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Dextran sulfate (DXS) is a hydrophilic, non-toxic, biodegradable, biocompatible and safe biopolymer. These biomedically relevant characteristics make DXS a promising building block in the development of nanocarrier systems for several biomedical applications, including imaging and drug delivery. DXS polyanion can bind with metal oxide nanomaterials, biological receptors and therapeutic drug molecules. By taking advantage of these intriguing properties, DXS is used to functionalize or construct nanocarriers for specific applications. In particular, the diagnostic or therapeutic active agent-loaded DXS nanoparticles are prepared by simple coating, formation of polyelectrolyte complexes with other positively charged polymers or through self-assembly of amphiphilic DXS derivatives. These nanoparticles show a potential to localize the active agents at the pathological site and minimize undesired side effects. As DXS can recognize and be taken up by macrophage surface receptors, it is also used as a targeting ligand for drug delivery. Besides as a nanocarrier scaffold material, DXS has intrinsic therapeutic potential. DXS binds to thrombin, acts as an anticoagulant and exhibits an inhibitory effect against coagulation, retrovirus, scrapie virus and human immunodeficiency virus (HIV). Herein, biomedical applications involving the use of DXS as nanocarriers for drugs, biomolecules, and imaging agents have been reviewed. A special focus has been made on strategies used for loading and delivering of drugs and biomolecules meant for treating several diseases, including cancer, inflammatory diseases and ocular disease. [ABSTRACT FROM AUTHOR]

Non-viral vectors for mRNA delivery primarily include lipid nanoparticles (LNPs) and polymers. While LNPs are known for their high mRNA delivery efficiency, they can induce excessive immune responses and cause off-target effects, potentially leading to side effects. In this study, we aimed to explore polymer-based mRNA delivery systems as a viable alternative to LNPs, focusing on their mRNA delivery efficiency and potential application in mRNA vaccines. We created a library of poly(β-amino ester) (PBAE) polymers by combining various amine monomers and acrylate monomers. Through screening this polymer library, we identified specific polymer nanoparticles (PNPs) that demonstrated high mRNA expression efficiency, with sustained mRNA expression for up to two weeks. Furthermore, the PNPs showed mRNA expression only at the injection site and did not exhibit liver toxicity. Additionally, when assessing immune activation, the PNPs significantly induced T-cell immune activation and were effective in the plaque reduction neutralization test. These results suggest that polymer-based mRNA delivery systems not only hold potential for use in mRNA vaccines but also show promise for therapeutic applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Engineering the membrane of the polymersomes with biologically relevant stimuli-responsive units enables spatial and temporal controlled drug release for effective therapy. Herein, we introduce a new-type of polymersomes featuring reactive oxygen species singlet oxygen (1O 2)-labile membrane by employing a versatile stereoregular amphiphilic poly(ethylene glycol)- block -poly(β -aminoacrylate)- block -poly(ethylene glycol) copolymers, which are synthesized through a facile one pot modular amino-alkynoate click polymerization between secondary amines and activated alkynes. These polymersomes readily co-encapsulate an anticancer drug doxorubicin (DOX) and a near infrared (NIR) photosensitizer IR-780 with hydrophobic characteristics in the membrane, and the resulting polymersomes show efficient uptake by the tumor cells. NIR light irradiation on the tumors, following intraperitoneal injection of the IR-780/DOX co -encapsulated polymersomes, facilitates tumor-specific release of DOX through disassembly of the polymersome nanostructure via 1O 2 -mediated photocleavage of the membrane. Moreover, IR-780 dye can convert NIR light energy into heat in addition to the generation of 1O 2, thus allows to realize both photothermal and photodynamic therapy. Accordingly, the NIR light-mediated on demand chemotherapy, in combination with appreciable phototherapy, of IR-780/DOX co -loaded polymersomes demonstrate an efficient tumor suppression in vivo. Unlabelled Image • ROS-labile block copolymers are synthesized by amino-alkynoate click polymerization. • Polymersomes bearing ROS (1O 2)-labile poly(β -aminoacrylate) membrane are prepared. • NIR-induced ROS-mediated polymersome degradation enabled tumor-specific drug release. • ROS-labile polymersomes showed effective tumor suppression by chemo-phototherapies. [ABSTRACT FROM AUTHOR]

