| It is the current scientific research hot spot to explore new treatment system on cancer research, change the delivery method of drugs, reduce the toxicity of drugs on normal tissue, delay the body resistance and improve the stability and bioavailability of drugs, etc. Graphene oxide (GO) has caused extensive concern and high attention as a drug carrier used on cancer study. GO has carboxyl, carbonyl, epoxy and hydroxyl groups in the edge and on the plane, so that acylation and esterification reaction with other chemical functional groups could take place. It also allows have strong π-π interactions with the aromatic moieties. Thus it has strong adsorption ability for hydrophilic or hydrophobic drugs to achieve efficient load. Also, hydroxyapatite (HA) used as a kind of drug carrier material, possesses pH sensibility, high absorption and carrying capacity for hydrophilic drugs. In addition, both GO and HA have excellent bioactivity and biocompatibility. The combination of above two kinds of materials for preparing new kinds of multi-stage drug carrier system and exploiting better application in antitumor have not been reported.In this paper, three new types of multi-stage drug carrier system, namely GO@PLA@HA composite microcapsule, GO/AuNRs/HA and GO@mSiO2/HA composite carrier materials, are designed and prepared based on the bioactive GO and HA. Their components, structures and properties also have been investigated. The main achievements can be summarized as follows:1. A new kind of multi-stage drug release system, GO@PLA@HA composite microcapsule, is constructed through double Pickering emulsion. GO and HA are used for stabilizing the water-in-oil (W1/O) and oil-in-water (O/W2) system respectively, in the preparation process. The uniform size, complete structure of GO@PLA@HA composite microcapsules can be obtained, when the volume ratio of W1:O:W2 is 3: 20:100 and the concentration of GO is 0.3 mg/mL, respectively. In this system, GO in the internal water phase (W1) can be used to carry hydrophilic drug (5-fluorouracil), while polylactic acid (PLA) as the capsule wall can be used for effective embedding hydrophobic drug (coumarin) and internal water phase (W1); The pH-sensitive HA in external water phase (W2) could also act as a vector to carry hydrophilic rhodamine B due to the excellent adsorption ability. In addition, the GO@PLA@HA composite microcapsules have good biocompatible, biodegradable and pH sensitive feature, so the drugs loaded in composites could be release by multi-stages and achieve better anti-cancer effect.2. The GO/AuNRs composite material is prepared by a simplemethod in a mild condition, using GO and gold nanorods (AuNRs) as raw material and PVP as the stabilizer, through the electrostatic attraction. Then the GO/AuNRs composite was employed as a template for the biomimetic synthesis of HA to obtain GO/AuNRs/HA composite material. Among them, anticancer drug 5 fluorouracil (5-FU) can be loaded on both GO and HA, coupled with excellent thermal property of AuNRs, Hela cell could be killed effectively through the combined chemotherapy with photothermal therapy. As a first-stage carrier, the pH sensitivity of HA can achieve the purpose in the controlled-release of drug and second-stage carrier, decrease of side effects to normal cell and enhancement of anti-cancer effect.3. The 2D sandwich-like graphene oxide-based mesoporous silica (GO@mSiO2) sheets are constructed, by means of controlled nucleation and growth of mesoporous silica on the surface of GO, through the principle of electrostatic adsorption and using CTAB as the pore-forming agent as well as sacrificial agent. The aggregation of graphene sheets could be reduced greatly owing to the protection of silica. Furthermore, the loading capacity of anti-cancer drug doxorubicin (DOX) hydrochloride in rGO@mSiO2 could be improved because of mesoporous characteristics of silica. After the modification on the surface of rGO@mSiO2 by amino and carboxyl group, the rGO@mSiO2/HA composites can also be obtained by biomimetic synthesis method. Thus the mesoporous of mSiO2 can be encapsulated by HA, which can effectively avoid the initial burst release of DOX, and also reduce the damage to normal cells.. With the aid of high loading of hydrophilic drugs in HA and the pH sensitive characteristics of HA, the drugs loaded on or in rGO@mSiO2/HA composite carrier could be released successively in lesion site for reducing the drug resistance and improving the anti-tumor effect. |
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