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1.
The use of biodegradable polymeric nanoparticles (NPs) for controlled drug delivery has shown significant therapeutic potential. Polyaspartic acid and polylactic acid are the most intensively studied biodegradable polymers. In the present study, novel amphiphilic biodegradable co-polymer NPs, poly(L-aspartic acid-co-lactic acid) with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) (poly(AA-co-LA)/DPPE) is synthesized and subsequently used to encapsulate an antitumor drug doxorubicin (DOX). The formulation parameters of the NPs are optimized to improve encapsulation efficiency. The resulting drug-loaded NPs possess better size homogeneity (polydispersity) and exhibit pH-responsive drug release profiles. Cellular viability assays indicate that the poly(AA-co-LA)/DPPE NPs did not induce cell death, whereas doxorubicin encapsulated NPs were cytotoxic to various types of tumor cells. In addition, the free NPs could not enter the cell nuclei after internalized in tumor cells. The DOX-loaded NPs exhibit efficient intracellular delivery in tumor cells with co-localization in lysosome and delay entering into the nucleus, which suggests a time- and pH-dependent drug release profile within cells. When applied to deliver chemotherapeutics to a mouse xenograft model of human lung adenocarcinoma, DOX-loaded NPs have a comparable antitumor activity with free DOX, and greatly reduce systemic toxicity and mortality. The delivery of cytotoxic drugs directly to the nucleus specifically within tumor cells is of great interest. These results demonstrate the feasibility of the application of the amphiphilic polyaspartic acid derivative, poly(AA-co-LA)/DPPE, as a nanocarrier for cell nuclear delivery of potent antitumor drugs.  相似文献   

2.
Two polymers chitosan and poly(lactide-co-glycolide) copolymer (PLGA) were investigated to develop nanoparticles (NPs) for delivery of protein drug substance into tumour cells. Cystatin was selected as a model protein drug due to its high potential to inhibit cysteine proteases, known to trigger the invasive process. Ionotropic gelation of chitosan with tripolyposphate and precipitation of PLGA polymer from a double emulsion system by a solvent diffusion process were used to produce 250-300 nm in diameter NPs. The cellular uptake of NPs was tested on a transformed human breast epithelial cell line, MCF-10A neoT, characterized by an increased expression of cysteine proteases and highly invasive cell phenotype. The influence of NPs on cell viability was evaluated by MTT test showing IC50 400 microg/ml for PLGA and 5 mg/ml for chitosan NPs. As determined by fluorescence microscopy chitosan NPs did not enter the cells during 1-hour incubation whereas the same amount of PLGA NPs were in the cells already after 5 min of incubation. Cystatin delivered into MCF-10A neoT cells by PLGA NPs effectively inhibited intracellular proteolytic activity of cathepsin B, as detected by specific fluorogenic substrate Z-Arg2 cresyl violet. On the contrary, free cystatin in solution did not internalise into the cells and inhibit cathepsin B. To conclude, PLGA NPs with cystatin but not chitosan NPs were targeted through endocytosis to the lysosomal compartments that are rich of proteases enzymes. Our results suggest new strategy to inactivate intracellular tumour-associated proteases, and consequently the invasion behaviour of tumour cells, which could contribute to cancer therapy.  相似文献   

3.
Many therapeutic drugs are excluded from entering the brain due to their lack of transport through the blood–brain barrier (BBB). The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous diseases. To overcome this problem, a viral fusion peptide (gH625) derived from the glycoprotein gH of Herpes simplex virus type 1 is developed, which possesses several advantages including high cell translocation potency, absence of toxicity of the peptide itself, and the feasibility as an efficient carrier for delivering therapeutics. Therefore, it is hypothesized that brain delivery of nanoparticles conjugated with gH625 should be efficiently enhanced. The surface of fluorescent aminated polystyrene nanoparticles (NPs) is functionalized with gH625 via a covalent binding procedure, and the NP uptake mechanism and permeation across in vitro BBB models are studied. At early incubation times, the uptake of NPs with gH625 by brain endothelial cells is greater than that of the NPs without the peptide, and their intracellular motion is mainly characterized by a random walk behavior. Most importantly, gH625 peptide decreases NP intracellular accumulation as large aggregates and enhances the NP BBB crossing. In summary, these results establish that surface functionalization with gH625 may change NP fate by providing a good strategy for the design of promising carriers to deliver drugs across the BBB for the treatment of brain diseases.  相似文献   