Incorporation of a desired stimuli-responsive unit in a stereospecific manner at the specific location within a nonlinear block copolymer architecture is a challenging task in synthetic polymer chemistry. Herein, we report a facile and versatile method to synthesize AB2 miktoarm block copolymers bearing a singlet oxygen (1O2)-labile regio and stereospecific β-aminoacrylate linkage with 100% E-configuration at the junction via a combination of amino-yne click chemistry and ring opening polymerization. Using this strategy, a series of 1O2-responsive AB2 amphiphilic miktoarm (MA) copolymers composed of hydrophilic polyethylene glycol (PEG) as the A constituent and hydrophobic polycaprolactone (PCL) as the B constituent (MA-PEG-b-PCL2) was synthesized by varying the block length of PCL. The self-assembly characteristics of these well-defined MA-PEG-b-PCL2 copolymers in an aqueous condition were studied by solvent displacement and thin-film hydration method, and their morphologies were investigated using transmission electron microscopy. The copolymers formed spherical, cylindrical, or lamella morphologies, depending on the chain length and preparation conditions. A hydrophobic photosensitizer chlorin e6 (Ce6) and anticancer drug doxorubicin (DOX) were efficiently encapsulated into the hydrophobic core of MA-PEG-b-PCL2 copolymer micelles. These coloaded micelles were taken up by human breast cancer (MDA-MB-231) cells. Upon red laser light irradiation, the 1O2-generated by the Ce6 induced photocleavage of the β-aminoacrylate moiety, leading to the dissociation of the micellar structure and triggered intracellular drug release for effective therapy. Overall, rapid disassembly upon 1O2 generation and subsequent controlled intracellular drug release suggested that these micelles bearing β-aminoacrylate linkage have a huge potential for on-demand drug delivery. [ABSTRACT FROM AUTHOR]

Herein, we report a biocompatible amphiphilic block copolymer micelle bearing a singlet oxygen-sensitive vinyldithioether cleavable linker at the core–shell junction, which undergoes singlet oxygen-mediated photocleavage in the presence of visible light. The micelle facilitates the light-responsive release of singlet oxygen and an anticancer drug for enhanced photodynamic therapy. [ABSTRACT FROM AUTHOR]

Highlights: [•] Dextran sulfate-b-poly(glycerol methacrylate) (DS-b-PGMA) copolymer is synthesized. [•] DS-coated superparamagnetic iron oxide nanoparticles (DS-SPIONs) were prepared. [•] DS-SPIONs showed high stability due to robust anchoring of PGMA segment on SPIONs. [•] DS-SPIONs were taken up by activated macrophages via receptor-mediated endocytosis. [•] DS-SPIONs produced contrast enhancement in the T 2-weighted MR cellular imaging. [ABSTRACT FROM AUTHOR]

Abstract: The therapeutic efficacy of most drugs is greatly depends on their ability to cross the cellular barrier and reach their intracellular target sites. To transport the drugs effectively through the cellular membrane and to deliver them into the intracellular environment, several interesting smart carrier systems based on both synthetic or natural polymers have been designed and developed. In recent years, hyaluronic acid (HA) has emerged as a promising candidate for intracellular delivery of various therapeutic and imaging agents because of its innate ability to recognize specific cellular receptors that overexpressed on diseased cells. The aim of this review is to highlight the significance of HA in cancer, and to explore the recent advances of HA-based drug carriers towards cancer imaging and therapeutics. [Copyright &y& Elsevier]

