A pH‐sensitive polymer was synthesized by introducing the N‐Boc‐histidine to the ends of a PLGA‐PEG‐PLGA block copolymer. The synthesized polymer was confirmed to be biodegradable and biocompatible, well dissolved in water and forming micelles above the CMC. DOX was employed as a model anticancer drug. In vitro drug release from micelles of N‐Boc‐histidine‐capped PLGA‐PEG‐PLGA exhibited significant difference between pH = 6.2 and pH = 7.4, whereas DOX release from micelles composed of un‐capped virgin polymers was not significantly sensitive to medium pH. Uptake of DOX from micelles of the new polymer into MDA‐MB‐435 solid tumor cells was also observed, and pH sensitivity was confirmed. Hence, the N‐Boc‐histidine capped PLGA‐PEG‐PLGA might be a promising material for tumor targeting.
The surface modification of hydroxyapatite (HA) nanoparticles by the ring opening polymerization (ROP) of γ‐benzyl‐L ‐glutamate N‐carboxyanhydride (BLG‐NCA) was proposed to prepare the poly(γ‐benzyl‐L ‐glutamate) (PBLG)‐grafted HA nanoparticles (PBLG‐g‐HA) for the first time. HA nanoparticles were firstly treated by 3‐aminopropylthriethoxysilane (APS) and then the terminal amino groups of the modified HA particles initiated the ROP of BLG‐NCA to obtain PBLG‐g‐HA. The process was monitored by XPS and FT‐IR. The surface grafting amounts of PBLG on HA ranging from 12.1 to 43.1% were characterized by thermal gravimetric analysis (TGA). The powder X‐ray diffraction (XRD) analysis confirmed that the ROP only underwent on the surface of HA nanoparticles without changing its bulk properties. The SEM measurement showed that the PBLG‐g‐HA hybrid could form an interpenetrating net structure in the self‐assembly process. The PBLG‐g‐HA hybrid could maintain higher colloid stability than the pure HA nanoparticles. The in vitro cell cultures suggested the cell adhesion ability of PBLG‐g‐HA was much higher than that of pure HA.
We fabricated composite fibrous scaffolds from blends of poly(lactide‐co‐glycolide) (PLGA) and nano‐sized hydroxyapatite (HA) via electrospinning. SEM‐EDX and AFM analysis demonstrated that HA was homogeneously dispersed in the nanofibers, and the roughness increased along with the amount of incorporated HA. When hMSCs were cultured on these PLGA/HA composite nanofibers, we found that incorporation of HA on the nanofibers did not affect cell viability whereas increased ALP activity and expression of osteogenic genes as well as the calcium mineralization of hMSCs. Our results indicate that the composite nanofibers can be offered as a potential bone regenerative biomaterial for stem cell based therapies.
Well‐defined amphiphilic linear‐dendritic prodrugs (MPEG‐b‐PAMAM‐DOX) are synthesized by conjugating doxorubicin (DOX), to MPEG‐b‐PAMAM through the acid‐labile hydrazone bond. The amphiphilic prodrugs form self‐assembled nanoparticles in deionized water and encapsulate the hydrophobic anticancer drug 10‐hydroxycamptothecin (HCPT) with a high drug loading efficiency. Studies on drug release and cellular uptake of the co‐delivery system reveal that both drugs are released in a pH‐dependent manner and effectively taken up by MCF‐7 cells. In vitro methyl thiazolyl tetrazolium (MTT) assays and drug‐induced apoptosis tests demonstrate the HCPT‐loaded nanoparticles suppress cancer cell growth more efficiently than the MPEG‐b‐PAMAM‐DOX prodrugs, free HCPT, and physical mixtures of MPEG‐b‐PAMAM‐DOX and HCPT at equivalent DOX or HCPT doses.
The antitumor activities of DOX‐loaded alginic acid/poly[2‐(diethylamino)ethyl methacrylate] (ALG‐PDEA) nanoparticles are evaluated both in vitro and in vivo. TEM imaging shows that the ALG‐PDEA NPs have a spherical morphology with a size of about 120 nm. CLSM observations reveal that the negatively charged ALG‐PDEA NPs can be taken up well by cells. In vivo NIR fluorescence imaging shows that the ALG‐PDEA NPs can passively target the tumor area because of the EPR effect in the H22 tumor‐bearing mouse. In vivo antitumor efficacy examinations indicate that DOX‐loaded ALG‐PDEA NPs have significantly superior efficacy in impeding tumor growth compared to free DOX and low toxicity to living mice.
