG with hydroxyl and azide groups at the chain‐end was used as enzymatic ROP initiator for synthesis of monoazido‐midfunctionalized block copolymer mPEG‐b‐PCL. The subsequent click reaction led to the formation of Y‐shaped asymmetric heteroarm terpolymer MPBC. The polymer structures were characterized by different analyses. The MPBC terpolymer self‐assembled into micelles and physically encapsulated drug doxorubicin (DOX) to form DOX‐loaded micelles, which showed good stability and slow drug release. In vitro cytotoxicity study indicated that the MPBC micelles were nontoxic and the DOX‐loaded micelles displayed obvious anticancer activity similar to free DOX against HeLa cells. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3346–3355     

Spindle‐Like Polypyrrole Hollow Nanocapsules as Multifunctional Platforms for Highly Effective Chemo–Photothermal Combination Therapy of Cancer Cells in Vivo

The monodispersed spindle‐like polypyrrole hollow nanocapsules (PPy HNCs) as the multifunctional platforms for combining chemotherapy with photothermal therapy for cancer cells are reported. Whereas the hollow cavity of nanocapsules can be used to load the anticancer drug (i.e., doxorubicin) for chemotherapy, the PPy shells can convert NIR light into heat for photothermal therapy. The release of the drug from the spindle‐like PPy HNCs is pH‐sensitive and near‐infrared (NIR) light‐enhanced. More importantly, the spindle‐like PPy HNCs can penetrate cells more rapidly and efficiently in comparison with the spherical PPy HNCs. Both in vitro and in vivo experiments demonstrated that the combination of DOX‐loaded spindle‐like PPy HNCs and NIR light provide a highly effective and feasible chemo‐photothermal therapy cancer method with a synergistic effect. Owing to their high photothermal conversion efficiency, large hollow cavity, and good biocompatibility, the spindle‐like PPy HNCs could be used as a promising new cancer drug‐nanocarrier and photothermal agent for localized tumorous chemo‐photothermal therapy.     

Fabrication and characterization of gold nanospheres‐cored pH‐sensitive thiol‐ended triblock copolymer: A smart drug delivery system for cancer therapy

Conventional chemotherapy suffers lack of multidrug resistance (MDR), lack of bioavailability, and selectivity. Nano‐sized drug delivery systems (DDS) are developing aimed to solve several limitations of conventional DDS. These systems have been offered for targeting tumor tissue owing to enhanced long circulation time, drug solubility, their retention effect, and improved permeability. As a result, the aim of this project was the design and development of DDS for biomedical applications. For this purpose, gold nanospheres (GNSs) covered by pH‐sensitive thiol‐ended triblock copolymer [poly(methacrylic acid) ‐b‐poly(acrylamide) ‐b‐poly(ε‐caprolactone)‐SH; PMAA‐b‐PAM‐b‐PCL‐SH] for delivery of anticancer drug doxorubicin (DOX). The chemical structures of triblock copolymer were investigated by proton nuclear magnetic resonance (¹H NMR) and Fourier transform infrared (FTIR) spectroscopies. ¹H NMR spectroscopy and gel permeation chromatography (GPC) were used for calculating the molecular weights of each part in the nanocarrier. The success of coating, GNSs with triblock copolymer was considered by means of dynamic light scattering (DLS), FTIR, ultraviolet‐visible (UV‐Vis), and transmission electron microscopy (TEM) measurement. The pH‐responsive drug release ability, (DOX)‐loading capacity, biocompatibility, and in vitro cytotoxicity effects of the nanocarriers were also studied. As a result, it is expected that the synthesized GNSs@polymer‐DOX considered as a potential application in nanomedicine demand like smart drug delivery, imaging, and chemo‐photothermal therapy.     

