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To promote bactericidal activity, improve photostability and safety, novel antibacterial nanoparticle system based on photodynamic action (PDA) was prepared here through conjugation of photosensitizer hematoporphyrin (HP) onto carboxymethyl chitosan (CMCS) via amide linkage and followed by ultrasonic treatment. The system was stable in PBS (pH 7.4) and could effectively inhibit the photodegradation of conjugated HP because of aggregation-caused quenching effect. ROS produced by the conjugated HP under light exposure could change the structure of nanoparticles by oxidizing the CMCS skeleton and thereby significantly promote the photodynamic activity of HP and its photodynamic activity after 6 h was higher than that of HP·2HCl under the same conditions. Antibacterial experiments showed that CMCS-HP nanoparticles had excellent photodynamic antibacterial activity, and the bacterial inhibition rates after 60 min of light exposure were greater than 97%. Safety evaluation exhibited that the nanoparticles were safe to mammalian cells, showing great potential for antibacterial therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In this study, a series of amphiphilic polymeric prodrugs (Azido-functionalized hyaluronan-triazole-imine-doxorubicin, HAimine-DOX) were designed and synthesized by the "Click" reaction with a remarkable grafting ratio of DOX. Nanoparticles with a core-shell structure can be obtained by self-assembling in aqueous media, which exhibited a particle size of 137-170 nm. Moreover, the HA-imine-DOX nanoparticles exhibited good stability in vitro, and the drug release was obviously mediated by the pH gradient. Subsequently, the CCK-8 assay indicated that this nano-system exhibited lower cytotoxicity in normal cells (Mouse fibroblast cell lines, L929) and a higher inhibition ratio in the tumor cells (Human cervical cancer cells, HeLa) in response to drug release with the endo/lysosomal pH environment. The cellular uptake and flow cytometric profiles of HeLa cells indicated an efficient internalization due to the receptor-mediated affinity of CD44 for HA with high specificity. It was believed that this pH-dependent polymeric prodrug had a potential application in cancer therapy.

Background: Micelles as drug carriers are characterized by their inherent instability due to the weak physical interactions that facilitate the self-assembly of amphiphilic block copolymers. As one of the strong physical interactions, the stereocomplexation between the equal molar of enantiomeric polylactides, i.e., the poly(L-lactide) (PLLA) and poly(D-lactide) (PDLA), may be harnessed to obtain micelles with enhanced stability and drug loading capacity and consequent sustained release., Aims/methods: In this paper, stereocomplexed micelles gama-PGA-g-PLA micelles) were fabricated from the stereocomplexation between poly(gama-glutamic acid)-graft-PLLA gama-PGA-g-PLA) and poly(gamaglutamic acid)-graft-PDLA gama-PGA-g-PLA). These stereocomplexed micelles exhibited a lower CMC than the corresponding enantiomeric micelles., Result: Furthermore, they showed higher drug loading content and drug loading efficiency in addition to more sustained drug release profile in vitro. In vivo imaging confirmed that the DiR-encapsulated stereocomplexed gama-PGA-g-PLA micelles can deliver anti-cancer drug to tumors with enhanced tissue penetration. Overall, gama-PGA-g-PLA micelles exhibited greater anti-cancer effects as compared with the free drug and the stereocomplexation may be a promising strategy for fabrication of anti-cancer drug carriers with significantly enhanced efficacy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Nanoparticles, such as polymeric micelles, are currently regarded as effective drug delivery vehicles. In this study, a series of carboxymethyl chitosan/daunorubicin (CMCS/DNR) conjugates with macromolecular carriers of different molecular weights (MWs) were prepared and structurally characterized by Fourier transform infrared spectroscopy (FT-IR) and 1H-NMR spectroscopy. The results indicated that the MWs of the carriers greatly influenced the drug loading capacity. DNR was conjugated to the polymer via an acid-sensitive hydrazone linkage susceptible to hydrolysis at pH 5–6, thereby enabling intracellular DNR release. In aqueous media, the conjugates spontaneously formed nano-sized particles with core–shell structures (CMCS and DNR as the shell and core, respectively). Dynamic light scattering (DLS) and trans-mission electron microscopy (TEM) indicated that the prepared nanoparticles were spherical in shape with diameters of 100–200 nm and had a slight negative surface charge. In addition, in vitro drug release studies demonstrated that the micelles were highly sensitive to mild acidic conditions (pH 5.0) but remained reasonably stable at pH 6.5 and pH 7.4. Importantly, cell counting kit-8 (CCK-8) assays demonstrated that DNR-conjugated nanoparticles exerted a cytotoxic effect on HeLa cells, with the IC50 being approximately 2 times higher than that of free-DNR. Furthermore, confocal laser scanning microscopy (CLSM) revealed that the CMCS-hyd-DNR nanosystem could efficiently deliver and release DNR in the nuclei of cancer cells. Taken together, the developed CMCS based pH-sensitive nanosystem may be a potential drug delivery vehicle for cancer therapy.

