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Radiotherapy is one of the general approaches to deal with malignant solid tumors in clinical treatment. To improve therapeutic efficacy, chemotherapy is frequently adopted as the adjuvant treatment in combination with radiotherapy. In this work, a reactive oxygen species (ROS)-responsive nanoparticle (NP) drug delivery system was developed to synergistically enhance the antitumor efficacy of radiotherapy by local ROS-activated chemotherapy, taking advantages of the enhanced concentration of reactive oxygen species (ROS) in tumor during X-ray irradiation and/or reoxygenation after X-ray irradiation. The ROS-responsive polymers, poly(thiodiethylene adipate) (PSDEA) and PEG-PSDEA-PEG, were synthesized and employed as the major components assembling in aqueous phase into polymer NPs in which an anticancer camptothecin analogue, SN38, was encapsulated. The drug-loaded NPs underwent structural change including swelling and partial dissociation in response to the ROS activation by virtue of the oxidation of the nonpolar sulfide residues in NPs into the polar sulfoxide units, thus leading to significant drug unloading. The in vitro performance of the chemotherapy from the X-ray irradiation preactivated NPs against BNL 1MEA.7R.1 murine carcinoma cells showed comparable cytotoxicity to free drug and appreciably enhanced effect on killing cancer cells while the X-ray irradiation being incorporated into the treatment. The in vivo tumor growth was fully inhibited with the mice receiving the local dual modality treatment of X-ray irradiation together with SN38-loaded NPs administered by intratumoral injection. The comparable efficacy of the local combinational treatment of X-ray irradiation with SN38-loaded NPs to free SN38/irradiation dual treatment corroborated the effectiveness of ROS-mediated drug release from the irradiated NPs at tumor site. The IHC examination of tumor tissues confirmed the significant reduction of VEGFA and CD31 expression with the tumor receiving the local dual treatment developed in this work, thus accounting for the absence of tumor regrowth compared to other single modality treatment.

The tumor-targeted delivery of near infrared (NIR)-triggered photothermal therapy (PTT) by varied nanocarriers has captured substantial attention. In order to boost the antitumor efficacy of PTT by promoting cellular uptake and tumor retention of PTT-carrying nanoparticles, the surface charge-changeable polymeric nanoparticles comprising poly(lactic-co-glycolic acid) (PLGA) cores covered with zwitterionic diblock copolymers, methoxypoly(ethylene glycol)-b-poly(methacrylic acid-co-histamine methacryamide), mPEG-b-P(MAA-co-HMA), were developed as vehicles of IR780. Due to the acid-triggered protonation of imidazole groups, the resulting positively charged HMA residues tend to form electrostatic complexes with negatively charged MAA residues, thus facilitating the embedding of outer PEG segments into the neutral and gel-like surfaces and thus the formation of inter-particle aggregation. Taking advantage of the weak acidity of tumor extracellular matrix, the IR780-loaded nanoparticles undergoing acidity-elicited dramatic structural transformation showed appreciably enhanced cellular uptake by TRAMP-C1 cells and prolonged tumor retention time.

A novel drug delivery strategy featured with enhanced uptake of nanoparticles (NPs) by targeted tumor cells and subsequent intratumoral cellular hitchhiking of chemotherapy to deep tumor regions was described. The NP delivery system was obtained from assembly of poly(lactic acid-co-glycolic acid)-grafted hyaluronic acid (HA-g-PLGA) together with an anticancer drug, SN38, in aqueous phase, followed by implementing the NP surface with a layer of methoxypoly(ethylene glycol)-b-poly(histamine methacrylamide) (mPEG-b-PHMA) via hydrophobic association to improve the colloidal stability both in vitro and in vivo. Upon arrival of these PEGylated NPs at the acidic tumor site through the EPR effect, mPEG-b-PHMA became detached from the NP surface by the charge transition of the PHMA blocks from neutral (hydrophobic) to positively charged (hydrophilic) state via acid-induced protonation of their imidazole groups in tumor microenvironment. The exposure of HA shell on the naked NP thus resulted in enhanced uptake of NPs by CD44-expressed tumor cells, including cancer cells and tumor-associated macrophages (TAMs). Along with the TAMs being further chemotactically recruited by hypoxia cells, the engulfed nanotherapeutics was thus transported into the avascular area in which the anticancer action of chemotherapy occurred by virtue of the drug release alongside PLGA degradation, similar to those arising in other tumor nonhypoxia regions.

