Targeted drug release system based on pH-responsive PAA-POSS nanoparticles.
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ABSTRACT:
SUBMITTER: Kim WJ
PROVIDER: S-EPMC9214607 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Self-regulated "smart" insulin administration system that mimic pancreatic endocrine function would be highly desirable for diabetes management. Here, a glucose-responsive continuous insulin delivery system is developed, where novel polyhedral oligosilsesquioxane (POSS) modified with 3-aminophenylboronic acid (APBA) were used to encapsulate insulin (insulin entrapment efficiency: 73.2%) to prepare a fast response, high stability, good distribution, and excellent biocompatible system. Due to the strong hydrophobicity of POSS, the POSS moiety is located at the core in aqueous solution and combines with the boronic group of APBA and the diol generated in PEG-insulin to form a nanomicelle structure, that is, nanoparticles naturally. Micelles self-assembled from these molecules possess glucose-responsiveness at varying glucose concentrations. The interaction of the PBA and diol containing insulin via boronate ester bond and its interchange with glucose was investigated by FT-IR, 1H NMR and XPS. Furthermore, the successful glucose-triggered release of insulin from the POSS-APBA micelles was investigated at neutral pH. A linear graph was plotted with the measured released insulin vs glucose concentrations, with a linear correlation coefficient (R2) value close to 1. Circular dichroism (CD) spectroscopy analysis was performed to measure insulin activity by comparing secondary structures of insulin, PEG-Insulin, and POSS-APBA@insulin. When confirming intracellular apoptosis signaling, cleaved caspase 3 and caspase 9 were not increased by 640 μg/ml POSS-APBA and POSS-APBA@insulin in HeLa, HDF and HUVE cells. Application in the biomedical field for controlled delivery of insulin appear to be promising.
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Project description:A responsive drug delivery system (DDS) for oxaliplatin (OX) has been designed with a view to overcoming several drawbacks associated with this anticancer agent, including fast degradation/deactivation in the blood stream, lack of tumor selectivity, and low bioavailability. The present approach is based on the direct host-guest encapsulation of OX by a pH-responsive receptor, carboxylatopillar[6]arene (CP6A). The binding affinities of CP6A for OX were found to be pH-sensitive at biologically relevant pH. For example, the association constant (Ka) at pH 7.4 [Ka = (1.02 ± 0.05) × 104 M-1] is 24 times larger than that at pH 5.4 [Ka = (4.21 ± 0.06) × 102 M-1]. Encapsulation of OX within the CP6A cavity did not affect its in vitro cytotoxicity as inferred from comparison studies carried out in several cancer cells (e.g., the HepG-2, MCF-7, and A549 cell lines). On the other hand, complexation by CP6A serves to increase the inherent stability of OX in plasma by 2.8-fold over a 24 h incubation period. The formation of a CP6A?OX host-guest complex served to enhance in a statistically significant way the ability of OX to inhibit the regrowth of sarcoma 180 (S180) tumors in Kunming (KM) mice xenografts. The improved anticancer activity observed in vivo for CP6A?OX is attributed to the combined effects of enhanced stability of the host-guest complex and the pH-responsive release of OX. Specifically, it is proposed that OX is protected as the result of complex formation and then released effectively in the acidic tumor environment.
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Project description:A novel two-step in situ method for targeted antitumor drug release by supramolecular assembly (Fc-CPT@HACD) was constructed using camptothecin prodrug (Fc-CPT) and β-cyclodextrin (β-CD)-modified hyaluronic acid (HACD). Benefiting from the overexpressed H2O2 and glutathione (GSH) in tumor cells, Fc-CPT@HACD can be disassembled by oxidation of ferrocene (Fc) to Fc+, leading to an efficient release of the anticancer drug camptothecin (CPT) to induce tumor cell apoptosis without affecting normal cells. The in vivo experiment results also demonstrated that Fc-CPT@HACD possessed higher anticancer efficiency than free CPT, accompanied by negligible side effects.