The purpose of the present study was to develop a robust and redox-sensitive nanocarrier based on amphiphilic hyaluronic acid nanoparticles, in which the hydrophobic core was crosslinked by photo-crosslinking and the hyaluronic acid shell was crosslinked via a bioreducible disulfide linkage. Dynamic light scattering showed that the shell and core crosslinked nanocarriers were obviously more stable than core crosslinked or non-crosslinked nanoparticles. Moreover, the particle size changed as the glutathione concentration was altered, exhibiting obvious redox sensitivity. Transmission electron microscopy showed that the nanoparticle structure was denser after crosslinking. Additionally, methotrexate was effectively encapsulated into nanoparticles with high drug-loading efficiency. In vitro methotrexate release assays showed that the methotrexate-loaded bioreducible hyaluronic acid nanoparticles greatly suppressed drug release in phosphate-buffered saline (pH 7.4) without or with 20 μM glutathione. In contrast, in phosphate-buffered saline (pH 7.4) with higher glutathione concentrations (2, 5, or 10 mM), methotrexate was released more rapidly and completely from the nanocarriers in 24 h. Furthermore, methotrexate was released completely and rapidly from the nanoparticles under simulated tumor cell conditions (pH 5.0 with 10 mM glutathione), suggesting potential applications in tumor-specific drug release. In vitro anticancer activity tests showed that the inhibition rate of methotrexate-loaded nanoparticles in HeLa cells reached 94%. However, excess hyaluronic acid decreased cell toxicity. Cellular uptake studies suggested that the prepared nanoparticles were probably internalized into the cancer cells via receptor-mediated endocytosis. Overall, our data demonstrated that the bio-reducible shell and core crosslinked nanoparticles could be used as a potential carrier for cancer therapy.