A biodegradable nanocarrier system based on PLGA applicable for FR targeting is described. PEI‐based conjugates with covalently coupled folic acid are synthesized, characterized with regard to their composition and used for DNA complexation. The preparation of composites is performed by a solvent displacement technique, assuming an electrostatic interaction of PEI‐based polyplexes with PLGA. The synthesis of a folic acid‐PEG3kDa‐PEI25kDa conjugate is achieved. Blending of PLGA with polyplexes results in spherical nanoparticles with sizes ≤ 250 nm. Incorporation of polyplexes and the localization of folic acid on the particle surface, performed by antibody binding, is confirmed. The method is suitable for the preparation of nanosized, folic‐acid‐decorated nanoparticles.
For efficient treatment of multidrug‐resistance (MDR) breast cancer cells, design of biocompatible mixed micelles with diverse functional moieties and superior stability is needed for targeted delivery of chemical drugs. In this study, polypropylene glycol (PPG)‐grafted hyaluronic acid (HA) copolymers (PPG‐g‐HA) are used to make mixed micelles with different amounts of pluronic L61, named PPG‐g‐HA/L61 micelles. Optimized PPG‐g‐HA/L61 micelles with 3% pluronic L61 exhibit great stability in aqueous solution, superior biocompatibility, and significantly increased uptake into MCF‐7 MDR cells via HA–CD44‐specific interactions when compared to free doxorubicin (DOX) and other types of micelles. In addition, DOX in PPG‐g‐HA/L61 micelles with 3% pluronic L61 have toxicity in MCF‐7 MDR cells but significantly lower toxicity in fibroblast L929 cells compared to free DOX. Thus, PPG‐g‐HA/L61 micelles with 3% pluronic L61 content can be a promising nanocarrier to overcome MDR and release DOX in a hyaluronidase‐sensitive manner without any toxicity to normal cells.
A monoclonal antibody (mAb) to P‐glycoprotein (Pgp), UIC2, is used as a targeting moiety for N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymer/drug [(meso chlorin e6 mono(N‐2‐aminoethylamide) (Mce6) or doxorubicin (DOX)] conjugates to investigate their cytotoxicity towards the Pgp‐expressing human ovarian carcinoma cell line A2780/AD. The binding, internalization, and subcellular trafficking of a fluorescein labeled UIC2 targeted HPMA copolymer are studied and show localization to the plasma membrane with limited internalization. The specificity of the UIC2‐targeted HPMA copolymer/drug conjugates are confirmed using the sensitive cell line A2780 that does not express Pgp.
A new type of fluorescent polymeric micelles is developed by self‐assembly from a series of amphiphilic block copolymers, poly(ethylene glycol)‐b‐poly[styrene‐co‐(2‐(1,2,3,4,5‐pentaphenyl‐1H‐silol‐1‐yloxy)ethyl methacrylate)] [PEG‐b‐P(S‐co‐PPSEMA)]. Their capability of loading doxorubicin (DOX) is investigated by monitoring the loading content, encapsulation efficiency, and photophysical properties of micelles. Förster resonance energy transfer from PPSEMA to DOX is observed in DOX‐loaded micelles, which can serve as an indication of successful encapsulation of DOX in these micelles. The application of this new type of fluorescent polymeric micelles as a fluorescent probe and an anticancer drug carrier simultaneously is explored by studying the intracellular uptake of DOX‐loaded micelles.
Backbone degradable, linear, multiblock N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymer–doxorubicin (DOX) conjugates are synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization followed by chain extension via thiol‐ene click reaction. The examination of molecular‐weight‐dependent antitumor activity toward human ovarian A2780/AD carcinoma in nude mice reveals enhanced activity of multiblock, second‐generation, higher molecular weight conjugates when compared with traditional HPMA copolymer–DOX conjugates. The examination of body weight changes during treatment indicates the absence of non‐specific adverse effects.