Development of NAMI-A-loaded PLGA-mPEG Nanoparticles: Physicochemical Characterization,in vitro Drug Release and in vivo Antitumor Efficacy

NAMI-A has showed extraordinary activities against metastatic tumors. However, the hydrolysis of DMSO from NAMI-A could reduce anti-metastatic activity. To enhance the circulation time and the anti-metastatic effect of NAMI-A, we first synthesized the NAMI-A-loaded nanoparticles. NAMI-A-loaded nanoparticles were prepared by the double emulsion method and characterized by scanning electron microscopy for surface morphology, laser light scattering for size and zeta potential for surface charge. Controlled release of NAMI-A was observed in a sustained manner. Compared with free NAMI-A, NAMI-A -loaded nanoparticles exhibited superior antitumor effect by delaying tumor growth in T739 mice. PLGA-mPEG nanoparticles are promising for further studies as drug delivery carriers.     

HPMA copolymer-doxorubicin-gadolinium conjugates: synthesis, characterization, and in vitro evaluation

This study describes the synthesis, characterization, and in vitro evaluation of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-gadolinium (Gd)-doxorubicin (Dox) conjugates. Copolymers of HPMA were derivatized to incorporate side chains for Gd chelation and Dox conjugation. The conjugates were characterized by their side chain contents, T(1) relaxivity (r(1)), stability, and in vitro cytotoxicity. High stability and relaxivity of these conjugates coupled with low toxicity show their potential for monitoring the in vivo fate of HPMA-based drug delivery systems by magnetic resonance imaging techniques.     

Aminosalicylate-based biodegradable polymers: Syntheses and in vitro characterization of poly(anhydride-ester)s and poly(anhydride-amide)s

Poly(anhydride-ester)s and poly(anhydride-amide)s derived from both 4- and 5-aminosalicylate acids (4- and 5-ASA) were synthesized and characterized by physicochemical methods. Thermal and solubility characteristics directly correlated to the polymer backbone composition; polymers based on 5-ASA had greater solubilities in organic solvents than polymers based on 4-ASA, and the poly(anhydride-ester)s thermally decomposed at temperatures nearly 100 °C higher than the corresponding poly(anhydride-amide)s. The polymers were self-contained, controlled-release systems that combine the drug and controlled-release mechanism into the polymer backbone. The erosion and degradation characteristics of the polymers were measured in physiologically relevant media. All polymer matrices fully degraded in media buffered to pH 7.4, whereas in acidic media (pH 1.2), all polymer matrices maintained greater than 50% mass over a 90-day time period. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 3667–3679, 2003     

Pharmacia and biological functionalities of nutrient broth dispersed multi-walled carbon nanotubes:A novel drug delivery system

A new drug delivery system was developed using the interaction of nutrient broth treated multi-walled carbon nanotubes(NBT-MWCNTs) and cefotaxime sodium(CTX) as a model.Investigated factors of the drug delivery system include dispersion effect,biocompatibility of NBT-MWCNTs,pharmacodynamic effect and delivery efficiency in vitro.It was found that MWCNTs can be well dispersed in the nutrient broth and stable at least for one week at 4 °C.The formed NBT-MWCNTs suspension scarcely exhibits toxicity to E.coli a...     

A surface-modified dendrimer set for potential application as drug delivery vehicles: synthesis, in vitro toxicity, and intracellular localization

The synthesis, cytotoxicity, and behavior in cell culture of a new set of first- (G1) and second-generation (G2) dendrimers is reported. The surface functionality of these dendrimers has been varied to see whether structure/toxicity relations can be observed. The outermost functional groups are amines that are decorated either with protons, tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz) protecting groups, Boc-protected or unprotected natural amino acid residues, ethylenediamine ligands, and/or dansyl fluorescence labels. The cytotoxicity was determined in vitro in concentration-dependent assays using the human MCF-7 breast cancer cell line. Cellular uptake and intracellular distribution was monitored by confocal fluorescence microscopy after internalization of the dansyl-labeled dendrimers by HeLa cells.     