The clinical application of melphalan (Me), an anticancer drug for the treatment of hematologic malignancies, has been limited due to its poor water solubility, rapid elimination and lack of target specificity. To solve these problems, O,N-carboxymethyl chitosan-peptide-melphalan conjugates were synthesized and characterized. All polymeric prodrugs showed satisfactory water solubility. It was found that the molecular weight of O,N-carboxymethyl chitosan (O,N-CMCS) and the peptide spacer played a crucial role in controlling the drug content, diameter and drug release properties of O,N-carboxymethyl chitosan-peptide-melphalan conjugates. The studies of in vitro drug release and cell cytotoxicity by MTT assay revealed that, employing the polymeric conjugation strategy and using the peptides glycylglycine (Gly-Gly) as a spacer, the conjugates have good cathepsin X-sensitivity and lower toxicity and the drug release behavior improved remarkably. In conclusion, O,N-carboxymethyl chitosan-peptide-melphalan conjugates could be promising prodrugs for anticancer application., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A novel amphiphilic thiolated carboxymethyl chitosan was synthesized. It self-assembled into disulfide bond cross-linked nanoparticles in deionized water. The TEM showed that these nanoparticles had a core-shell structure with an average diameter of 160 nm. Dynamic light scattering showed that the nanoparticles were stable in water solution. The particle size changed with pH values and GSH concentrations, and reached a maximum diameter at pH 7.0 and 20mM GSH respectively, exhibiting an obvious pH/redox responsibility. Methotrexate was encapsulated in nanoparticles reaching encapsulation efficiency as much as 43.4%. Release profiles of methotrexate showed a release rate of 19 wt% in pH 7.4 buffer containing 10 μM GSH, whereas as high as 93 wt% in pH 5.0 buffer containing 20mM GSH, indicating that the nanoparticles may be used for tumor-specific drug release. The anticancer activity test in vitro showed that the inhibition rate of methotrexate-loaded nanoparticles against HeLa cells reached 90%., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Nanoscale metal–organic framework (nMOF) based nano drug delivery systems show great potential in the biomedical field. In this work, a drug delivery system combined with chemotherapy and phototherapy (DOX/ICG@UiO-66-TK-PEG-F3 or simplified as DI@UiO-TPF3) was designed for the targeted therapy of tumors. The chemotherapeutic drug doxorubicin (DOX) and the photothermal therapeutic agent indocyanine green (ICG) were loaded onto the pH-sensitive UiO-66-NH2 carrier core by physical adsorption, and the surface of UiO-66-NH2 was modified by the multifunctional polymer TK-PEG-F3 to improve the stability and targeting of the drug-loaded core. Characterizations show that the drug delivery system DI@UiO-TPF3 was successfully prepared with an excellent drug loading rate (21.6%) and photothermal conversion efficiency (32.92%). DI@UiO-TPF3 not only shows the ability to stimulate a response to release drugs, but also achieves the synergistic anti-tumor effects of chemotherapy and photothermal/photodynamic therapy (PTT/PDT), which was confirmed by in vitro evaluation. In addition, cell experiments have confirmed that DI@UiO-TPF3 connected with F3 peptide can selectively bind to the nucleolin overexpressed on the surface of tumor cells and reduce the toxicity to normal cells. Therefore, DI@UiO-UTPF3 provided a feasible strategy for constructing a targeted drug delivery platform integrating chemotherapy and phototherapy. [ABSTRACT FROM AUTHOR]

Osteomyelitis is a bone infection disease which is caused by bacteria or other germs, and could cause serious impact on the health and working capacity of the patients. Alendronate (ALN) can chelate strongly with the calcium ion of hydroxyapatite (HA) which is commonly used to treat osteoporosis. Nanomedicine has attracted a lot of attention in that the nano-sized carrier can deliver drug molecules to specific site of interest with the aid of targeting moiety and achieve sustained release, resulting in improved therapeutic effect and reduced side effect. In this study, micelles self-assembled from poly(lactic acid-co-glycolic acid)-block-poly(ethylene glycol)-alendronate (PLGA-PEG-ALN) copolymer were prepared for bone-targeted delivery of vancomycin (Van). The chemical structure of PLGA-PEG-ALN was confirmed by proton nuclear magnetic resonance (1H-NMR) spectroscopy. The formation of the nanoparticles was characterized by dynamic light scattering, transmission electronic microscopy as well as the critical micelle concentration measurement. Release profiles from the micelles revealed that the conjugation of ALN to the surface of micelle did not pose adverse effect on the drug-loading capacity and release behaviors. The cytotoxicity of Van-loaded PLGA-PEG-ALN micelles as well as the blank micelles was evaluated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay toward rat bone marrow stromal cells (rBMSCs) and human embryonic hepatocytes (L02 cells), and results showed that this Van-loaded micelle possesses appropriate cytotoxicity and is safe in the potential treatment of osteomyelitis. Thein vitroaffinity of PLGA-PEG-ALN micelles to the HA was also confirmedin vitro. The antibacterial effect of Van-loaded PLGA-PEG-ALN micelles was tested againstStaphylococcus aureus(SA) which is the main pathogenic bacteria in osteomyelitis, and the results showed that the Van-loaded micelles can effectively inhibit the growth of SA. These results demonstrated that the PLGA-PEG-ALN micelles may be potentially used for the bone targeted delivery of Van. [ABSTRACT FROM PUBLISHER]

