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INTRODUCTION: Polymer prodrug nanoparticles have become an emerging drug delivery system in cancer therapy due to their high drug loading. However, their poor drug release and lack of tumor cell targeting limit their clinical application. OBJECTIVE: This study aimed to prepare targeted and reduction-reactive polyprodrug nanocarriers based on curcumin (CUR) for co-delivery of doxorubicin (DOX), labeled as DOX/HAPCS NPs, and to investigate their anticancer activity. METHODS: The polymer was synthesized and characterized by chemical method. The drug loading and drug release behavior of DOX and CUR in polymer nanoparticles were determined. Moreover, the antitumor effects of polymer nanoparticles were evaluated using an MTT experiment and tumor inhibition experiment, and the synergistic effect of co-delivered DOX and CUR was explored. RESULTS: The particle size of DOX/HAPCS NPs was 152.5nm, and the potential was about -26.74 mV. The drug-carrying capacity of DOX and CUR was about 7.56% and 34.75%, respectively, indicating high drug-carrying capacity and good stability. DOX and CUR released over 90% within 24 hours in the tumor environment. Compared with free DOX, DOX/HAPCS NPs demonstrated significantly enhanced cell and tumor inhibitory effects (P< 0.05) in vivo and in vitro and changed drug distribution to avoid toxic side effects on normal tissues. The combined index showed that DOX and CUR showed synergistic anticancer effects at a set ratio. CONCLUSION: The prepared reduction-responsive targeted polymer nanomedical DOX/HAPCS NPs exhibited a synergistic anti-cancer effect, with high drug loading capacity and the ability to release drugs in proportion, making it a promising polymer nanoparticle drug delivery system.

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Biotin receptors are overexpressed in various cancer cell types, essential in tumor development, metabolism, and metastasis. Chemotherapeutic agents may be more effective and have fewer adverse effects if they specifically target the biotin receptors on cancer cells. Polymeric micelles (PMs) with nanoscale size via the EPR effect to accumulate near tumor tissue. We utilized the solvent exchange technique to crate polymeric Biotin-PEG-SeSe-PBLA micelles. This underwent self-assembly to create uniformly dispersed PMs with a hydrodynamic diameter of 81.54 ± 0.23 nm. The resulting PMs characterized by 1HNMR, 13CNMR, FTIR, and Raman spectroscopy. PMs exhibited a high efficacy of Doxorubicin encapsulation (EE) and loading content (DLC), with values of 5.93 wt% and 74.32 %, respectively. DOX@Biotin-PEG-SeSe-PBLA micelles showed optimal DOX release, around 89 % and 74 % in 10 mM glutathione and 0.1 % H2O2, respectively, within 72 hours, in the simulated cancer redox pool. Fascinatingly, the blank Biotin-PEG-SeSe-PBLA micelles did not affect the HaCaT or HeLa cell lines; approximately 85 % of the cells were metabolically active. Contrarily, at a 5 µg/ml concentration, DOX@Biotin-PEG-SeSe-PBLA specifically inhibited the proliferation of roughly 76 % of HeLa cells and 11 % of HaCaT cells. The fluorescence microscopy results demonstrated that biotin-decorated micelles were more successfully internalized by HeLa cells, which overexpress the biotin receptor, than by non-targeted micelles in vitro. In summary, the diselenide-linked Biotin-PEGSeSe-PBLA formed smart PMs that could offer DOX specific to cancer cells with precision and are physiologically durable.

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Liposomes and polymersomes are colloidal vesicles that are self-assembled from lipids and amphiphilic polymers, respectively. Because of their ability to encapsulate both hydrophilic and hydrophobic therapeutics, they are of great interest in drug delivery research. Today, the applications of liposomes and polymersomes have expanded to a wide variety of complex therapeutic molecules, including nucleic acids, proteins and enzymes. Thanks to their chemical versatility, they can be tailored to different drug delivery applications to achieve maximum therapeutic index. This review article evaluates liposomes and polymersomes from a perspective that takes into account the physical and biological barriers that reduce the efficiency of the drug delivery process. In this context, the design approaches of liposomes and polymersomes are discussed with representative examples in terms of their physicochemical properties (size, shape, charge, mechanical), targeting strategies (passive and active) and response to different stimuli (pH, redox, enzyme, temperature, light, magnetic field, ultrasound). Finally, the challenges limiting the transition from laboratory to practice, recent clinical developments, and future perspectives are addressed.