Stimuli‐responsive zein‐based nanoparticles as a potential carrier for ellipticine: Synthesis,release, and in vitro delivery

In the present research, we have investigated a drug delivery system based on the pH‐responsive behaviors of zein colloidal nanoparticles coated with sodium caseinate (SC) and poly ethylene imine (PEI). These systematically designed nanoparticles were used as nanocarriers for encapsulation of ellipticine (EPT), as an anticancer drug. SC and PEI coatings were applied through electrostatic adsorption, leading to the increased size and improved polydispersity index of nanoparticles as well as sustained release of drug. Physicochemical characteristics such as hydrodynamic diameter, size distribution, zeta potential and morphology of nanoparticles prepared using different formulations and conditions were also determined. Based on the results, EPT was encapsulated into the prepared nanoparticles with a high drug loading capacity (5.06%) and encapsulation efficiency (94.8%) under optimal conditions. in vitro experiments demonstrated that the release of EPT from zein‐based nanoparticles was pH sensitive. When the pH level decreased from 7.4 to 5.5, the rate of drug release was considerably enhanced. The mechanism of pH‐responsive complexation in the drug encapsulation and release processes was extensively investigated. The pH‐dependent electrostatic interactions and drug state were hypothesized to affect the release profiles. Compared to the EPT‐loaded zein/PEI nanoparticles, the EPT‐loaded zein/SC nanoparticles exhibited a better drug sustained‐release profile, with a smaller initial burst release and longer release period. According to the results of in vitro cytotoxicity experiments, drug‐free nanoparticles were associated with a negligible cytotoxicity, whereas the EPT‐loaded nanoparticles displayed a high toxicity for the cancer cell line, A549. Our findings indicate that these pH‐sensitive protein‐based nanoparticles can be used as novel nanotherapeutic tools and potential antineoplastic drug carriers for cancer chemotherapy with controlled release.     

Formulation characterization and in vitro evaluation of acacia gum–calcium alginate beads for oral drug delivery systems

In the present work, new matrix bead formulations based on linear and branched polysaccharides have been developed using an ionic gelation technique, and their potential use as oral drug carriers has been evaluated. Using calcium chloride as a cross‐linking agent and sodium diclofenac (SD), as a model drug, acacia gum–calcium alginate matrix beads were formulated. The response surface methodology based on 3² factorial design was used as a statistical method to evaluate and optimize the effects of the biopolymers‐blend ratio and the concentration of calcium chloride on the particle size (mm), density (g/cm³), drug encapsulation efficiency (%), and the cumulative drug release after 8 hours (R_8h,%). The optimized beads with the highest drug encapsulation efficiency were examined for a drug‐excipients compatibility by powder X‐ray diffraction, differential scanning calorimetry, thermo‐gravimetric analysis, and Fourier transform‐infrared spectroscopy analyses. The swelling and degradation of the matrix beads were found to be influenced by the pH of medium. Higher degrees of swelling were observed in intestinal pH than in stomach pH. Accordingly, the drug release study showed that the amount of SD released from the acacia gum–calcium alginate beads was higher in intestinal pH than in stomach pH. Therefore, the in vitro drug release from the SD‐loaded beads appears to follow the controlled‐release (Hixson‐Crowell) pattern involving a case‐2 transport mechanism operated by swelling and relaxation of the polymeric blend matrix.     

Preparation,formulation, and chemical characterization of silver nanoparticles using Melissa officinalis leaf aqueous extract for the treatment of acute myeloid leukemia in vitro and in vivo conditions