A facile approach of forming stable polymeric complexes by the two-stage phase transition of the graft copolymer comprising poly(acrylic acid) (PAAc) as the backbone and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts in water was illustrated. Rather loose and hydrated polymeric aggregates with a characteristic hydrophobic multicore structure, achieved by the first-stage thermally induced phase transition of PNIPAAm grafts, underwent the core structure rearrangement (including multicore fragmentation and fusion) upon the second-stage dehydration of mPEG grafts at 90 °C. This was followed by hydrogen-bond pairings of mPEG and PNIPAAm chain segments with unionized AAc residues acting as an effective protective shell against potential hydration of the hydrophobic inner cores during the annealing process. The polymer complexes thus obtained show surprisingly enhanced hydrophobicity of inner cores at 25 °C in water and excellent stability of the morphological structure in response to the temperature disturbance.

Shell cross-linked (SCL) assemblies are prepared from the thermally induced three-layered, onion-like micelles of graft copolymers comprising acrylic acid (AAc) and 2-methacryloylethyl acrylate (MEA) as the backbone units and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts via radical polymerization of the MEA residues within the AAc-rich interfacial layers in the aqueous phase of pH 5.0 at 60 °C. The resulting nanosized SCL assemblies exhibit versatile structural regulations in a fully reversible manner in response to changes in pH and temperature. At 20 °C, SCL assemblies retain the morphology of vesicle-like hollow microspheres with pH-controlled water influx and particle size. At pH 7.0, SCL assemblies remain invariant in both vesicular structure and size irrespective of the temperature increase beyond the coil-to-globule phase transition of PNIPAAm grafts occurring primarily in a highly individual manner. When the temperature increases from 20 to 60 °C at pH 5.0, the hollow particle size is greatly reduced, accompanied by the development of hydrophobic, impermeable PNIPAAm lumens attached to the inside surfaces of the interfacial gel layers. In addition, SCL assemblies undergo a dramatic thermally induced transformation from the vesicle-like to micelle-like morphology by virtue of yielding hydrophobic PNIPAAm inner cores at pH 3.0. The thermally evolved morphology of SCL assemblies is governed by the vesicle structure in response to the effect of pH on the AAc ionization within the interfacial gel layers at ambient temperature.

Two graft copolymers comprising acrylic acid (AAc) and 2-methacryloylethyl acrylate (MEA) units as the backbone and either poly(N-isopropylacrylamide) (PNIPAAm) alone or both PNIPAAm and monomethoxypoly(ethylene glycol) (mPEG) as the grafts were synthesized. These copolymers in the aqueous phase (pH 5.0) underwent thermally induced self-assembly into micelles. For the copolymer containing PNIPAAm grafts only, extensive interactions between un-ionized AAc residues and PNIPAAm segments occurred, thereby rendering polymer backbones partially embedded within the hydrophobic cores of thermally induced micelles. This then led to bulk (core/shell) cross-linking of micelles upon radical polymerization of the MEA units within the micellar assemblies in the aqueous phase. By contrast, with mPEG being incorporated into the copolymer, association of the backbones with PNIPAAm is greatly retarded. As a result, three-layer onion-like polymeric micelles consisting of hydrophobic PNIPAAm cores surrounded by AAc-rich shel...

