Cellular Uptake of Upconversion Nanoparticles Based on Surface Polymer Coatings and Protein Corona.

Upconversion nanoparticles (UCNPs) are materials that provide unique advantages for biomedical applications. There are constantly emerging customized UCNPs with varying compositions, coatings, and upconversion mechanisms. Cellular uptake is a key parameter for the biological application of UCNPs. Uptake experiments have yielded highly varying results, and correlating trends between cellular uptake with different types of UCNP coatings remains challenging. In this report, the impact of surface polymer coatings on the formation of protein coronas and subsequent cellular uptake of UCNPs by macrophages and cancer cells was investigated. Luminescence confocal microscopy and elemental analysis techniques were used to evaluate the different coatings for internalization within cells. Pathway inhibitors were used to unravel the specific internalization mechanisms of polymer-coated UCNPs. Coatings were chosen as the most promising for colloidal stability, conjugation chemistry, and biomedical applications. PIMA-PEG (poly(isobutylene-alt-maleic) anhydride with polyethylene glycol)-coated UCNPs were found to have low cytotoxicity, low uptake by macrophages (when compared with PEI, poly(ethylenimine)), and sufficient uptake by tumor cells for surface-loaded drug delivery applications. Inductively coupled plasma-optical emission spectroscopy (ICP-OES) studies revealed that PIMA-coated NPs were preferentially internalized by the clathrin- and caveolar-independent pathways, with a preference for clathrin-mediated uptake at longer time points. PMAO-PEG (poly(maleic anhydride-alt-1-octadecene) with polyethylene glycol)-coated UCNPs were internalized by energy-dependent pathways, while PAA- (poly(acrylic acid)) and PEI-coated NPs were internalized by multifactorial mechanisms of internalization. The results indicate that copolymers of PIMA-PEG coatings on UCNPs were well suited for the next-generation of biomedical applications.

Grafting of maleic anhydride on poly(lactic acid)/hydroxyapatite composites augments their ability to support osteogenic differentiation of human mesenchymal stem cells.

Implantation of bone substitutes is the treatment of choice for bone defects exceeding a critical size, when self-healing becomes impossible. The use of 3D printing techniques allows the construction of scaffolds with customized properties. However, there is a lack of suitable materials for bone replacement. In this study, maleic anhydride-grafted poly (lactic acid) (MAPLA) was investigated as a potential compatibilizer agent for 3D-printed polylactic acid (PLA)/hydroxyapatite (HA) composites, in order to enhance the physicochemical and biological properties of the scaffolds. The grafting process was performed by reactive processing in a torque rheometer, with the evaluation of the use of different concentrations of maleic anhydride (MA). The success of the grafting reaction was confirmed by titration of acid groups and spectroscopic analyses, indicating the presence of succinic anhydride groups on the PLA chain. Morphological analysis of the PLA/HA 3D scaffolds, using SEM, revealed that the use of the compatibilizer resulted in a structure free from voids and holes. The compatibilization also increased the degradation process. On the other hand, TGA and DSC analyses revealed that the use of a compatibilizer had little effect on the thermal properties of the composite. Most importantly, the samples with compatibilizer were demonstrated to have a minimal cytotoxic effect on human mesenchymal stem cells (MSCs), promoting the osteogenic differentiation of these cells in a medium without the addition of classical osteogenic factors. Therefore, the grafting of PLA/HA composites improved their physicochemical and biological properties, especially the induction of MSC osteogenic differentiation, demonstrating the potential of these scaffolds for bone tissue replacement.

Formation of Multicolor Nanogels Based on Cationic Polyfluorenes and Poly(methyl vinyl ether-alt-maleic monoethyl ester): Potential Use as pH-Responsive Fluorescent Drug Carriers.