The demand for nanoparticles is increasing day by day due to their wide range of applications in various areas including pharmaceutical industry. Nanoparticles are formally synthesized by chemical methods in which the toxic and flammable chemicals are used. Synthesis of nanoparticles from various biological systems has been reported, but among all, biosynthesis of nanoparticles from plants is considered as the most suitable method. The current study confirms the potential of aqueous extract of Melissa officinalis grown under in vitro condition for the green synthesis of silver nanoparticles (AgNPs). Also, we revealed the cytotoxicity, antioxidant, and anti-acute myeloid leukemia effects of AgNPs compared to mitoxantrone in a leukemic mouse model. The synthesized AgNPs were characterized using several techniques including UV–Vis., FT-IR, TEM, FE-SEM, and EDS. In vivo experiment, induction of acute myeloid leukemia was done by DMBA in 75 mice. The obtained results were fed into SPSS-22 software and analyzed by one-way ANOVA. By quantitative real-time PCR, S1PR1 and S1PR5 mRNA expression in lymphocytes were significantly (p ≤ 0.01) increased by treating the leukemic mice with the AgNPs and mitoxantrone. Also, AgNPs similar to mitoxantrone, significantly (p ≤ 0.01) enhanced the platelet, lymphocyte, and RBC parameters and the anti-inflammatory cytokines (IL4, IL5, IL10, IL13, and IFNα) and reduced the total WBC, blast, monocyte, neutrophil, eosinophil, and basophil counts and the pro-inflammatory cytokines (IL1, IL6, IL12, IL18, IFNY, and TNFα) as compared to the untreated mice. In vitro experiment, AgNPs similar to mitoxantrone had low cell viability dose-dependently against murine C1498, human HL-60/vcr, and 32D-FLT3-ITD cell lines without any cytotoxicity on HUVEC cell line. Furthermore, the DPPH assay showed similar antioxidant potentials for AgNPs and mitoxantrone. Above results approve the excellent anti-acute myeloid leukemia, cytotoxicity, and antioxidant properties of AgNPs compared to mitoxantrone.     

Chitosan,Polyethylene Glycol and Polyvinyl Alcohol Modified MgFe2O4 Ferrite Magnetic Nanoparticles in Doxorubicin Delivery: A Comparative Study In Vitro

Cancer-based magnetic theranostics has gained significant interest in recent years and can contribute as an influential archetype in the effective treatment of cancer. Owing to their excellent biocompatibility, minute sizes and reactive functional surface groups, magnetic nanoparticles (MNPs) are being explored as potential drug delivery systems. In this study, MgFe₂O₄ ferrite MNPs were evaluated for their potential to augment the delivery of the anticancer drug doxorubicin (DOX). These MNPs were successfully synthesized by the glycol-thermal method and functionalized with the polymers; chitosan (CHI), polyvinyl alcohol (PVA) and polyethylene glycol (PEG), respectively, as confirmed by Fourier transform infrared (FTIR) spectroscopy. X-ray diffraction (XRD) confirmed the formation of the single-phase cubic spinel structures while vibrating sample magnetometer (VSM) analysis confirmed the superparamagnetic properties of all MNPs. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) revealed small, compact structures with good colloidal stability. CHI-MNPs had the highest DOX encapsulation (84.28%), with the PVA-MNPs recording the lowest encapsulation efficiency (59.49%). The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) cytotoxicity assays conducted in the human embryonic kidney (HEK293), colorectal adenocarcinoma (Caco-2), and breast adenocarcinoma (SKBR-3) cell lines showed that all the drug-free polymerized MNPs promoted cell survival, while the DOX loaded MNPs significantly reduced cell viability in a dose-dependent manner. The DOX-CHI-MNPs possessed superior anticancer activity (<40% cell viability), with approximately 85.86% of the drug released after 72 h in a pH-responsive manner. These MNPs have shown good potential in enhancing drug delivery, thus warranting further optimizations and investigations.     