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Project description:Background:Stimuli-responsive gold nano-assemblies have attracted attention as drug delivery systems in the biomedical field. However, there are challenges achieving targeted delivery and controllable drug release for specific diseases. Materials and Methods:In this study, a glutathione (GSH)-modified fluorescent gold nanoparticle termed AuLA-GSH was prepared and a Co2+-induced self-assembly drug delivery platform termed AuLA-GSH-Co was constructed. Both the pH-responsive character and drug loading behavior of AuLA-GSH-Co were studied in vitro. Kidney-targeting capability was investigated in vitro and in vivo. Finally, the anti-fibrosis efficiency of AuLA-GSH-Co in a mouse model of unilateral ureteral obstruction (UUO) was explored. Results:AuLA-GSH-Co was sensitive to pH changes and released Co2+ in acidic conditions, allowing it to have controllable drug release abilities. AuLA-GSH-Co was found to improve cellular uptake of Co2+ ions compared to CoCl2 in vitro. AuLA-GSH exhibited specific renal targeting and prolonged renal retention time with low non-specific accumulation in vivo. Moreover, the anti-fibrosis efficiency of AuLA-GSH-Co was higher compared to CoCl2 in a mouse model of unilateral ureteral obstruction (UUO). Conclusion:AuLA-GSH-Co could greatly enhance drug delivery efficiency with renal targeting capability and obviously relieve renal fibrosis, providing a promising strategy for renal fibrosis therapy.
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Project description:We present here the development of multifunctional doxorubicin (DOX)-conjugated poly(amidoamine) (PAMAM) dendrimers as a unique platform for pH-responsive drug release and targeted chemotherapy of cancer cells. In this work, we covalently conjugated DOX onto the periphery of partially acetylated and folic acid (FA)-modified generation 5 (G5) PAMAM dendrimers through a pH-sensitive cis-aconityl linkage to form the G5.NHAc-FA-DOX conjugates. The formed dendrimer conjugates were well characterized using different methods. We show that DOX release from the G5.NHAc-FA-DOX conjugates follows an acid-triggered manner with a higher release rate under an acidic pH condition (pH = 5 or 6, close to the acidic pH of tumor microenvironment) than under a physiological pH condition. Both in vitro cytotoxicity evaluation and cell morphological observation demonstrate that the therapeutic activity of dendrimer-DOX conjugates against cancer cells is absolutely related to the DOX drug released. More importantly, the FA conjugation onto the dendrimers allowed a specific targeting to cancer cells overexpressing FA receptors (FAR), and allowed targeted inhibition of cancer cells. The developed G5.NHAc-FA-DOX conjugates may be used as a promising nanodevice for targeted cancer chemotherapy.
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Project description:Silk has traditionally been used as a suture material because of its excellent mechanical properties and biocompatibility. These properties have led to the development of different silk-based material formats for tissue engineering and regenerative medicine. Although there have been a small number of studies about the use of silk particles for drug delivery, none of these studies have assessed the potential of silk to act as a stimulus-responsive anticancer nanomedicine. This report demonstrates that an acetone precipitation of silk allows the formation of uniform silk nanoparticles (98 nm diameter, polydispersity index 0.109), with an overall negative surface charge (-33.6 ± 5.8 mV), in a single step. Silk nanoparticles are readily loaded with doxorubicin (40 ng doxorubicin/?g silk) and show pH-dependent release (pH 4.5? 6.0 > 7.4). In vitro studies with human breast cancer cell lines demonstrates that the silk nanoparticles are not cytotoxic (IC50 > 120 ?g mL(-1) ) and that doxorubicin-loaded silk nanoparticles are able to overcome drug resistance mechanisms. Live cell fluorescence microscopy studies show endocytic uptake and lysosomal accumulation of silk nanoparticles. In summary, the pH-dependent drug release and lysosomal accumulation of silk nanoparticles demonstrate the ability of drug-loaded silk nanoparticles to serve as a lysosomotropic anticancer nanomedicine.
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Project description:Infection-controlled release of antibacterial agents is of great importance, particularly for the control of peri-implant infections in the postoperative phase. Polymers containing antibiotics bound via enzymatically cleavable linkers could provide access to drug release systems that could accomplish this. Dispersions of nanogels were prepared by ionotropic gelation of alginate with poly-l-lysine, which was conjugated with ciprofloxacin as model drug via a copper-free 1,3-dipolar cycloaddition (click reaction). The nanogels are stable in dispersion and form films which are stable in aqueous environments. However, both the nanogels and the layers are degraded in the presence of an enzyme and the ciprofloxacin is released. The efficacy of the released drug against Staphylococcus aureus is negatively affected by the residues of the linker. Both the acyl modification of the amine nitrogen in ciprofloxacin and the sterically very demanding linker group with three annellated rings could be responsible for this. However the basic feasibility of the principle for enzyme-triggered release of drugs was successfully demonstrated.
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