In this study, we employed the copolymer poly(methyl vinyl ether-alt-maleic monoethyl ester) (PMVEMA-Es) and three fluorene-based cationic conjugated polyelectrolytes to develop fluorescent nanoparticles with emission in the blue, green and red spectral regions. The size, Zeta Potential, polydispersity, morphology, time-stability and fluorescent properties of these nanoparticles were characterized, as well as the nature of the interaction between both PMVEMA-Es and fluorescent polyelectrolytes. Because PMVEMA-Es contains a carboxylic acid group in its structure, the effects of pH and ionic strength on the nanoparticles were also evaluated, finding that the size is responsive to pH and ionic strength, largely swelling at physiological pH and returning to their initial size at acidic pHs. Thus, the developed fluorescent nanoparticles can be categorized as pH-sensitive fluorescent nanogels, since they possess the properties of both pH-responsive hydrogels and nanoparticulate systems. Doxorubicin (DOX) was used as a model drug to show the capacity of the blue-emitting nanogels to hold drugs in acidic media and release them at physiological pH, from changes in the fluorescence properties of both nanoparticles and DOX. In addition, preliminary studies by super-resolution confocal microscopy were performed, regarding their potential use as image probes.

In vitro/vivo antitumor study of modified-chitosan/carboxymethyl chitosan "boosted" charge-reversal nanoformulation.

Major obstacles in the development of nanoformulations as efficient drug delivery systems are the rapid clearance from blood circulation and lysosomal entrapment. To overcome these problems, a polysaccharide-based core-shell type charge-switchable nanoformulation (CS-LA-DMMA/CMCS/PAMAM@DOX) is constructed to improve antitumor efficacy of DOX. By applying carboxymethyl chitosan (CMCS) as bridge polymer and negatively charged chitosan-derivative as outer shell, the stability and pH-sensitivity of this nanoformulation is promisingly enhanced. Furthermore, the positively charged PAMAM@DOX could escape from lysosomes via "proton sponge effect" and "cationic-anionic interaction with lysosome membranes". Admirable cellular uptake and high apoptosis/necrosis rate were detected in this study. In vitro assays demonstrate that the CS-LA-DMMA/CMCS/PAMAM@DOX was internalized into HepG2 cells predominantly via the clathrin-mediated endocytosis pathway. Excitingly, in vivo studies showed that high accumulation of CS-LA-DMMA/CMCS/PAMAM@DOX in tumor tissue led to enhanced tumor inhibition. Compared with free DOX, the tumor inhibition rate of nanoformulation was improved up to 226%.

Improvement of Impact Strength of Polylactide Blends with a Thermoplastic Elastomer Compatibilized with Biobased Maleinized Linseed Oil for Applications in Rigid Packaging.

This research work reports the potential of maleinized linseed oil (MLO) as biobased compatibilizer in polylactide (PLA) and a thermoplastic elastomer, namely, polystyrene-b-(ethylene-ran-butylene)-b-styrene (SEBS) blends (PLA/SEBS), with improved impact strength for the packaging industry. The effects of MLO are compared with a conventional polystyrene-b-poly(ethylene-ran-butylene)-b-polystyrene-graft-maleic anhydride terpolymer (SEBS-g-MA) since it is widely used in these blends. Uncompatibilized and compatibilized PLA/SEBS blends can be manufactured by extrusion and then shaped into standard samples for further characterization by mechanical, thermal, morphological, dynamical-mechanical, wetting and colour standard tests. The obtained results indicate that the uncompatibilized PLA/SEBS blend containing 20 wt.% SEBS gives improved toughness (4.8 kJ/m2) compared to neat PLA (1.3 kJ/m2). Nevertheless, the same blend compatibilized with MLO leads to an increase in impact strength up to 6.1 kJ/m2, thus giving evidence of the potential of MLO to compete with other petroleum-derived compatibilizers to obtain tough PLA formulations. MLO also provides increased ductile properties, since neat PLA is a brittle polymer with an elongation at break of 7.4%, while its blend with 20 wt.% SEBS and MLO as compatibilizer offers an elongation at break of 50.2%, much higher than that provided by typical SEBS-g-MA compatibilizer (10.1%). MLO provides a slight decrease (about 3 °C lower) in the glass transition temperature (Tg) of the PLA-rich phase, thus showing some plasticization effects. Although MLO addition leads to some yellowing due to its intrinsic yellow colour, this can contribute to serving as a UV light barrier with interesting applications in the packaging industry. Therefore, MLO represents a cost-effective and sustainable solution to the use of conventional petroleum-derived compatibilizers.