Synthesis and characterization of a microsphere‐based coating for textiles with potential as an in situ bioactive delivery system

Proteinaceous microspheres have a wide range of biomedical applications, including their use as drug delivery systems. On the other hand, bioactive and antimicrobial textiles are promising substrates for medical care, in particular, as wound‐dressings. This work relates the development of a new process for the functionalization of textiles through the simultaneous formation and linkage of protein‐based microspheres onto textile fibers by sonochemical techniques. The microspheres developed by this process possess antimicrobial properties by themselves, but other may be incorporated by the encapsulation of various pharmaceutical formulations. This new type of microspheres and particularly their fixation onto textile materials encourage the development of textiles that can be used as delivery systems in a simple, fast, and non‐toxic process. Here it is reported the production of microspheres with a combination of bovine serum albumin (BSA), L ‐Cysteine (L ‐Cys), and n‐dodecane, using the ultrasound technology. The size distribution and morphology of the microspheres was determined as a function of several parameters such as irradiation time and BSA and L ‐Cys concentrations. The produced microspheres were analyzed using a laser light scattering size analyzer, an optical microscope and a scanning electron microscope. The new coating of BSA + L ‐Cys microspheres revealed a high stability and excellent antibacterial properties being a promising alternative to design textile‐based bioactive delivery systems with potential application in the development of textile‐based wound‐dressings. Copyright © 2011 John Wiley & Sons, Ltd.     

Hydrogels for colon‐specific drug delivery: Swelling kinetics and mechanism of degradation in vitro

Hydrogels based on n‐alkyl methacrylate esters (n‐AMA) of various chain lengths, acrylic acid, and acrylamide crosslinked with 4,4′‐di(methacryloylmino)azobenzene were prepared. Swelling kinetics and the mechanism of degradation in vitro of the hydrogels as well as the mutual relations between both were studied by the immersion of slabs in buffered solutions at pH 7.4. The diffusion of water into the slabs was discussed on the stress‐relaxation model of polymer chains. The results obtained agreed well with Schott's second‐order diffusion kinetics. The gels are degradable by anaerobes in the colon. The results obtained showed that the degradation of networks proceeded via a pore mechanism. The factors influencing the swelling and degradation of the gels include the degree of crosslinking, the lengths of the n‐AMA side chains, and the composition. These hydrogels have the potential for colon‐specific drug delivery. © 2001 John Wiley & Sons, Inc. J Polym Sci Part B: Polym Phys 39: 3128–3137, 2001     

Synthesis and characterization of a multiarm poly(acrylic acid) star polymer for application in sustained delivery of cisplatin and a nitric oxide prodrug

Functionalized polymeric nanocarriers have been recognized as drug delivery platforms for delivering therapeutic concentrations of chemotherapies. Of this category, star‐shaped multiarm polymers are emerging candidates for targeted delivery of anticancer drugs, due to their compact structure, narrow size distribution, large surface area, and high water solubility. In this study, we synthesized a multiarm poly(acrylic acid) star polymer via macromolecular design via the interchange (MADIX)/reversible addition fragmentation chain transfer (MADIX/RAFT) polymerization and characterized it using nuclear magnetic resonance (NMR) and size exclusion chromatography. The poly(acrylic acid) star polymer demonstrated excellent water solubility and extremely low viscosity, making it highly suited for targeted drug delivery. Subsequently, we selected a hydrophilic drug, cisplatin, and a hydrophobic nitric oxide (NO)‐donating prodrug, O²‐(2,4‐dinitrophenyl) 1‐[4‐(2‐hydroxy)ethyl]‐3‐methylpiperazin‐1‐yl]diazen‐1‐ium‐1,2‐diolate, as two model compounds to evaluate the feasibility of using poly(acrylic acid) star polymers for the delivery of chemotherapeutics. After synthesizing and characterizing two poly(acrylic acid) star polymer‐based nanoconjugates, poly(acrylic acid)–cisplatin (acid–Pt) and poly(acrylic acid–NO (acid–NO) prodrug, the in vitro drug release kinetics of both the acid–Pt and the acid–NO were determined at physiological conditions. In summary, we have designed and evaluated a polymeric nanocarrier for sustained‐delivery of chemotherapies, either as a single treatment or a combination therapy regimen. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012