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Vaginal candidiasis is a common form of infection in women caused by Candida species. Due to several drawbacks of conventional treatments, the current research is attempted to formulate and optimize a miconazole nitrate-loaded in situ spray gel for vaginal candidiasis. The stimuli-responsive (pH and thermo-responsive) polymers selected for the in situ gel were chitosan and poloxamer 407, respectively, whereas hydroxypropyl methylcellulose (HPMC) was introduced in the formulation to further improve the mucoadhesive property. The dispersion of each polymer was carried out using the cold method, whereas the optimization of the formulation was achieved using Box-Behnken statistical design considering viscosity and gelation temperature as dependent variables. Present design achieved the optimized outcome with HPMC, poloxamer and chitosan at 0.52% (w/v), 18.68% (w/v) and 0.41% (w/v), respectively. Evaluation of drug-excipients compatibility was performed using differential scanning calorimetry, Fourier transform infrared spectroscopy, and thermogravimetric analysis where the results showed the absence of any chemical interaction between the polymers and drug component. The optimized formulation showed gelation temperature at 31°C allowing in situ phase transition in a vaginal environment; pH of 4.21 is suitable for use in the vaginal cavity, and appropriate viscosity (290 cP) at storage temperature (below 30°C) would allow spraying at ease, whereas strong mucoadhesive force (22.4±0.513 g) would prevent leaking of the formulation after application. The drug release profile showed sustained release up to 24 h with a cumulative drug release of 81.72%, which is significantly better than the marketed miconazole nitrate cream. In addition, an improved antifungal activity could be correlated to the sustained release of the drug from the formulation. Finally, the safety of the formulation was established while tested on HaCaT cell lines. Based on our findings, it could be concluded that the in situ hydrogel formulation using stimuli-responsive polymers could be a viable alternative to the conventional dosage form that can help to reduce the frequency of administration with ease of application to the site of infection, thus will provide better patient compliance.

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Switchable polymeric materials, which can respond to triggering signals through changes in their properties, have become a major research focus for parenteral controlled delivery systems. They may enable externally induced drug release or delivery that is adaptive to in vivo stimuli. Despite the promise of new functionalities using switchable materials, several of these concepts may need to face challenges associated with clinical use. Accordingly, this review provides an overview of various types of switchable polymers responsive to different types of stimuli and addresses opportunities and challenges that may arise from their application in biomedicine.

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For efficient delivery of messenger (m)RNA, delivery carriers need two major functions: protecting mRNA from nucleases and translocating mRNA from endolysosomes to the cytoplasm. Herein, these two complementary functionalities are integrated into a single polyplex by fine-tuning the catiomer chemical structure and incorporating the endosomal escape modality. The effect of the methylene spacer length on the catiomer side chain is evaluated by comparing poly(l-lysine) (PLL) with a tetramethylene spacer and poly(L-ornithine) (PLO) with a trimethylene spacer. Noteworthily, the nuclease stability of the mRNA/catiomer polyplexes is largely affected by the difference in one methylene group, with PLO/mRNA polyplex showing enhanced stability compared to PLL/mRNA polyplex. To introduce the endosomal escape function, the PLO/mRNA polyplex is wrapped with a charge-conversion polymer (CCP), which is negatively charged at extracellular pH but turns positive at endosomal acidic pH to disrupt the endosomal membrane. Compared to the parent PLO/mRNA polyplex, CCP facilitated the endosomal escape of the polyplex in cultured cells to improve the protein expression efficiency from mRNA by approximately 80-fold. Collectively, this system synergizes the protective effect of PLO against nucleases and the endosomal escape capability of CCP in mRNA delivery.

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Soft tissue in biological system is a hydrogel with elaborate structure exhibiting repeatable dynamic function. In order to approach such sophisticated system, precise construction of a designed network with multi-components is desired. This communication presents a novel hydrogel having highly dense stimuli-responsive free-end chains around crosslinking structure. A key molecule is a core-crosslinked star-shaped polymer with multiple thermoresponsive arms, which can be prepared by reversible addition-fragmentation chain transfer polymerization of divinyl crosslinker with poly(N-isopropylacrylamide) (PNIPAAm) macro-chain transfer agent and have a number of unreacted carbon-carbon double bonds in the core. These unreacted double bonds can be utilized as a crosslinker for poly(acrylamide) (PAAm) gel synthesis by free radical polymerization. The obtained gel contains homogeneously dispersed star PNIPAAms as crosslinking points and exhibits thermoresponsive swelling behavior in water depending on the star contents. In particular, the gel with low content of the star crosslinker shows localized responsive behavior with expansion and shrinkage of the star in one molecule. The mechanical properties of the star-crosslinked gel are significantly high compared to the conventional PAAm gels particularly in compressive strength (≈9 MPa). Moreover, the star-crosslinked gel has thermoresponsive mechanical toughening property.