Abstract: Polymeric nanoparticles, capable of encapsulating imaging agents and therapeutic drugs, have significant advantages for simultaneous diagnosis and therapy. Nonetheless, improvements in the loading contents of the active agents are needed to achieve enhanced imaging and effective therapeutic outcomes. Aiming to make these improvements, a hydrotropic micelle (HM) was explored to encapsulate superparamagnetic iron oxide nanoparticles (SPIONs) as the magnetic resonance (MR) imaging agent and paclitaxel (PTX) as the hydrophobic anticancer drug. Owing to its hydrotropic inner core with hydrophobic nature, HM could effectively encapsulate both of PTX and SPION via the simple dialysis method. The hydrodynamic size of HM increased from 68 to 178nm after physical encapsulation of SPION and PTX. Transmission electron microscopy analysis of HM bearing SPION and PTX (HM-SPION-PTX) revealed a spherical morphology with SPION clusters in the micelle cores. The micelles released PTX in a sustained manner. The bare HM and HM-SPION showed no toxicity to SCC7 cells, whereas HM-PTX and HM-SPION-PTX showed dose-dependent cytotoxicity that was lower than free PTX. HM-SPION-PTX exhibited 8.1-fold higher T 2 relaxivity than HM-SPION, implying potential of HM-SPION-PTX as the contrast agent for MR imaging. When systemically administered to tumor-bearing mice, HM-SPION-PTX was effectively accumulated at the tumor site, allowing its detection using MR imaging and effective therapy. Overall, these results suggested that HM-SPION-PTX is a promising candidate for combined diagnosis and treatment of cancer. [Copyright &y& Elsevier]

Abstract: Amphiphilic hyaluronic acid conjugates were synthesized as a potential drug carrier by chemical conjugation of an amine-terminated hydrotropic oligomer, which has a unique ability to enhance the solubility of paclitaxel (PTX), to a hyaluronic acid (HA) backbone using carbodiimide chemistry. The physicochemical properties of the hydrotropic hyaluronic acid (HydroHA) conjugates were investigated using 1H NMR, dynamic light scattering, transmission electron microscopy (TEM), and fluorescence spectroscopy. HydroHA conjugates could form self-assembled nanoparticles in an aqueous medium because of hydrophobic interactions among hydrotropic oligomers. Their particle sizes were in the range of 274–356nm, depending on the degree of substitution (DS) of the hydrotropic oligomer. TEM images showed that particle morphology was spherical in shape. Critical aggregation concentrations of HydroHA conjugates ranged from 0.034 to 0.125mg/mL, which decreased with an increase in the DS of the hydrotropic oligomer. The HydroHA conjugates were selectively taken up by the cancer cell line (SCC-7) over-expressing CD44, a hyaluronic receptor. The nanoparticles could encapsulate PTX up to 20.7wt.% by the dialysis method. The in vitro release pattern of PTX from nanoparticles was significantly dependent on drug loading content, in which the release rate was lower for the nanoparticles that contained larger amounts of the drug. From the cytotoxicity test, it was found that the drug-loaded HydroHA nanoparticles exhibited stronger cytotoxicity to SCC-7 than to normal fibroblast cell (CV-1). These results suggest that HydroHA nanoparticles have potential as the carrier of PTX for cancer therapy. [Copyright &y& Elsevier]

Abstract: Chitosan has prompted the continuous impetus for the development of safe and effective drug delivery systems because of its unique physicochemical and biological characteristics. The primary hydroxyl and amine groups located on the backbone of chitosan allow for chemical modification to control its physical properties. When the hydrophobic moiety is conjugated to a chitosan molecule, the resulting amphiphile may form self-assembled nanoparticles that can encapsulate a quantity of drugs and deliver them to a specific site of action. Chemical attachment of the drug to the chitosan throughout the functional linker may produce useful prodrugs, exhibiting the appropriate biological activity at the target site. Mucoadhesive and absorption enhancement properties of chitosan increase the in vivo residence time of the dosage form in the gastrointestinal tract and improve the bioavailability of various drugs. The main objective of this review is to provide an insight into various target-specific carriers, based on chitosan and its derivatives, towards low molecular weight drug delivery. The first part of the review is concerned with the organ-specific delivery of low molecular drugs using chitosan and its derivatives. The subsequent section considers the recent developments of drug delivery carriers for cancer therapy with special focus on various targeting strategies. [Copyright &y& Elsevier]