Graft copolymers comprising poly(acrylic acid) (PAAc) as the backbone and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts were prepared and characterized. These copolymers with the AAc residues in the negatively charged state underwent self-assembling into large polymeric aggregates in water in the range 32−35 °C due to the formation of the multicore structure (comprising several solidlike hydrophobic PNIPAAm cores surrounded by the liquidlike interfacial layers) and the intercore PEG connections. These rather labile intercore PEG connections were partially destroyed due to the continual dehydration and solidification of the liquidlike interfacial layers with increasing temperature, thereby leading to fragmentation of the original aggregates into smaller particles with the more distinct core/shell structure. The final particle size was virtually governed by the structure of the hydrophobic PNIPAAm microdomains in response to the effects of the PNIPAAm conce...

Amphiphilic graft copolymers comprising monomeric units of methoxy poly(ethylene glycol) (mPEG)-acrylate, 2-hydroxyethyl methacrylate (HEMA)–cholesterol conjugates and HEMA were synthesized and their properties characterized. The value of the critical micelle concentration (CMC) for these copolymers is linearly proportional to the ratio of the number of mPEG–acrylates to that of the HEMA–cholesterol conjugates per macromolecule (NPEG/Nc), which is the most important parameter which influences the formation of polymeric micelles. The latter show excellent colloidal stability and their sizes decrease with increasing CMC. Based on the quenching of pyrene fluorescence, the relatively high levels of the loading capacity of pyrene are attributed to the elevated hydrophobicity of the micelle core. The loading capacity of pyrene decreases with increasing CMC. The weight-average partition coefficient for pyrene in polymeric micelles increases with increasing polymer concentration because more micelles are available for accommodating pyrene. Copyright © 2004 Society of Chemical Industry

In this study, dextran hydrogels were obtained by free radical copolymerization of methacrylated dextran with acrylic acid (AAc) in aqueous solution. The fractions of dissociation of AAc units within hydrogel in response to changes in pH and ionic strength of external aqueous solution were determined by FTIR-ATR spectroscopy. The influence of small ion concentration within hydrogel on the dissociation constant of AAc follows the Debye–Huckel behavior. Based on the results from the FTIR-ATR measurements, the total ion concentration difference inside and outside the hydrogel was determined according to the Donnan equilibrium theory, taking account of the counterion condensation effect quantitatively. The swelling response of hydrogels to changes in external pH and ionic strength was governed mainly by the ionic osmotic pressure due to the accumulation of diffusible ions within hydrogels. The energy balance between the osmotic and elastic retractile responses indicates the non-Gaussian behavior of elastically effective subchains with increasing swelling.

In this study, pH-responsive dextran hydrogels were prepared by radical copolymerization of methacrylated dextran (MA-dextran) with acrylic acid (AAc) in aqueous solution, using ammonium peroxydisu...

pH-Sensitive dextran hydrogels were prepared by free radical polymerization of methacrylate derivatized dextran, acrylic acid and N-t-butylacrylamide. Incorporation of acrylic acid in hydrogels was confirmed by Fourier transform infrared spectroscopy. The pH-dependent swelling of hydrogels was strongly influenced by the acrylic acid content, conjugation degree of methacrylate moiety with dextran and modified dextran concentration. Intermolecular polymerization that occurred to a greater extent with a lower degree of conjugation of methacrylate and/or higher concentration of modified dextran effectively increased the network density of hydrogels. An increase of acrylic acid reduced the enzymatic degradability of pre-swollen hydrogels by dextranase, although the increased equilibrium swelling was observed.

Synthesis of Temperature/pH-Sensitive Hydrogels Containing Disulfide Linkages as Cross-Links and Their Characterization

Amphiphilic graft copolymers of alkyl methacrylates, methoxy poly(ethylene glycol) (PEG) acrylate, and acrylic acid were synthesized by free radical polymerization. PEG graft copolymers with respect to structure, composition, and average molecular weight were characterized by FT-IR, 1 H NMR, and GPC. The critical micelle concentration and molar mass of the polymeric micelles were determined by fluorescence spectroscopy using pyrene as the fluorescence probe and static laser light scattering, respectively. The formation of polymeric micelles was influenced by the balance of hydrophobicity and hydrophilicity and other factors such as molecular weight of the copolymer products. The molar mass of polymeric micelles increased with mole content of hydrophobic comonomers. Loading capacity and weight average partition coefficient for the pyrene molecules into polymeric micelles were estimated via fluorescence quenching by Cu 2+ . Fluorescence quenching studies of pyrene indicated that a loose structure of micelles was formed from the graft copolymer containing high content of hydrophilic monomethoxy poly(ethylene glycol) (mPEG) and acrylic acid.