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Environmentally responsive nanomaterials have been developed for drug delivery applications, in an effort to target and accumulate therapeutic agents at sites of disease. Within a biological system, these nanomaterials will experience diverse conditions which encompass a variety of solute identities and concentrations. In this study, we developed a new quartz crystal microbalance with dissipation (QCM-D) assay, which enabled the quantitative analysis of nanogel swelling, protein adsorption, and biodegradation in a single experiment. As a proof of concept, we employed this assay to characterize non-degradable and biodegradable poly(acrylamide-co-methacrylic acid) nanogels. We compared the QCM-D results to those obtained by dynamic light scattering to highlight the advantages and limitations of each method. We detailed our protocol development and practical recommendations, and hope that this study will serve as a guide for others to design application-specific QCM-D assays within the nanomedicine domain.

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The versatility and applicability of thermoresponsive polymeric systems have led to great interest and a multitude of publications. Of particular significance, multifunctional poly(N-isopropylacrylamide) (PNIPAAm) systems based on PNIPAAm copolymerized with various functional comonomers or based on PNIPAAm combined with nanomaterials exhibiting unique properties. These multifunctional PNIPAAm systems have revolutionized several biomedical fields such as controlled drug delivery, tissue engineering, self-healing materials, and beyond (e.g., environmental treatment applications). Here, we review these multifunctional PNIPAAm-based systems with various cofunctionalities, as well as highlight their unique applications. For instance, addition of hydrophilic or hydrophobic comonomers can allow for polymer lower critical solution temperature modification, which is especially helpful for physiological applications. Natural comonomers with desirable functionalities have also drawn significant attention as pressure surmounts to develop greener, more sustainable materials. Typically, these systems also tend to be more biocompatible and biodegradable and can be advantageous for use in biopharmaceutical and environmental applications. PNIPAAm-based polymeric nanocomposites are reviewed as well, where incorporation of inorganic or carbon nanomaterials creates synergistic systems that tend to be more robust and widely applicable than the individual components.

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A novel adhesion control method for hydrogels utilizing swelling-induced wrinkling gel films is developed. Structures such as flat, crease, and wrinkle at the interface of adhered gels are controlled by swelling ratio of gel films. The role of microstructures at the gel-gel interface is investigated by adhesive strength measurement. Aligned wrinkles are fabricated with anisotropic swelling films. The adhesive strength of hydrogels with wrinkles parallel to tensile direction is larger than that with perpendicular wrinkles. Adhered gels detach without damage to their surfaces when the wrinkle structures are disrupted by peeling of the wrinkled film. Moreover, thermoresponsive film is used to control wrinkle structures at the adhered interface by temperature. The adhered interface is stable in cold water because of the existence of wrinkles; however, they detach in hot water due to wrinkle deformation. By using wrinkle structure at adhesive interfaces, both strong adhesion and easy detachment of hydrogels are achieved.

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In the present study, poly(ethylene glycol)-b-poly(N,N-diethylaminoethyl methacrylate) (PEG-b-PDEAEM) amphiphilic block copolymers were synthetized by reversible addition-fragmentation chain transfer (RAFT) polymerization using two different macro chain transfer agents containing PEG of 2000 and 5000 g/mol and varying the length of the PDEAEM segment. From the obtained block copolymers, polymersome type nanometric aggregates were obtained by two different techniques. By direct dispersion, particle diameters around 200 nm were obtained, while by solvent exchange using THF and water, the obtained diameters were around 100 nm. These block copolymers were used to encapsulate gold nanorods and doxorubicin (DOX) with good efficiencies to obtain nanomaterials with potential use as dual stimuli-sensitive drug delivery systems for combined anticancer therapies. Drug delivery studies showed that the release rate of DOX was accelerated when the pH was lowered from 7.4 to 5.8 and also when the systems were irradiated with a NIR laser at pH 7.4. The combination of lower pH and near infrared (NIR) irradiation resulted in higher drug release only in the case of polymersomes with lower molecular weight PEG.

