Poly(ethylene imine)–poly(l-lysine)–poly(l-glutamic acid) (PKE) polymers
with various glutamic acid portions
were synthesized by ring opening polymerization of l-lysine N-carboxyanhydride (NCA) and l-glutamic acid NCA
from poly(ethylene imine) 1.8 kDa (PEI1.8k) as a macroinitiator.
It was found that their glutamic acid residues could buffer endosomal
pH. PK5E9 polymer could form nanoparticles by
self-assembly and nanosized polyplexes, possessing pH-responsive charge-conversion
properties. PK5E9 or its polyplex nanoparticles
showed polyhedral structures with bumpy surfaces. Its cytotoxicity
was marginal at both pH 7.4 and 6.0, and its transfection efficiency
was highly increased at pH 6.0. The improved transfection efficiency
in acidic conditions was thought to be induced by elevated cellular
uptake of the polyplexes via charge-conversion from negative to positive
charges. Its transfection was also found to be mediated by endosomal
escape through endosome buffering by bafilomycin A1-treated transfection.
In conclusion, PK5E9 polymer with self-assembly
and endosome buffering ability was found to possess potentials for
efficient gene delivery systems in acidic conditions via charge conversion,
which may be applied for tumor microenvironment-targeting.
Tumor tissue represents a slightly acidic pH condition compared to normal tissue due to the accumulation of lactic acids via anaerobic metabolism. In this work, pH-responsive charge-conversional polymer (poly(ethylene imine)-poly(l-lysine)-poly(l-glutamic acid), PKE polymer) was employed for endowing charge-conversional property and serum stability to poly(ethylene imine) conjugated reduced graphene oxide-based drug delivery system (PEI-rGO). Zeta-potential value of PEI-rGO coated with PK5E7 polymer (PK5E7(PEI-rGO)) was −10.9 mV at pH 7.4 and converted to 29.2 mV at pH 6.0, showing pH-responsive charge-conversional property. Sharp-edged plate morphology of PEI-rGO was transformed to spherical nanostructures with vague edges by PK5E7 coating. Size of PK5E7(PEI-rGO) was found to be smaller than that of PEI-rGO in the serum condition, showing its increased serum stability. Loaded doxorubicin (DOX) in PK5E7(PEI-rGO) could be released rapidly in lysosomal condition (pH 5.0, 5 mM glutathione). Furthermore, DOX-loaded PK5E7(PEI-rGO) showed enhanced anticancer activity in HeLa and A549 cells in the tumor microenvironment-mimicking condition (pH 6.0, serum), which would be mediated by non-specific cellular interaction with decorated serum proteins. These results indicate that the pH-responsive charge-conversional PKE polymer coating strategy of cationic rGO nanostructures possesses a potential for acidic tumor microenvironment-targeted drug delivery systems.
i-motif is cytosine (C)-rich oligonucleotide (ODN) which shows pH-responsive structure change in acidic condition. Therefore, it has been utilized for the trigger of intercalated drug release, responding to environmental pH change. In this study, 2.76 molecules of i-motif binding ODNs (IBOs) were conjugated to each hyaluronic acid (HA) via amide bond linkages. Synthesis of HA-IBO conjugate (HB) was confirmed by FT-IR and agarose gel electrophoresis with Stains-All staining. After hybridization of HB with i-motif ODN (IMO), it was confirmed that doxorubicin (DOX) could be loaded in HB-IMO hybrid structure (HBIM) with 65.6% of drug loading efficiency (DLE) and 25.0% of drug loading content (DLC). At pH 5.5, prompt and significant DOX release from HBIM was observed due to the disruption of HBIM hybrid structure via i-motif formation of IMO, contrary to pH 7.4 condition. Then, HBIM was complexed with low molecular weight polyethylenimine (PEI1.8k), forming positively charged nanostructures (Z-average size: 126.0 ± 0.4 nm, zeta-potential: 16.1 ± 0.3 mV). DOX-loaded HBIM/PEI complexes displayed higher anticancer efficacy than free DOX in A549 cells, showing the potential for pH-responsive anticancer drug delivery systems.
In this study, hydroxyapatite-coated biopolymer nanofibrous membrane was synthesized by mineralizing the electrospun polycaprolactone nanofiber. The effect of the hydroxyapatite-coated nanofibrous membrane was mainly investigated on the proliferation and differentiation of human periodontal ligament fibroblast, which is necessary for periodontal tissue regeneration. Scanning electron microscopy revealed favorable cell attachment and spreading appearance on 1 d and MTS assay showed increased cell proliferation on the hydroxyapatite-coated nanofiber membrane during 14 d. From 7 to 14 d, alkaline phosphatase activity of the hydroxyapatite-coated nanofiber was significantly increased when compared to that of control group. Hydroxyapatite-coated nanofibrous membrane showed prominent mineral formation on day 14. As a result, it was clarified that the developed hydroxyapatite-coated nanofibrous membrane had favorable effects on the proliferation and differentiation of human periodontal ligament fibroblast and might be a good candidate material for periodontal tissue regeneration.
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