In Vivo Positive Magnetic Resonance Imaging Applications of Poly(methyl vinyl ether-alt-maleic acid)-coated Ultra-small Paramagnetic Gadolinium Oxide Nanoparticles.

The study of ultra-small paramagnetic gadolinium oxide (Gd2O3) nanoparticles (NPs) as in vivo positive (T1) magnetic resonance imaging (MRI) contrast agents is one of the most attractive fields in nanomedicine. The performance of the Gd2O3 NP imaging agents depends on the surface-coating materials. In this study, poly(methyl vinyl ether-alt-maleic acid) (PMVEMA) was used as a surface-coating polymer. The PMVEMA-coated paramagnetic ultra-small Gd2O3 NPs with an average particle diameter of 1.9 nm were synthesized using the one-pot polyol method. They exhibited excellent colloidal stability in water and good biocompatibility. They also showed a very high longitudinal water proton spin relaxivity (r1) value of 36.2 s-1mM-1 (r2/r1 = 2.0; r2 = transverse water proton spin relaxivity) under a 3.0 tesla MR field which is approximately 10 times higher than the r1 values of commercial molecular contrast agents. High positive contrast enhancements were observed in in vivo T1 MR images after intravenous administration of the NP solution sample, demonstrating its potential as a T1 MRI contrast agent.

Cutaneous microenvironment responsive microneedle patch for rapid gene release to treat subdermal tumor.

Transdermal gene therapy is a useful treatment for many skin lesions. By penetrating stratum corneum directly, microneedle patch (MNP) has been widely investigated to improve transdermal gene delivery. However, considering the operability and patience compliance, quick gene release was required after insertion. In this research, by utilizing acidic cutaneous environment, pH-responsive polyelectrolyte multilayers (PEM) were coated on the surface of polycaprolactone (PCL) microneedles by layer-by-layer assembly to realize rapid gene release. Dimethylmaleic anhydride-modified polylysine (PLL-DMA), a charge reversible polymer, was introduced to PEM. The PEM composed of two parts: the transition layers of (PLL-DMA/polyethyleneimine)12 and the gene-loaded layers of (p53 expression plasmid/polyethyleneimine)16. Microneedle patch modified with such PEM was marked as tr-MNP. In following experiment, Hoechst 33258 dyed model DNA was used to track modification process, fluorescent intensity of tr-MNP was obviously strengthened while the number of bilayers increased and the morphology could be maintained. Each tr-MNP could load 31µg model DNA and improve gene release. To prove this character, MNP without transition layers (ntr-MNP) was fabricated as control. Tr-MNP could release 33% of model DNA in simulative cutaneous environment (phosphate buffer saline; pH=5.5) while ntr-MNP could only release 4%. That was because PLL-DMA could achieve charge reversal in acidic cutaneous environment, leading to the collapse of transition layers and promoted the gene release. In vivo experiment showed tumor inhibit efficacy of tr-MNP treated mice could reach 90.1% while that of ntr-MNP treated mice and intravenous administration mice was only 46.4% and 30.5%. Overall, the pH-responsive gene loaded MNP could treat subcutaneous tumor efficiently and showed potential to be a platform to load many biomacromolecule.

Preparation and characterization of coffee hull fiber for reinforcing application in thermoplastic composites.