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Multiple factors are involved in the development of cancers and their effects on survival rate. Many are related to chemo-resistance of tumor cells. Thus, treatment with a single therapeutic agent is often inadequate for successful cancer therapy. Ideally, combination therapy inhibits tumor growth through multiple pathways by enhancing the performance of each individual therapy, often resulting in a synergistic effect. Polymeric nanoparticles prepared from block co-polymers have been a popular platform for co-delivery of combinations of drugs associated with the multiple functional compartments within such nanoparticles. Various polymeric nanoparticles have been applied to achieve enhanced therapeutic efficacy in cancer therapy. However, reported drug ratios used in such systems often vary widely. Thus, the same combination of drugs may result in very different therapeutic outcomes. In this review, we investigated polymeric co-delivery systems used in cancer treatment and the drug combinations used in these systems for synergistic anti-cancer effect. Development of polymeric co-delivery systems for a maximized therapeutic effect requires a deeper understanding of the optimal ratio among therapeutic agents and the natural heterogenicity of tumors.

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Betanin (BET) can reduce the side effects of potent anticancer drugs e.g. doxorubicin (DOX) on the normal tissues in co-administration with them because of the synergistic therapeutic effect and consequently the reduced required amount of anticancer agents. Despite interest in the use of BET, incomplete oral absorption and low stability of BET limit its application. Thus, in this study to overcome the restrictions of BET and providing the synergistic effect of DOX@BET, we designed a new pH-responsive nanocarrier via decoration of gelatin nanoparticles (GNPs) by (methoxy poly (ethylene glycol)-poly ((2-dimethylamino) ethyl methacrylate-co-itaconic acid) (PGNPs). DOX and BET were effectively loaded (the loading capacity of 20.5% and 16.25%, respectively) into the PGNPs and this nanoplatform exhibited the suitable small particle size (162 nm). Additionally, the triggered release ability of drugs was studied through the assessment of simulated physiological and tumor tissue environments and showed the controlled release of DOX and BET with adjusting the pH of environment. Moreover, the synergistic effect of DOX@BET loaded PGNPs decreased the cell viability amount of breast cancer cells (MCF-7) respect to the free form of DOX or BET which indicated that the developed smart nanocarrier will be a hopeful nanocarrier for cancer therapy.

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Diselenide-bond-linked poly(N-isopropylacrylamide)-paclitaxel chemical conjugates are synthesized as a drug release carrier. The conjugates can self-assemble into "core-shell" nanoscaled micelles in aqueous solution and show thermal and redox dual-responsiveness. The conjugates can afford a high encapsulation efficiency of up to 72.3%, and deliver hydrophobic anticancer drug paclitaxel in a temperature and oxidization or reduction stress-mode. The in vitro 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and in vivo anticancer assays are performed to assess the cytotoxicity and anticancer activity of the conjugates, suggesting that the developed conjugates can be used to treat carcinoma as a novel and highly efficient drug delivery system.

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In recent decades, nanoparticles have shown significant promise as an oncology treatment modality. Responsive polymers represent a promising class of nanoparticles that can trigger delivery through the exploitation of a specific stimuli. Response to a stimulus is one of the most basic processes found in living systems. As such, the desire to engineer dynamic and functional materials is becoming more prevalent in an effort to achieve precise control over our environment. The combination of controlled radical polymerization and high yielding chemistry strategies provide an excellent basis for the development of the next generation of drug delivery systems. The versatility of polymer chemistries available enables the synthesis of increasingly complex architectures with enhanced delivery specificity and control over the desired properties to interface with biological systems. This tutorial review highlights recent developments in polymer-based approaches to internally responsive nanoparticles for oncology. Presented are concise overviews of the current challenges and opportunities in cancer nanomedicine, common polymer-based architectures, and the basis for internally triggered stimuli-response relationships commonly employed in oncology applications. Examples of the chemistry used in the design of environmentally labile nanomaterials are discussed, and we outline recent advances in creating advanced bioresponsive drug delivery architectures.

