Search

Dopamine-modified hyaluronic acid (DA-HA) has been initially developed as an efficient coating and adhesion material for industrial uses. However, the biological activity and safety of DA-HA in the brain have not been explored yet. Here, we report a series of evidence that DA-HA exhibits similar functionality as dopamine (DA), but with much lower toxicity arising from autoxidation. DA-HA shows very little autoxidation even after 48-h incubation. This is profoundly different from DA and its derivatives including l-DOPA, which all induce severe neuronal death after pre-autoxidation, indicating that autoxidation is the cause of neuronal death. Furthermore, in vivo injection of DA-HA induces significantly lower toxicity compared to 6-OHDA, a well-known oxidized and toxic form of DA, and alleviates the apomorphine-induced rotational behavior in the 6-OHDA animal model of Parkinson's disease. Our study proposes that DA-HA with DA-like functionalities and minimal toxicity has a great potential to treat DA-related disease.

Various nanopatterning techniques have been developed to improve cell proliferation and differentiation efficiency. As we previously reported, nanopillars and pores are able to sustain human pluripotent stem cells and differentiate pancreatic cells. From this, the nanoscale patterns would be effective environment for the co-culturing of epithelial and mesenchymal cell types. Interestingly, the nanopatterning selectively reduced the proliferative rate of mesenchymal cells while increasing the expression of adhesion protein in epithelial type cells. Additionally, co-cultured cells on the nanopatterning were not negatively affected in terms of cell function metabolic ability or cell survival. This is in contrast to conventional co-culturing methods such as ultraviolet or chemical treatments. The nanopatterning appears to be an effective environment for mesenchymal co-cultures with typically low proliferative rates cells such as astrocytes, neurons, melanocytes, and fibroblasts without using potentially damaging treatments.

Mitochondrial targeting is a promising approach for solving current issues in clinical application of chemotherapy and diagnosis of several disorders. Here, we discuss direct conjugation of mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated in vitro and in vivo, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors. KEY WORDS: Anticancer agents, Antioxidants, Direct conjugation, Mitochondria-targeting, Sensing agents

Abstract Background Mucoadhesive polymers, which may increase the contact time between the polymer and the tissue, have been widely investigated for pharmaceutical formulations. In this study, we developed a new polysaccharide-based mucoadhesive polymer with thermogelling properties. Methods Hexanoyl glycol chitosan (HGC), a new thermogelling polymer, was synthesized by the chemical modification of glycol chitosan using hexanoic anhydride. The HGC was further modified to include thiol groups to improve the mucoadhesive property of thermogelling HGC. The degree of thiolation of the thiolated HGCs (SH-HGCs) was controlled in the range of 5–10% by adjusting the feed molar ratio. The structure of the chemically modified polymers was characterized by 1H NMR and ATR-FTIR. The sol-gel transition, mucoadhesiveness, and biocompatibility of the polymers were determined by a tube inverting method, rheological measurements, and in vitro cytotoxicity tests, respectively. Results The aqueous solution (4 wt%) of HGC with approximately 33% substitution showed a sol-gel transition temperature of approximately 41 °C. SH-HGCs demonstrated lower sol-gel transition temperatures (34 ± 1 and 31 ± 1 °С) compared to that of HGC due to the introduction of thiol groups. Rheological studies of aqueous mixture solutions of SH-HGCs and mucin showed that SH-HGCs had stronger mucoadhesiveness than HGC due to the interaction between the thiol groups of SH-HGCs and mucin. Additionally, we confirmed that the thermogelling properties might improve the mucoadhesive force of polymers. Several in vitro cytotoxicity tests showed that SH-HGCs showed little toxicity at concentrations of 0.1–1.0 wt%, indicating good biocompatibility of the polymers. Conclusions The resultant thiolated hexanoyl glycol chitosans may play a crucial role in mucoadhesive applications in biomedical areas.

Abstract Background Cancer is one of the deadliest threats to human health. Abnormal physiochemical conditions and dysregulated biosynthetic intermediates in the tumor microenvironment (TME) play a significant role in modulating cancer cells to evade or defend conventional anti-cancer therapy such as surgery, chemotherapy and radiotherapy. One of the most important challenges in the development of anti-tumor therapy is the successful delivery of therapeutic and imaging agents specifically to solid tumors. Main body The recent progresses in development of TME responsive nanoparticles offers promising strategies for combating cancer by making use of the common attributes of tumor such as acidic and hypoxic microenvironments. In this review, we discussed the prominent strategies utilized in the development of tumor microenvironment-responsive nanoparticles and mode of release of therapeutic cargo. Conclusion Tumor microenvironment-responsive nanoparticles offers a universal approach for anti-cancer therapy.