Nowadays, there is an increasing concern toward substituting the scarce wood fibers with alternative lignocellulosic fibers that originate from crop residue to reinforce biocomposites. In this paper, the potential application of coffee hull (CH) of the reinforced polyethylene (PE) matrix composites was studied for the first time. Experiments of composite that enhanced with CH on mechanical properties, hydroscopicity, thermogravimetric analysis, fiber treatment, and microstructures were tested in this study. The PE matrix was reinforced with varying volume fractions of CH and was studied. The results show that incorporation of coffee hull markedly improved the mechanical properties of the reinforced high-density polyethylene (HDPE) matrix composites. Micrographs show a strong interfacial adhesion between the CH fiber particles. This property may be the main reason for the stability between composites. At the same time this work investigated the effect of different treatments on the mechanical properties and water absorption behavior of composites. The fiber surface treatments were done using active chemicals such as calcium hydroxide (Ca(OH)2), silane coupling agent (SCA), maleic anhydride grafted polypropylene (MA-g-PP), stearic acid (SA), ethylene bis stearamide (EBS) and the combination (MA-g-PP, SA, EBS). The results show that (Ca(OH)2)treatment is the best way to improve its properties. Probably because attributed to removal of surface active functional groups (-OH) from the CH fiber and induction of hydrophobicity that in turn improved the compatibility with the polymer matrix. As a result, the use of coffee hull in composites could have great significance for the industry.

Dynamic Titania Nanotube Surface Achieves UV-Triggered Charge Reversal and Enhances Cell Differentiation.

Stimuli-responsive biomaterials supply a promising solution to adapt to the complex physiological environment for different biomedical applications. In this study, a dynamic UV-triggered pH-responsive biosurface was constructed on titania nanotubes (TNTs) by loading photoacid generators, diphenyliodonium chloride, into the nanotubes, and grafting 2,3-dimethyl maleic anhydride (DMMA)-modified hyperbranched poly(l-lysine) (HBPLL) onto the surface. The local acidity was dramatically enhanced by UV irradiation for only 30 s, leading to the dissociation of DMMA and thereby the transformation of surface chemistry from negatively charged caboxyl groups to positively charged amino groups. The TNTs-HBPLL-DMMA substrate could better promote proliferation and spreading of rat bone mesenchymal stem cells (rBMSCs) after UV irradiation. The osteogenic differentiation of rBMSCs was enhanced because of the charge reversal in combination with the titania-based substrates.

Coadministration of chemotherapy and PI3K/Akt pathway treatment with multistage acidity/CathB enzyme-responsive nanocarriers for inhibiting the metastasis of breast cancer.

As the principal reason for the inducement of high mortality, tumor metastasis is regulated by different pathways owing to its complexity and multistep process. In order to inhibit the proliferation and metastasis of human breast cancer simultaneously, controlling the codelivery of chemotherapeutics and pathway inhibitors precisely has been considered as a high-potential strategy to accurately eliminate tumor metastasis. In this study, polymer PLGA-p-PEI-DA was synthesised and automatically assembled into a cascade "trinity" response drug delivery system, i.e., PPP-DA/NPs (PLGA: poly(lactin-co-glycolic acid), PEI: polyethyleneimine, DA: 2,3-dimethylmaleic anhydride). In the tumor microenvironment, PPP-DA/NPs could remove the outer DA molecules via the pH-sensitive hydrolysis of ß-carboxylic amide bonded with DA and PEI. Then, PPP-DA/NPs were broken up owing to the enzymatically cleavable GFLGF (Gly-Phe-Leu-Gly-Phe) linker. The structure of the polymer and the properties of PPP-DA/NPs were evaluated in detail. Moreover, studies on the antitumor metastasis efficiency and antitumor mechanism of PPP-DA/NPs were carried out in detail. As demonstrated in this study, PPP-DA/NPs could reverse the potential in pH 6.8 PBS and showed elevated cellular uptake efficiency. Moreover, PPP-DA/NPs exhibited strong antitumor metastasis ability in vitro and in vivo. The tumor inhibiting rate (TIR) of PPP-DA/NPs (68.4%) was significantly higher than that of docetaxel (DTX) (5.9%). The antitumor mechanistic studies confirmed that PPP-DA/NPs could down-regulate the expressions of Akt, MMP-9 and pro-caspase-3/9 protein, as indicated by western blot analysis. This multifunctional drug delivery system (DDS) is highly selective and effective in inhibiting tumor metastasis, which shows a great potential in inventing smart nanocarriers for targeted tumor-metastasis therapy.