Amphiphilic graft copolymers comprising monomeric units of stearyl methacrylate, methyl acrylate, acrylic acid and poly(ethylene glycol) acrylate were synthesized and their properties in aqueous systems characterized. The structures of these copolymers were analysed by Fourier transform infra-red and nuclear magnetic resonance spectroscopies while their molecular weights were estimated by static light scattering. The study of critical micelle concentrations and micellar sizes indicated that the formation of micelles is primarily determined by the hydrophobic/hydrophilic properties of these copolymers. Encapsulation of pyrene (as a drug model) into the micelles was found to be dependent on their stearyl methacrylate content. These copolymers also exhibited a sustained release pattern for pyrene in aqueous solutions and might indicate their future applications as potential drug delivery systems.

Poly(ethylene glycol) (PEG), with molecular weight 2,000 and 5,100, were conjugated to dextran (T40) with three different degrees of substi tution. The biodegradation of the six PEG-dextran conjugates was evaluated, using dextranase, isolated rat cecum cell free extracts (CFE), and rat liver lysosomal enzymes. All the substrates were degraded by dextranase; however, the rate of the degradation decreased with an increase in the degree of modification as well as in the molecular weight of PEG. When incubated with CFE, these conjugates were degraded with reduced rates, but a similar trend was observed, indicating the presence of an endo-acting dextranase in the rat cecum contents. The modified dextrans, however, resisted degradation by lyso somal enzymes in vitro during 36 h incubation at 37°C. The degradation of modified dextrans was evaluated by gel permeation chromatography (GPC). For the degradation of dextran conjugates by dextranase, two additional methods were also employed, i.e., static light scattering (SLS), and dynamic light scat tering (DLS). The results, as compared to those published on the modification of dextrans with low molecular weight reagents, demonstrated the PEGs' unique effects on the interaction of modified substrates with proteins. It ap pears that PEG conjugation reduced the enzymatic degradability of dextran conjugates not only due to the modification of dextran structure and the sterical hindrance to the formation of the enzyme-substrate complex, but also by the participation of PEG chains in the repulsion of enzyme molecules.

This work presents an important example of novel hybrid vesicles with pH-triggered transmembrane channels prepared by co-assembly of poly(acrylic acid)-g-poly(monomethoxy ethylene glycol) (PAAc-g-mPEG) with a cationic lipid, didodecyldimethylammonium bromide (DDAB), via electrostatic interaction for effective doxorubicin (DOX) release.

Graft copolymer comprising acrylic acid (AAc) units as the backbone and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts undergoes phase transition and supramolecular assembly into colloidal particles in water upon the thermally induced hydrophobic association. The structural characteristics of the polymeric assemblies made from the graft copolymer in water are strongly dependent on the copolymer concentration and the way that the copolymer solution is subjected to heating from 25 degrees C to the phase transition region (occurring in the range 30 approximately 35 degrees C). The resultant assemblies are characterized by forming hydrophobic PNIPAAm regions with the multicore architecture and intercore connections. Interesting enough, these colloidal systems obtained from the copolymer solutions at different concentrations (10.0 and 1.0 mg/mL) and heating methods (fast and slow heating) exhibit very different structural responses when subjected to further temperature increase (from 30 approximately 35 to 60 degrees C). The mutual interactions among the components (PAAc backbone and PNIPAAm and mPEG grafts) of the copolymer were shown to play a crucial role in the evolution of the ultimate assembly structure. A molecular packing model was proposed to illustrate the mechanisms of the thermally induced structural transformation processes for the amphiphilic graft copolymer in water.