Two chondrogenic factors, Dex and TGF‐β1, were incorporated into PLGA scaffolds and their chondrogenic potential was evaluated. The Dex‐loaded PLGA scaffold was grafted with AA and heparin, the heparin‐immobilized one was then reacted with TGF‐β1, yielding a PLGA/Dex‐TGF (PLGA/D/T) scaffold. The scaffolds were seeded with rabbit MSCs and cultured for 4 weeks. The results show that the scaffolds including chondrogenic factors strongly upregulated the expression of cartilage‐specific genes and clearly displayed type‐II collagen immunofluorescence. The functionalized PLGA scaffolds could provide an appropriate niche for chondrogenic differentiation of MSC without a constant medium supply of Dex and TGF‐β1.
An electroactive amino/carboxyl‐capped aniline tetramer (AT) is covalently grafted to the surface of hydroxyapatite (HA) nanoparticles to generate novel electroactive HA‐AT nanoparticles. The amount of AT ranges from 16.5 to 34.0 wt% and is characterized by thermogravimetric analysis (TGA). The HA‐AT nanoparticles are characterized by Fourier transform IR (FTIR) spectroscopy, X‐ray photoelectron spectroscopy (XPS), X‐ray diffraction, and scanning electron microscopy (SEM). For the excellent electroactivity of HA‐AT, the mixture of HA‐AT and PLA shows much better adhesion ability and proliferation ability than that of HA and a PLA matrix. At a 15 wt% AT grafting amount, the matrix shows the best biocompatibility.
A hyaluronic acid‐based anionic nanogel formed by self‐assembly of cholesteryl‐group‐bearing HA is designed for protein delivery. The HA nanogel spontaneously binds various types of proteins without denaturation, such as recombinant human growth hormone, erythropoietin, exendin‐4, and lysozyme. The HA nanogel shows unique colloidal properties, in particular that an injectable hydrogel is formed by salt‐induced association of the HA nanogel. A pharmacokinetic study in rats shows that an in situ gel formulation, prepared by simply mixing rhGH and HA nanogel in phosphate buffer, maintains plasma rhGH levels within a narrow range over one week. Therefore, HA nanogels offer a simple method for easy formulation of therapeutic proteins and are effective for sustained protein release systems.
A highly effective drug carrier is constructed by coating folic acid‐terminated poly(ethylene glycol) (PEG‐FA) on single walled carbon nanotubes (SWNTs) in a facile non‐covalent method. The anti‐cancer drug, doxorubicin (DOX), is further loaded on the surface of SWNTs at a very high loading efficiency, 149.3 ± 4.1%. The drug system (DOX/PEG‐FA/SWNTs) exhibits excellent stability under neutral pH conditions such as serum, but dramatically releases DOX at reduced pH typical of the tumour environment and intracellular lysosomes and endosomes. With the help of FA, DOX/PEG‐FA/SWNTs tend to selectively attach onto cancer cells and enter the lysosomes or endosomes by clathrin‐mediated endocytosis. This can greatly improve the pharmaceutical efficiency and reduce potential side effects.
Combined cancer treatment via co‐delivery of siRNAs and an anticancer drug can be a promising strategy due to the synergistic effect of simultaneously minimizing gene/drug administration. In this study, Bcl‐xL siRNA and doxorubicin (DOX) are encapsulated into designed methoxy‐poly(ethylene glycol)‐block‐poly(D ,L ‐lactic acid) (mPEG‐b‐PLA) block copolymer polymersomes (PSomes). A study of the cytotoxicity of Bcl‐xL siRNA and DOX co‐encapsulated PSomes (CPSomes) shows more inhibited proliferation of MKN‐45 and MKN‐28 human gastric cancer cell lines than only gene‐ and drug‐loaded ones. Consequently, these results demonstrate that co‐delivery of genes and drugs using PSomes results in a synergistic efficacy and indicates the potential of PSomes as efficient nanocarriers for combined cancer therapy.
Poly(dimethylsiloxane)‐block‐poly(methyl methacrylate)‐block‐poly(2,2,3,3,4,4,4‐heptafluorobutyl methacrylate) was successfully synthesized via ATRP. The chemical composition and structure of the copolymer was characterized by NMR and FT‐IR spectroscopy and molecular weight measurement. Gel permeation chromatography was used to study the molecular weight distribution of the triblock copolymer. The surface properties of the resulting copolymer were investigated. The effects of fluorine content and bulk structure on surface energy were investigated by static water contact angle measurements. Surface composition was studied by XPS.
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