For enhanced intracellular accumulation of 6-mercaptopurine (6-MP) in leukemia, a folate receptor-targeted and glutathione (GSH)-responsive polymeric prodrug nanoparticle was made. The nanoparticles were prepared by conjugating 6-MP to carboxymethyl chitosan via a GSH-sensitive carbonyl vinyl sulfide linkage, ultrasonic self-assembly and surface decoration with folate. The TEM graphs shows that the as-synthesized nanoparticles are spherical with a particle size of 170~220 nm. In vitro drug release of nanoparticles demonstrated acceptable stability in PBS containing 20 μM GSH at pH 7.4. However, the cumulative drug release rate of the samples containing 20 mM and 10 mM GSH medium reached 78.9% and 64.8%, respectively, in pH 5.0 at 20 h. This indicated that this nano-sized system is highly sensitive to GSH. The inhibition ratio of folate-modified nanoparticles compared to unmodified nanoparticles was higher in cancer cells (human promyelocytic leukemia cells, HL-60) while their cytotoxicity was lower in normal cells (mouse fibroblast cell lines, L929). Furthermore, in vitro cancer cell incubation studies confirmed that folate-modified nanoparticles therapeutics were significantly more effective than unmodified nanoparticles therapeutics. Our results suggest that folate receptor-targeting and GSH-stimulation can significantly elevate tumour intracellular drug release. Therefore, folate-modified nanoparticles containing chemoradiotherapy is a potential treatment for leukemia therapy. [ABSTRACT FROM AUTHOR]

Abstract: The liver targeting and controlled release nanoparticles based on carboxymethyl chitosan derivatives were prepared: firstly, novel thiolated lactosaminated carboxymethyl chitosan (LAC-CMC) was synthesized, its chemical structure was characterized by 1H NMR spectroscopy. Then, glycyrrhizic acid was chosen as model drug and encapsulated within thiolated LAC-CMC nanoparticles through ionic gelification. The crosslinked glycyrrhizic acid-loaded nanoparticles dissociated to release drug in the presence of glutathione (GSH) at a concentration comparable to the intracellular environment, featuring the potential ability of this system for intracellular delivery. Crosslinked nanoparticles modify the tissue distribution profile of the glycyrrhizic acid solution, the kidney excretion rate is reduced and the drug accumulation in the liver is increased. According to these results, the nanoparticles have the potential to be used as drug delivery system with hepatic targeting and controlled release properties. [Copyright &y& Elsevier]

Abstract: A series of 6-mercaptopurine-carboxymethyl chitosans (6-MP-CMC) were prepared and structurally characterized. Their in vitro drug release behaviors in the buffer solutions containing glutathione (GSH) were investigated. 6-MP-CMC did not release any 6-MP in the media without GSH and containing 2μM GSH. By comparison, the obvious 6-MP release could be observed within an hour in the media containing 2mM and 10mM GSH. And the maximum cumulative release rates were 65.1% and 74.4%, respectively. The buffer pH and the 6-MP content in 6-MP-CMC had obvious influences on the 6-MP release. At 10mM GSH, the maximum cumulative release rate at pH 5 was higher than that at pH 7.4. 6-MP-CMC in pH 7.4 PBS could self-assemble into nanoparticles. Their mean hydrodynamic diameter determined by dynamic light scattering (DLS) was 155.8±6.0nm. The particles observed by transmission electron microscopy (TEM) were spherical in shape and had the size of about 100nm. [ABSTRACT FROM AUTHOR]