The effects of alpha- and beta- cyclodextrin-conjugated poly(epsilon-lysine)s (CDPLs) on the fluorescence spectra of 6-(p-toluidino)-2-napthalenesulfonate (TNS) are investigated under various environmental conditions. The results obtained from the combination of the cooperative host-guest interactions and the ionic interaction between the negatively charged TNS moieties and the positive amino groups of poly(epsilon-lysine) are presented.

Study has revealed several consequences of inclusion complexation of CD-conjugated polymers in particular the rapid assembly of beta-CDPL and the guest molecule at only physiological pH and the temperature-sensitive character of this inclusion complex system, allowing for a sharp phase transition upon a small amount of cooling. The results indicated that the beta-CDPL inclusion complex system could be considered as a potential carrier for drug delivery system.

We prepared pyrene-labeled peptide amphiphiles (PAs) consisting of a hydrophobic linear- or branchedalkyl chain (for 1 or 2, respectively) and a hydrophilic histidine-rich peptide of HGGGHGHGGGHG (HG12). Both peptides have a strong tendency to form nanofibrils (NFs) in aqueous media. The resulting histidine-coated NFs show a great binding affinity to Cu2+ as a fluorescence "light-off" sensor. Interestingly, the emission spectra of the pyrene probe show that the different supramolecular assemblies between 1 and 2 can significantly affect the binding affinity to specific metal ions. In particular, "light-up" fluorescent Ag+ detection of NFs of 2 through inhibition of photoinduced electron transfer (PET) was observed even at a low concentration of PA solution. As a means to determine the biological responsibility of 2 to Ag+, intracellular detection using the "turn-on" response was performed. A considerable enhancement of fluorescence in NF-loaded HeLa cells was observed. In addition, the NFs were used as a template scaffold for the production of Ag nanoparticles (AgNPs) with high monodispersity and stability. The NFs decorated with AgNPs are shown to possess highly effective and long-term antibacterial activity against both Gram-negative and -positive bacteria. [ABSTRACT FROM AUTHOR]

A multifunctional nanomedicine combining magnetic resonance imaging (MRI) and photodynamic therapy (PDT) functionalities is a promising integrated platform that allows for targeted drug delivery, noninvasive monitoring of therapeutic responses, and simultaneous cancer diagnosis and treatment. A hybrid nanoparticle (NP) system with a core/shell-structured magnetic iron oxide/gold (Fe[sub 3]O[sub 4]/Au) NP and a photosensitizer (PS)-conjugated heparin surface layer is investigated as a novel multifunctional carrier in PDT. A thiolated heparin-pheophorbide a (PhA) conjugate (H-PhA), which is a macromolecular PS, is synthesized and introduced onto the NP surface through a gold-thiol interaction. The photoactivity of the PhA moieties on the NP surface is significantly suppressed by the quenching effect of the Fe[sub 3]O[sub 4]/Au NP. However, their photoactivity can be restored in a glutathione (GSH)-rich intracellular environment, which allows GSH-mediated switchable photoactivity in the hybrid NP system. As a result, marked phototoxicity and strong fluorescence signals are observed in NP-treated A549 cells under light irradiation. In an animal tumor model, Fe[sub 3]O[sub 4]/Au/H-PhA NPs are efficacious in photodynamic cancer treatment and exhibit prolonged circulation characteristics, enhanced tumor specificity, and higher therapeutic efficacy compared with free PhA. In addition, in vitro MRI studies reveal that the NPs could potentially serve as MRI contrast agents in cancer diagnosis and may be used to monitor the photodynamic treatment response used to accurately guide light irradiation. The present findings show that the Fe[sub 3]O[sub 4]/Au/H-PhA NP is a promising nanomedicine platform in PDT and cancer diagnosis. [ABSTRACT FROM AUTHOR]

A multifunctional nanomedicine combining magnetic resonance imaging (MRI) and photodynamic therapy (PDT) functionalities is a promising integrated platform that allows for targeted drug delivery, noninvasive monitoring of therapeutic responses, and simultaneous cancer diagnosis and treatment. A hybrid nanoparticle (NP) system with a core/shell-structured magnetic iron oxide/gold (Fe3O4/Au) NP and a photosensitizer (PS)-conjugated heparin surface layer is investigated as a novel multifunctional carrier in PDT. A thiolated heparin-pheophorbide a (PhA) conjugate (H-PhA), which is a macromolecular PS, is synthesized and introduced onto the NP surface through a gold-thiol interaction. The photoactivity of the PhA moieties on the NP surface is significantly suppressed by the quenching effect of the Fe3O4/Au NP. However, their photoactivity can be restored in a glutathione (GSH)-rich intracellular environment, which allows GSH-mediated switchable photoactivity in the hybrid NP system. As a result, marked phototoxicity and strong fluorescence signals are observed in NP-treated A549 cells under light irradiation. In an animal tumor model, Fe3O4/Au/H-PhA NPs are efficacious in photodynamic cancer treatment and exhibit prolonged circulation characteristics, enhanced tumor specificity, and higher therapeutic efficacy compared with free PhA. In addition, in vitro MRI studies reveal that the NPs could potentially serve as MRI contrast agents in cancer diagnosis and may be used to monitor the photodynamic treatment response used to accurately guide light irradiation. The present findings show that the Fe3O4/Au/H-PhA NP is a promising nanomedicine platform in PDT and cancer diagnosis. [ABSTRACT FROM AUTHOR]