Polyethylenimine modified with 2,3-dimethylmaleic anhydride potentiates the antitumor efficacy of conventional chemotherapy.

Conventional chemotherapy is a standard care for many cancers at present. However, their severe dose-dependent side effects are the major impediment for successful cancer therapy. Herein nanoparticles were used as a potentiator to enhance the uptake of free chemotherapeutic agents by cancer cells during chemotherapy. A pH-sensitive ß-carboxylate amide group-containing polymer, bPEI-DMA, was obtained by a one-step chemical reaction of commercially available branched polyethyleneimine with 2,3-dimethylmaleic anhydride. The obtained single-macromolecule nanoparticles with a size of 6.4 nm possessed zwitterions and a slight net negative charge at neutral pH, and thereby showed low cytotoxicity. Incubation of MCF-7 cells with bPEI-DMA at tumor acidic pHs led to leakage of lactate dehydrogenase from the cells. Sequential incubation of bPEI-DMA and doxorubicin with MCF-7 cells at tumor acidic pHs caused enhanced uptake of doxorubicin by the cells. These results can be attributed to the tumor pH-triggered positive charge generation on the nanoparticles due to the hydrolysis of the ß-carboxylate amide groups, and subsequently the positive charge caused an increase in cell membrane permeability. Sequential injection of bPEI-DMA and free doxorubicin or free cisplatin into nude mice bearing human tumors markedly inhibited the tumor growth, leading to a ~ 68% decrease in tumor volumes compared to injection of the free drugs alone. Sequential injection of bPEI-DMA and a half dose of free doxorubicin resulted in even greater tumor inhibition but less side effects than injection of a full dose of doxorubicin alone.

Super-tough poly (l-lactide) materials: Reactive blending with maleic anhydride grafted starch and poly (ethylene glycol) diacrylate.

Super-tough poly (l-lactide) (PLLA) without compromising its biodegradability and biocompatibility was fabricated by reactive blending with PLLA and maleic anhydride grafted starch (MS)/poly (ethylene glycol) diacrylate (PEGDA). PEGDA as reactive compatibilizer exhibits higher compatibilization efficiency and significant plasticization effect in PLLA matrix. Fourier transform infrared spectroscopy (FT-IR) confirmed that PEGDA monomer successfully located at the molecules of MS and some interesterification reactions occurred between PEGDA and PLLA. The ductility of PLLA materials were significantly improved, for example, the elongation of break increased to 298% at the optimum PLLA/MS/PEGDA content. Dynamic mechanical thermal analysis (DMTA) demonstrated the glass transition temperature of blends decreased with the contents of MS/PEGDA increasing. The differential scanning calorimeter (DSC) results revealed that cold crystallization temperature and melting temperature of blends were decreased with the augment of the contents of MS/PEGDA. Wide angle X-ray diffraction (WARD) and DSC certified that a high crystalline article was obtained through practical extrusion process, which could propagate shear yielding deformation to dissipate energy during tensile fracture. Scanning electron microscope (SEM) demonstrated that the blends with PEGDA did not exhibit a visible phase-separated morphology from cryogenic fractured surfaces compared with the blend without PEGDA.

Fabrication of bioactive rifampicin loaded κ-Car-MA-INH/Nano hydroxyapatite composite for tuberculosis osteomyelitis infected tissue regeneration.

