| Due to the capacity of responsiveness to biotic environmental factors (such as temperature, pH, ionic strength, concentration of oxygen, etc.), variously stimuli-sensitive nanomaterials have been widely used in biomedical research, including drug delivery system and fluorescence imaging. As we know from many reports, there are signs appeared to change the tissue microenvironment in some ways once normal tissue lesions. Based on the importance of biotic environment, people focus on disease diagnosis by detecting some suspicious factors of tissue environment, for example, as a ubiquitous biological messenger molecule, hydrogen sulfide (H2S) plays the active roles in the regulation of various physiological processes, abnormal H2S regulation has been associated with an array of diseases such as hypertension, Alzheimer's disease, Down's syndrome and diabetes, thus many fluorescent probe responded to H2S have been developed in the past ten years. On the other hand, considering the difference of some environmental factors between normal and diseased tissue, stimuli-responsive drug delivery systems triggered drug release from nanocarriers by temperature, pH and oxygen triggers, have been investigated to ensure more drug accumulated after reaching a specific site. Many studies with pH microelectrodes have demonstrated lower pH values in tumors relative to normal tissues, and the endosomes into which nanocarriers are incorporated via endocytosis develop markedly acidified lumens (pH 4.5-5.5) primarily through the activity of V-type H+ATPase, thus pH-sensitive nanocarriers become popular drug delivery platform to enhance drug release inside the tumor site and endosomes. We have designed and synthesized a series of stimuli-responsive polymer, and they have been used in preparation of biomaterials for cancer treatment and biological diagnosis, which can be further categorized into four parts as described below.1. A lipid-polymer hybrid drug delivery system was constructed, which can intelligently respond to the tumor microenvironment. In this delivery system, a hydrophobic core of doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) (PLGA) was encased by a pH-sensitive hybrid outer shell composed of lipid and an amphiphilic poly(ethylene glycol) (PEG) derivative, which was triggered to collapse at low pH and release DOX rapidly. As a control, the N=C bond in the pH-sensitive polymerwas desensitized via reduction with sodium borohydride. The in-vitro release experiment showed that the pH-sensitive polymer in the hybrid nanocarriers effectively regulated the release of the loaded DOX at different pH levels. The in-vitro cytotoxicity experiment verified that the DOX-loaded pH-sensitive lipid-polymer hybrid nanoparticles (SLPHNPs) were more effective than the DOX-loaded pH-insensitive lipid-polymer hybrid nanoparticles (ILPHNPs) under the same conditions, because the endosomes or lysosomes acidity led to the rapid release of DOX from SLPHNPs, thus inhibiting tumor cells growth. Furthermore, the endocytosis inhibition experiment also demonstrated that the different intracellular release behaviors between DOX@SLPHNPs and DOX@ILPHNPs may be attributed to the differences in the response to acidic environment of endosomes or lysosomes, but not due to endocytosis.2. The pH-sensitive lipid-polymer hybrid nanoparticles (LPHNPs) were prepared by self-assembly through a modified nanoprecipitation method in this study. LPHNPs were composed of (1) a PLGA hydrophobic core, (2) a soybean lecithin monolayer, and (3) an amphiphilic pH-sensitive polymer mPEG-N=C-DOX. The LPHNPs were prepared and evaluated for anticancer drug delivery. The PEG shell of pH-sensitive LPHNPs could be shed triggered by low pH, which resulted in aggregation of the nanoparticles and the rapid release of DOX. Cell experiments showed that LPHNPs displaying higher cytotoxicity after acid PBS treated. Once internalized in the cells, pH-sensitive LPHNPs efficiently delivered DOX to the cell nuclei. LPHNPs combine the merits of polymer prodrug and liposomes, demonstrating the potential of pH-sensitive LPHNPs for the effective intracellular delivery of anticancer drugs.3. We developed a drug delivery system by tethering doxorubicin onto the surface of magnetic iron oxide nanoparticles with a poly(ethylene glycol) coating via an acid-labile linkage. Release of DOX from this drug carrier was more obvious at pH 5.0 than that at pH 7.4 or 6.0, and the rate accelerated gradually along with reducing pH value. HeLa cells were employed to investigate the cytotoxicity and cellular uptake of DOX-SPIONs. Due to the magnetic property of SPIONs, designed DOX-SPIONs had both magnetic and acidic sensibility. Through measurement by MTT assay, the MIONPs with/without magnetic field (MF) showed no toxicity to HeLa cells, and compared with DOX-SPIONs without MF, DOX-SPIONs with MF killed the cells more efficiently. The confocal microscopy and flow cytometry studies also showed that the HeLa cells uptake of DOX-SPIONs under MF was significantly higher than the uptake without MF.4. We have designed and synthesized an amphiphilic polymer (AIE-1) with aggregation-induced emission characteristics. The strong green fluorescence of uniformly sized and highly storage stable nano micelles (AIE-M), prepared from AIE-1 by simple ultrasonic treatment of solid AIE-1 in water, buffer, or cell culture medium, can be quickly quenched by Cu2+based on the formation of complexes between Cu2+ and sal en groups in salicyladazine unit of AIE-1. The selective and sensitive fluorescence recovery of AIE-M-Cu with Na2S can be applied in the detection of S2" in solution. Furthermore, fast and sensitive fluorescence imaging of mitochondrial H2S can be realized in HeLa cells by prior cellular uptake of AIE-M-Cu and succedent incubation with Na2S. We anticipate that this new AIE-based micelles, integrating small sizes, high stability, nontoxicity, and mitochondrial accumulation ability, will be valuable for exploring a wide range of biological function of H2S. |
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