• A novel esterification strategy was used to prepare Melphalan-based polymer prodrugs. • The prodrug based nanosystem could effectively inhibit the hydrolysis of Melphalan. • The nanosystem showed long-circulation and pH/enzyme-triggerd drug release behavior. • The inhibition effect of the system on 4T1 tumor cells was significantly enhanced. • The nanosystem is a promising drug delivery system for cancer therapy. To improve hydrolytic stability and biological half-life and anticancer efficacy of the anti-cancer drug melphalan (Mel), a novel esterification strategy was developed to fabricate a pH/enzyme dual-responsive polymer prodrug (mPEG-Mel) via the formation of an ion bond between the carboxyl group in Mel and diazotized p-aminobenzoate-terminated poly(ethylene glycol) monomethyl ether (mPEG-N 2 +) followed by light-induced conversion of the ionic bond to an ester bond. The prodrug could self-assemble into nanoparticles. Under physiological conditions (pH 7.4), the nanoparticles exhibited a regular core-shell structure with about 100 nm, which could effectively inhibit the hydrolysis of pharmacophores in Mel structure and showed the long-circulation ability. While pH dropped to 5.0, an obvious increase in the nanoparticle size was observed and enhanced by different concentrations of cathepsin B (CTB), reaching a diameter of 675 nm or more in the presence of 2.0 µg/mL CTB. The nanoparticles showed minimal drug release at pH 7.4 (less than 10% in 24 h); however, drug release could be significantly accelerated in a CTB-containing medium at pH 5.0. Cell experiments showed that the half-inhibitory concentration (IC50) of nanoparticles was 1.00 µg/mL, which was about 5 times lower than that of free Mel (5.00 µg/mL), and indicating that the nanoparticles were more cytotoxic to cancer cells (4T1 cells). However, significantly reduced cytostatic effects were observed for normal cells (3T3 cells). In addition, cell uptake observation further supported the above experimental results, a stronger red fluorescence in 4T1 cells was observed for NR-loaded nanoparticles, which meant that the nanoparticles could release drug in response to pH/enzyme stimulation. Thus, mPEG-Mel based pH/enzyme double-response polymer prodrug nanoparticles could effectively enhance drug stability and anticancer efficacy. [ABSTRACT FROM AUTHOR]

(A) Synthesis schematics of Carboxymethylchitosan-10-Hydroxycamptothecin polymer prodrug and (B) processes of its self-assembly and pH/enzyme dual stimuli-response release of drug. • Amphiphilic 10-hydroxycamptothecin-conjugated carboxymethylchitosan polymer prodrug was synthesized. • The nanosystem based on the polymeric prodrug showed pH/enzyme dual response. • The system showed very little drug release at pH 7.4 without or with 0.2 μM papain. • An accelerated release was observed at pH 5.0 with 2 μM papain (simulating tumor intracellular media). • The system showed the potential in the improvement of drug stability and cancer therapy. For enhanced stability and anticancer efficacy, the 10-Hydroxycamptothecin (10-HCPT) structure based pH/enzyme responsive polymeric prodrug nanoparticles were constructed by conjugating 10-HCPT to carboxymethylchitosan (CMCS) via pH/enzyme sensitive succinyl linkage followed by ultrasonic dispersion. At pH 7.4 the nanoparticles exhibited a core–shell structure and good in vitro stability with very little drug release. However, upon exposure to pH 5.0, the nanoparticles showed nanogel-like morphology, accompanied by a cumulative drug release rate of up to 71.4% in 60 h in the presence of 2 μM papain, which was nearly two times as much as that in the case of 0.2 μM papain, indicating that enzyme and pH dual-stimulation can significantly elevate tumor cell-selective drug release. In comparison with IC 50 of free 10-HCPT, HCPT-g-CMCS nanoparticles exhibited about 4.5 times increase in cytotoxicity on 4T1 cancer cells, while an obviously reduced cell inhibition was observed for healthy liver cell line L-O2. Furthermore, in vitro cell studies confirmed the enhanced intracellular drug release of the system in the 4T1 cancer cells. Hence, the pH/enzyme-sensitive prodrug nanoparticles based on HCPT-g-CMCS may be a promising nano-drug delivery system for cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract: Galactose group was coupled with carboxymethyl chitosan for liver specificity. The chemical structure of lactosaminated carboxymethyl chitosan (LAC-CMC) was characterized by FT-IR and 1H NMR techniques. Glycyrrhizic acid was chosen as model drug and encapsulated within LAC-CMC nanoparticles through ionic gelification. Transmission electron microscope (TEM) and dynamic light scattering (DLS) were employed to characterize the nanoparticles for morphology and size. The effects, including LAC-CMC molecular weight (MW), glycyrrhizic acid concentration and LAC-CMC concentration on the physicochemical properties of the nanoparticles were studied. Glycyrrhizic acid release from the nanoparticles exhibited a biphasic pattern, initial burst release and consequently sustained release. Glycyrrhizic acid-loaded nanoparticles modify the tissue distribution profile of the glycyrrhizic acid solution, the kidney excretion rate is reduced and drug accumulation in the liver is increased. The experimental results show that the novel lactosaminated carboxymethyl chitosan nanoparticles may be used as a potential drug delivery system with hepatic targeting properties. [Copyright &y& Elsevier]