Biocompatible polymers and ceramic materials have been identified as vital components to fabricate drug delivery and tissue engineering applications because of their high drug loading capability, sustained release and higher mechanical strength with remarkable in-vivo bioavailability. In the present work, initially we designed κ-carrageenan grafted with maleic anhydride and then reacted it with isoniazid drug (κ-Car-MA-INH). The polymeric system was cross linked with nanohydroxyapatite (NHAP) via electrostatic interaction followed by the addition of rifampicin (RF) and loaded to fabricate κ -Car-MA-INH/NHAP/RF nanocomposites. The chemical modification and interaction of drug with the polymeric-ceramic system were characterised by Fourier Transform Infrared spectroscopy (FT-IR). The zeta potential of the κ -Car-MA-INH/NHAP/RF nanocomposite was observed to be -20.04 mV using Zetasizer. The in vitro drug release studies demonstrated that the nanocomposite releases 76% of RF and 82% of INH in 12 days at pH 5.5. Scanning Electron Microscope analysis revealed the structural deformation of Staphylococcus aureus and Klebsiella pneumoniae upon treatment with this nanocomposite. By using ex-vivo studies combined with physio-chemical characterization methods on the erythrocytes, L929 and MG-63 cell lines, this composite was found to be biocompatible, non-cytotoxic and inducing cell proliferation with less significant hemolysis. Thus, our modified drug delivery nanocomposites afforded higher drug bioavailability with large potential for fabrication as long-acting drug delivery nanocomposites, especially with hydrophobic drugs inducing the growth of osteoblastic bone cells.

Cross-Linkable Liquid-Crystalline Biopolyesteramide as a Multifunctional Polymeric Platform Designed from Corn Oil Side-Stream Product of Bioethanol Industry.

A tunable biopolyesteramide platform is designed from the corn oil (CnO) side-stream product of bioethanol industry. The (trans)amidation of CnO by diethanolamine (DEA) leads to the generation of a diol monomer (MCnO). The subsequent polymerization of MCnO with maleic anhydride (MA) generated a new kind of branched and brushed amphiphilic polymer (PCnO). This explorative investigation aims to understand the relationship between the reactivity, topology, self-organization, and photoluminescence properties of PCnO and its cross-linked homologous (CPCnO). This strategy offers an easy, inexpensive, and versatile way to design sustainable and soft smart materials.

Enhanced osteogenic proliferation and differentiation of human adipose-derived stem cells on a porous n-HA/PGS-M composite scaffold.

This study explored the applicability, cellular efficacy, and osteogenic activities of porous nano-hydroxyapatite/Poly (glycerol sebacate)-grafted maleic anhydride (n-HA/PGS-g-M) composite scaffolds. Nuclear magnetic resonance (NMR) analyses indicated that approximately 43% of the hydroxide radicals in PGS were displaced by maleic anhydride. Resonance bands at 1036 cm-1 occurred in scaffolds containing nHA powders, and peak areas increased when n-HA weight increased in PGS-M-n-HA-0.4, PGS-M-n-HA-0.5, and PGS-M-n-HA-0.6 scaffolds. The n-HA/PGS-g-M composite scaffolds exhibited porous microstructure with average pore size of 150-300 µm in scanning electron microscopy (SEM) analysis. Differential scanning calorimetry (DSC) identified the glass transition temperature (Tg) as -25-30 °C, indicative of quality resilience. The modulus of compressibility increased when n-HA content increased. Interestingly, viability of human adipose-derived stem cells (hADSCs) in vitro and expression of the osteogenic related genes RUNX2, OCN, and COL1A1 was enhanced in the n-HA/PGS-g-M composite scaffolds compared to those factors observed in PGS-g-M scaffolds. Finally, simulated body fluid (SBF) tests indicated more apatite deposits on the surface of n-HA/PGS-g-M scaffolds compared to PGS-g-M scaffolds. Overall, porous n-HA/PGS-g-M composite scaffolds possessed acceptable biocompatibility and mechanical properties, and they stimulated hADSC cell proliferation and differentiation. Given these qualities, the composite scaffolds have potential applications in bone tissue engineering.