To achieve a targeted drug delivery system for chemotherapy, we synthesized a ligand-mediated nanoparticulate drug carrier composed of folate-conjugated heparin-based copolymers. The use of a heparin-based drug delivery system is of special interest due to the attractive anticancer properties of heparin. Heparin–poly(β-benzyl-l-aspartate) (HP) and folate–poly(ethylene glycol)-conjugated HP (FPHP) amphiphilic copolymers were synthesized for delivery of doxorubicin (DOX). DOX was effectively incorporated into HP and FPHP nanoparticles at a high loading content and efficiency by a simple dialysis method. The DOX-loaded HP and FPHP nanoparticles had average diameters of 86–210 nm, depending on the drug loading content and the compositions of copolymers. Both DOX-loaded HP and FPHP nanoparticles had a sustained drug release pattern, and DOX-release from nanoparticles at pH 5.0 was much faster than that at pH 7.4. This pH-dependent DOX release property may ensure intracellular drug release due to decreases in pH values inside the endosomes and lysosomes of tumor cells. Furthermore, the DOX-loaded FPHP nanoparticles exhibited a greater extent of intracellular uptake against folate-receptor positive KB cells than DOX-loaded HP nanoparticles, indicating that the FPHP nanoparticles may serve as an effective active targeting carrier. The DOX-loaded FPHP nanoparticles also showed more potent cytotoxic effect on KB cells than on folate-receptor negative A549 cells. These results suggested that the FPHP nanoparticle is a promising candidate for targeted delivery of anticancer drugs to folate-receptor positive cells. [ABSTRACT FROM AUTHOR]

The purpose of this investigation was to characterize the in vitro stability and in vivo disposition of paclitaxel in rats after solubilization of paclitaxel into hydrotropic polymeric micelles. The amphiphilic block copolymers consisted of a micellar shell-forming poly(ethylene glycol) (PEG) block and a core-forming poly(2-(4-vinylbenzyloxy)-N,N-diethylnicotinamide) (P(VBODENA)) block. N,N-Diethylnicotinamide (DENA) in the micellar inner core resulted in effective paclitaxel solubilization and stabilization. Solubilization of paclitaxel using polymeric micelles of poly(ethylene glycol)-b-P(d,l-lactide) (PEG-b-PLA) served as a control for the stability study. Up to 37.4 wt % paclitaxel could be loaded in PEG-b-P(VBODENA) micelles, whereas the maximum loading amount for PEG-b-PLA micelles was 27.6 wt %. Thermal analysis showed that paclitaxel in the polymeric micelles existed in the molecularly dispersed amorphous state even at loadings over 30 wt %. Paclitaxel-loaded hydrotropic polymeric micelles retained their stability in water for weeks, whereas paclitaxel-loaded PEG-b-PLA micelles precipitated in a few days. Hydrotropic polymer micelles were more effective than PEG-PLA micelle formulations in inhibiting the proliferation of human cancer cells. Paclitaxel in hydrotropic polymer micelles was administered orally (3.8 mg/kg), intravenously (2.5 mg/kg), or via the portal vein (2.5 mg/kg) to rats. The oral bioavailability was 12.4% of the intravenous administration. Our data suggest that polymeric micelles with a hydrotropic structure are superior as a carrier of paclitaxel due to a high solubilizing capacity combined with long-term stability, which has not been accomplished by other existing polymeric micelle systems. [ABSTRACT FROM AUTHOR]

Hydrophilic poly(ethylene glycol) (PEG) grafts were introduced into superporous hydrogels (SPHs) to enhance the water absorption rate and swelling kinetics. PEG-grafted SPHs were prepared by copolymerization of acrylic acid and acrylamide monomers in the presence of PEG acrylate accompanied by a gas blowing foaming process to create superporous structures. PEG-grafted SPHs swelled 3 ∼ 6 times faster than the control SPHs. The equilibrium swelling time was significantly reduced by introduction of hydrophilic PEG grafts and was further shortened by moisture. PEG-grafted SPHs containing 28wt% of moisture reached their equilibrium swelling within 20s. These PEG-grafted SPHs with fast swelling and superabsorbent properties may be useful for bioapplications where fast swelling kinetics is critical. [ABSTRACT FROM AUTHOR]

Studies the properties of beta-cyclodextrin-conjugated polylysine. Stimuli-responsive polymers; Complexation-induced aggregations; Kinetics of the aggregation phenomena.