Polymers are well-recognized carriers useful for delivering therapeutic drug and imaging probes to the target specified in the defined pathophysiological site. The functional drug molecules and imaging agents were chemically attached or physically loaded in the carrier polymer matrix via cleavable spacers. Using appropriate targeting moieties, these polymeric carriers (PCs) loaded with functional molecules were designed to realize target-specific delivery at the cellular level. The biodistribution of these carriers can be tracked using imaging agents with suitable imaging techniques. The drug molecules can be released by cleaving the spacers either by endogenous stimuli (e.g., pH, redox species, glucose level and enzymes) at the targeted physiological site or exogenous stimuli (e.g., light, electrical pulses, ultrasound and magnetism). Recently, two-photon absorption (2PA)-mediated drug delivery and imaging has gained significant attention because TPA from near-infrared light (700–950 nm, NIR) renders light energy similar to the one-photon absorption from ultraviolet (UV) light. NIR has been considered biologically safe unlike UV, which is harmful to soft tissues, cells and blood vessels. In addition to the heat and reactive oxygen species generating capability of 2PA molecules, 2PA-functionalized PCs were also found to be useful for treating diseases such as cancer by photothermal and photodynamic therapies. Herein, insights attained towards the design, synthesis and biomedical applications of 2PA-activated PCs are reviewed. In particular, specific focus is provided to the imaging and drug delivery applications with a special emphasis on multi-responsive platforms. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs), which dampen the therapeutic efficacy of cancer immunotherapy, are the key players in the immunosuppressive tumor microenvironment (TME). Therefore, reprogramming TAMs into tumoricidal M1 macrophages possesses considerable potential as a novel immunotherapy. However, the low bioavailability of polarization agents and limited accumulation of TAMs restrict their anti-tumor efficacy. In this study, we developed a polymer-based hypoxia-responsive nanocomplex to target TAMs in hypoxia for enhanced cancer immunotherapy. We synthesized a hypoxia-cleavable polymer poly(ethylene glycol)-azo-poly(l -lysine) (PEG-azo-PLL) and formulated a nanocomplex by simple mixing PEG-azo-PLL and poly(I:C). By mimicking in vitro hypoxia conditions, PEG-azo-PLL/poly(I:C) complexes could transform the physicochemical properties to enhance the delivery efficiency of poly(I:C) to tumor hypoxia, where M2-like TAMs are accumulated. Furthermore, PEG-azo-PLL/poly(I:C) could successfully reduce the population of M2-like TAMs in hypoxic tumors and promoted infiltration of CD8+ T cells in vivo , resulting in the favorable conversion of immunosuppressive TME. Finally, PEG-azo-PLL/poly(I:C) could elicit a significant in vivo anti-tumor effect in B16F10-bearing mice in addition to a prolonged survival time, demonstrating that the hypoxia-responsive nanocomplex PEG-azo-PLL/poly(I:C) is a promising approach for TAM reprogramming immunotherapy for solid tumors. [Display omitted] • A new hypoxia-cleavable poly(I:C) delivery carrier with an azobenzene linker. • Hypoxia-responsive nanocomplex enhanced the re-programming of tumor-associated macrophages. • Hypoxia-targeted poly(I:C) delivery could convert the tumor microenvironment and suppressed the tumor growth. [ABSTRACT FROM AUTHOR]