Induction of a non-apoptotic mode of cell death associated with autophagic characteristics with steroidal maleic anhydrides and 7ß-hydroxycholesterol on glioma cells.

Steroidal maleic anhydrides were prepared in one step: lithocholic, chenodeoxicholic, deoxicholic, ursocholic, and hyodeoxicholic acid derivatives. Their capability to induce cell death was studied on C6 rat glioma cells, and 7ß-hydroxycholesterol was used as positive cytotoxic control. The highest cytotoxicity was observed with lithocholic and chenodeoxicholic acid derivatives (23-(4-methylfuran-2,5-dione)-3α-hydroxy-24-nor-5ß-cholane (compound 1a), and 23-(4-methylfuran-2,5-dione)-3α,7α-dihydroxy-24-nor-5ß-cholane (compound 1b), respectively), which induce a non-apoptotic mode of cell death associated with mitochondrial membrane potential loss and reactive oxygen species overproduction. No cells with condensed and/or fragmented nuclei, no PARP degradation and no cleaved-caspase-3, which are apoptotic criteria, were observed. Similar effects were found with 7ß-hydroxycholesterol. The cell clonogenic survival assay showed that compound 1b was more cytotoxic than compound 1a and 7ß-hydroxycholesterol. Compound 1b and 7ß-hydroxycholesterol also induce cell cycle modifications. In addition, compounds 1a and 1b, and 7ß-hydroxycholesterol favour the formation of large acidic vacuoles revealed by staining with acridine orange and monodansylcadaverine evocating autophagic vacuoles; they also induce an increased ratio of [LC3-II / LC3-I], and modify the expression of mTOR, Beclin-1, Atg12, and Atg5-Atg12 which is are autophagic criteria. The ratio [LC3-II / LC3-I] is also strongly modified by bafilomycin acting on the autophagic flux. Rapamycin, an autophagic inducer, and 3-methyladenine, an autophagic inhibitor, reduce and increase 7ß-hydroxycholesterol-induced cell death, respectively, supporting that 7ß-hydroxycholesterol induces survival autophagy. Alpha-tocopherol also strongly attenuates 7ß-hydroxycholesterol-induced cell death. However, rapamycin, 3-methyladenine, and α-tocopherol have no effect on compounds 1a and 1b-induced cell death. It is concluded that these compounds trigger a non apoptotic mode of cell death, involving the mitochondria and associated with several characteristics of autophagy.

3D Printing of Poly(propylene fumarate) Oligomers: Evaluation of Resin Viscosity, Printing Characteristics and Mechanical Properties.

Complex three-dimensional (3D) pore geometries, useful for tissue engineering scaffolds, can be fabricated via photo-crosslinking of resorbable poly(propylene fumarate) (PPF) resins using stereolithography (SLA) and/or continuous digital light processing (cDLP) methods. Physico-chemical parameters inherent to 3D printable resin design, include viscosity, polymer concentration, degree of polymerization, and resin printing temperature. We report here on our study of these parameters and their influence the cDLP 3D printing process and the resulting mechanical properties. A series of PPF oligomers were synthesized by the ring-opening copolymerization (ROCOP) of maleic anhydride and propylene oxide followed by a base-catalyzed isomerization. The resin viscosities were measured as a function of number-average molecular mass ([Formula: see text]) of the PPF oligomers (1.1, 1.7 and 2.0 kDa), concentrations of PPF in the reactive diluent diethyl fumarate (DEF) (50 and 75 wt %) and resin temperature (25 to 55 °C). The zero-shear viscosity (η0) of the resins was found to be temperature-dependent and follow a linear Arrhenius relationship. Tensile tests demonstrated mechanical properties within the range of trabecular bone, with the ultimate strength at break above 15 MPa and elastic moduli between 178 and 199 MPa.