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Poly(doxorubicin) (PDOX) is synthesized with Mn of 1.66 × 104 and DOX content of 78% as prodrug for tumor-specific triggered release, via a facile condensation polymerization of DOX-SS-DOX and adipic dihydrazide. The PDOX nanoparticles (PDOX-NPs) could completely release DOX-SH within 1.5 days at the simulated tumor microenvironment, but no measurable leakage in the physiological media. The in vitro controlled release results show that the releasing rate is influenced by the dosage and independent of the particle size, while the solubility of the degraded products should be the main determining factor for the drug release from the PDOX-NPs. The PDOX-NPs are expected to be promising prodrug nanopharmaceutics for the on-demand self-delivery of DOX with enhanced anticancer efficacy in future tumor treatment.

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Liquid crystal polymer networks (LCNs) lead the research geared toward macroscopic motion of materials. These actuators are molecularly programed to adapt their shape in response to external stimuli. Non-photo-responsive thin films of LCNs covered with heat absorbers (e.g., graphene or ink) are shown to continuously oscillate when exposed to light. The motion is governed by the heat dissipated at the film surface and the anisotropic thermal deformation of the network. The influence of the LC molecular alignment, the film thickness, and the LC matrix on the macroscopic motion is analyzed to probe the limits of the system. The insights gained from these experiments provide not only guidelines to create actuators by photo-thermal or pure photo-effects but also a simple method to generate mechanical oscillators for soft robotics and automated systems. © 2018 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1331-1336.

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A folic acid targeted mixed micelle system based on co-assembly of poly(ε-caprolactone)-b-poly(methoxytri(ethylene glycol) methacrylate-co-N-(2-methacrylamido)ethyl folatic amide) and poly(ε-caprolactone)-b-poly(diethylene glycol monomethyl ether methacrylate) is developed to encapsulate indocyanine green (ICG) for photothermal therapy and photodynamic therapy. In this study, the use of folic acid is not only for specific cancer cell recognition, but also in virtue of the carboxylic acid on folic acid to regulate the pH-dependent thermal phase transition of polymeric micelles for controlled drug release. The prepared ICG-loaded mixed micelles possess several superior properties such as a preferable thermoresponsive behavior, excellent storage stability, and good local hyperthermia and reactive oxygen species generation under near-infrared (NIR) irradiation. The photototoxicity induced by the ICG-loaded micelles has efficiently suppressed the growth of HeLa cells (folate receptor positive cells) under NIR irradiation compared to that of HT-29, which has low folate receptor expression. Hence, this new type of mixed micelles with excellent features could be a promising delivery system for controlled drug release, effective cancer cell targeting, and photoactivated therapy.

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A synthetic strategy to efficiently prepare main-chain peptide-polymer conjugates probing their aggregation in solution is described. An in situ tandem reaction based on aminolysis/thio-bromo "click" reaction is performed to tether an amyloidogenic peptide fragment amyloid-ß17-20 (Leu-Val-Phe-Phe (LVFF)) to the ω-chain end of poly(diethylene glycol methyl ether acrylate) (PDEGA), prepared via reversible addition fragmentation chain transfer polymerization. Structural confirmation of the constructed conjugates PDEGA-LVFF (Mn,SEC = 5600, Ð = 1.21), (Mn,SEC = 7600, Ð = 1.16), and (Mn,SEC = 8900, Ð = 1.15) is successfully made by combined studies of 1 H NMR, size-exclusion chromatography, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry, and electrospray ionization time-of-flight (ESI-TOF) mass spectrometry. The effect of the peptidic constituent on the thermoresponsive behavior of the polymer is examined by UV-vis spectroscopy, and the self-assembly behavior of the amphiphilic conjugate is further exploited, exhibiting micellar morphology in aqueous solution.

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Metal-organic frameworks (MOFs) are nanoporous, crystalline hybrid materials, which enable various functionalities by incorporating functional organic molecules. By using organic linker molecules that possess photoswitchable azobenzene side groups, the remote control over certain properties was introduced to MOFs. Different MOF materials in the form of powders and thin films have been used to demonstrate the photoswitching. The applications of these stimuli-responsive nanoporous solids range from switching the adsorption capacity of various gases over remote-controlled release of guest molecules to continuously tunable membrane separation of molecular mixtures. A particular focus of this review is the effect of the azobenzene photoswitching on the host-guest interaction, enabling smart applications of the material. Steric hindrance, which may suppress the photoswitching in some MOF structures, is also discussed.

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