We have reported rational design of a polymeric NO delivery micelle as a cytosol-selective NO bomb. Protected NO-donors are released from the micelle under endolysosomal conditions, and then deprotected by cytosolic glutathione. Cytosol-selective NO delivery facilitates significant tumor regression without the aid of other therapeutic modalities even in intravenous administrations. [ABSTRACT FROM AUTHOR]

Abstract: The successful clinical translation of siRNA-based therapeutics requires efficient carrier systems that can specifically deliver siRNA within the cytosol of the target cells. Although numerous polymeric nanocarriers forming ionic complexes with siRNA have been investigated for cancer therapy, their poor stability and lack of tumor targetability have impeded their in vivo applications. To surmount these limitations, we synthesized a novel type of biodegradable hyaluronic acid-graft-poly(dimethylaminoethyl methacrylate) (HPD) conjugate that can form complexes with siRNA and be chemically crosslinked via the formation of the disulfide bonds under facile conditions. The crosslinked siRNA-HPD (C-siRNA-HPD) complexes exhibited high stability in a 50% serum solution, as compared to the uncrosslinked siRNA-HPD (U-siRNA-HPD) complexes and free siRNA. Both the C-siRNA-HPD and U-siRNA-HPD complexes were efficiently taken up by the CD44-overexpressing melanoma cells (B16F10), but not by the normal fibroblast cells (NIH3T3). When the RFP-expressing B16F10 cells were treated with the complexes or free siRNA, the C-siRNA-HPD complexes showed the highest decrease in RFP expression. In vivo studies demonstrated the selective accumulation of C-siRNA-HPD complexes at the tumor site after their systemic administration into tumor-bearing mice, resulting in an efficient gene silencing effect. Overall, these results suggest that the HPD conjugate could be used as an efficient carrier for the tumor-targeted delivery of siRNA. [Copyright &y& Elsevier]

Abstract: The in vivo stability and tumor targetability of self-assembled polymeric nanoparticles are crucial for effective drug delivery. In this study, to develop biostable nanoparticles with high tumor targetability, poly(ethylene glycol)-conjugated hyaluronic acid nanoparticles (PEG-HANPs) were mineralized through controlled deposition of inorganic calcium and phosphate ions on the nanoparticular shell via a sequential addition method. The resulting nanoparticles (M-PEG-HANPs) had a smaller size (153.7±4.5nm) than bare PEG-HANPs (265.1±9.5nm), implying that mineralization allows the formation of compact nanoparticles. Interestingly, when the mineralized nanoparticles were exposed to acidic buffer conditions (

The amphiphilic block copolymer, composed of hydrophilic dextran sulfate as the targeting ligand and hydrophobic polycaprolactone as the hydrophobic segment, was prepared via click chemistry to develop self-assembled nanoparticles for targeting rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is widely known as an effective vasodilator at low concentrations. Drug delivery systems combined with NO can dilate blood vessels surrounding tumor tissues, and the drug accumulation in tumors is accelerated by the enhanced permeability and retention effect, leading to an improvement in the anti-tumor effect. N-heterocyclic carbene-based NO donors (e.g., 1,3-bis-(2,4,6-trimethylphenyl)imidazolylidene nitric oxide (IMesNO) have been developed for stable NO storing in air and water, and NO release by thermolysis. Herein, we demonstrated on-demand NO release by high-intensity focused ultrasound (HIFU) as a stimulus, which generated high heat and exerted an ablation effect when treated in vivo. We demonstrated IMesNO to be a HIFU-responsive NO donor and its potential application in vivo using IMesNO-loaded micelles. Moreover, IMesNO-loaded micelles mixed with drug-loaded micelles (IMesNO/DOX@MCs) showed acceleration of drug accumulation in tumor sites and enhanced tumor growth inhibition. Thus, our findings suggest a potential clinical bioapplication of NO-releasing drug-loaded micelles owing to the therapeutic function of NO and HIFU treatment for anti-cancer therapy. [ABSTRACT FROM AUTHOR]