Nanolongan with Multiple On-Demand Conversions for Ferroptosis-Apoptosis Combined Anticancer Therapy.

As a type of programmed cell death, ferroptosis is distinct from apoptosis. The combination of the two thus provides a promising modality with which to significantly improve anticancer treatment efficacy. To fully utilize this combination, we herein designed a nanolongan delivery system, which possessed a typical structure of one core (up-conversion nanoparticles, UCNP) in one gel particle (Fe3+ cross-linked oxidized starch) with multiple on-demand conversions. The charge conversion of the nanolongan surface in a slightly acidic microenvironment enhanced circulation time for utilizing the enhanced permeability and retention effect, enabled efficient uptake by tumor cells, and induced subsequently lysosomal escape. As the core component, the UCNP with light conversion from near-infrared light to ultraviolet light circumvented the impediment of limited penetration depth and enabled the reduction of Fe3+ to Fe2+. Accordingly, gel networks of nanolongan could be deconstructed due to this valence conversion, leading to the rapid release of Fe2+ and doxorubicin (Dox). In this case, the Fenton reaction between Fe2+ and intracellular H2O2 generated potent reactive oxygen species for ferroptosis, while the co-released Dox penetrated into nucleus and induced apoptosis in a synergistic way. As a result, superior anticancer therapeutic effects were achieved with little systemic toxicity, indicating that our nanolongan could serve as a safe and high-performance platform for ferroptosis-apoptosis combined anticancer therapy.

Two-photon semiconducting polymer nanoparticles as a new platform for imaging of intracellular pH variation.

Intracellular pH (pHi) plays a crucial role in cell physiological and pathological processes. We herein report an efficient pH-sensitive sensor based on two-photon excitable semiconducting polymer nanoparticles (PFV/PSMA-DA NPs) for pHi sensing. PFV/PSMA NPs were functionalized with redox-active dopamine (DA) and the obtained PFV/PSMA-DA NPs showed sensitive and reversible pH response over the pH range of 5.0-9.0. Owning to the high biocompatibility and pH-responsive DA, PFV/PSMA-DA NPs show low cytotoxicity and the quantification and imaging of intracellular pH changes of HeLa cells were successfully realized. Moreover, the detection of intracellular pH fluctuation induced by redox species such as NAC (N-acetylcysteine) and H2O2 was also achieved by both one- and two-photon excitation of the PFV/PSMA-DA NPs probe. This work clearly shows that nanoprobe based on two-photon PFV/PSMA-DA NPs could serve as a promising platform for quantitatively monitoring the intracellular pH fluctuations.

pH-triggered charge-reversal and redox-sensitive drug-release polymer micelles codeliver doxorubicin and triptolide for prostate tumor therapy.

AIM: To significantly promote cancer cell uptake and to achieve combination therapy and on-demand drug release, a pH-triggered charge-switchable and redox-responsive drug-release nanovehicle was developed in this study. MATERIALS AND METHODS: The nanocarrier was constructed by conjugating 3,3'-dithiodipropionic acid-modified doxorubicin (DTPA-DOX) and 2,3-dimethylmaleic anhydride (DMA) to the side amino groups of poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL) and by encapsulating triptolide (TRI) into the hydrophobic core. The surface charge of the obtained nanocarriers (DA-ss-DT) can change from negative to positive in response to tumor extracellular acidity pH, and the nanocarriers capably release two drugs in response to intracellular high glutathione (GSH) environment. RESULTS: Compared to the control group, the in vitro cellular uptake of DA-ss-DT by human prostate cancer PC-3 cells was significantly promoted in slightly acidic conditions, and the drug could be rapidly released in the high concentration of GSH conditions. The in vitro and in vivo antitumor experiments exhibited that the DA-ss-DT nanoparticles have a great antitumor effect in comparison to the control group. CONCLUSION: These findings demonstrated that the DA-ss-DT nanoparticles supply a useful strategy for promoting cellular uptake and synergetic anticancer therapy.