4.
Nanoparticles (NPs) are versatile scaffolds for numerous biomedical applications including drug delivery and bioimaging. The surface functionality of NPs essentially dictates intracellular NP uptake and controls their therapeutic action. Using several pharmacological inhibitors, it is demonstrated that the cellular uptake mechanisms of cationic gold NPs in both cancer (HeLa) and normal cells (MCF10A) strongly depend on the NP surface monolayer, and mostly involve caveolae and dynamin‐dependent pathways as well as specific cell surface receptors (scavenger receptors). Moreover, these NPs show different uptake mechanisms in cancer and normal cells, providing an opportunity to develop NPs with improved selectivity for delivery applications.  相似文献   

5.
Nanoparticle technology for drug delivery across the blood-brain barrier   总被引:20,自引:0,他引:20  
Nanoparticles (NP) are solid colloidal particles ranging in size from 1 to 1000 nm that are utilized as drug delivery agents. The use of NPs to deliver drugs to the brain across the blood-brain barrier (BBB) may provide a significant advantage to current strategies. The primary advantage of NP carrier technology is that NPs mask the blood-brain barrier limiting characteristics of the therapeutic drug molecule. Furthermore, this system may slow drug release in the brain, decreasing peripheral toxicity. This review evaluates previous strategies of brain drug delivery, discusses NP transport across the BBB, and describes primary methods of NP preparation and characterization. Further, influencing manufacturing factors (type of polymers and surfactants, NP size, and the drug molecule) are detailed in relation to movement of the drug delivery agent across the BBB. Currently, reports evaluating NPs for brain delivery have studied anesthetic and chemotherapeutic agents. These studies are reviewed for efficacy and mechanisms of transport. Physiological factors such as phagocytic activity of the reticuloendothelial system and protein opsonization may limit the amount of brain delivered drug and methods to avoid these issues are also discussed. NP technology appears to have significant promise in delivering therapeutic molecules across the BBB.  相似文献   

6.
In drug delivery systems, pH‐sensitive polymers are commonly used as drug carriers, and significant efforts have been devoted to the aspects of controlled delivery and release of drugs. However, few studies address the possible autophagic effects on cells. Here, for the first time, using a fluorescent autophagy‐reporting cell line, this study evaluates the autophagy‐induced capabilities of four types of pH‐sensitive polymeric nanoparticles (NPs) with different physical properties, including size, surface modification, and pH‐sensitivity. Based on experimental results, this study concludes that pH‐sensitivity is one of the most important factors in autophagy induction. In addition, this study finds that variation of concentration of NPs could cause different autophagic effect, i.e., low concentration of NPs induces autophagy in an mTOR‐dependent manner, but high dose of NPs leads to autophagic cell death. Identification of this tunable autophagic effect offers a novel strategy for enhancing therapeutic effect in cancer therapy through modulation of autophagy.  相似文献   

7.
To further increase the therapeutic activity of drugs known to act on intracellular target sites, in vivo drug delivery approaches must actively mediate the specific delivery of drug molecules to the subcellular site of action. We show here that surface modification of nanocarriers with mitochondriotropic triphenylphosphonium cations facilitates the efficient subcellular delivery of a model drug to mitochondria of mammalian cells and improves its activity in vitro and in vivo.  相似文献   

8.
The last decade has seen remarkable advances in the development of drug delivery systems as alternative to parenteral injection‐based delivery of insulin. Neonatal Fc receptor (FcRn)‐mediated transcytosis has been recently proposed as a strategy to increase the transport of drugs across the intestinal epithelium. FcRn‐targeted nanoparticles (NPs) could hijack the FcRn transcytotic pathway and cross the epithelial cell layer. In this study, a novel nanoparticulate system for insulin delivery based on porous silicon NPs is proposed. After surface conjugation with albumin and loading with insulin, the NPs are encapsulated into a pH‐responsive polymeric particle by nanoprecipitation. The developed NP formulation shows controlled size and homogeneous size distribution. Transmission electron microscopy (TEM) images show successful encapsulation of the NPs into pH‐sensitive polymeric particles. No insulin release is detected at acidic conditions, but a controlled release profile is observed at intestinal pH. Toxicity studies show high compatibility of the NPs with intestinal cells. In vitro insulin permeation across the intestinal epithelium shows approximately fivefold increase when insulin is loaded into FcRn‐targeted NPs. Overall, these FcRn‐targeted NPs offer a toolbox in the development of targeted therapies for oral delivery of insulin.  相似文献   

9.
10.
Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell‐mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer‐specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP‐PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti‐BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP‐PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP‐PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell–cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The “self‐powered” immune cell‐mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.  相似文献   

11.
Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA‐NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active‐targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self‐amplified drug release for effective drug delivery. The RLPA‐NPs are constructed by encapsulation of a pH‐sensitive polymer octadecylamine‐poly(aspartate‐1‐(3‐aminopropyl) imidazole) (OA‐P(Asp‐API)) and a ROS‐generation agent, β‐Lapachone (Lap), in micelles assembled by the tumor‐penetration peptide internalizing RGD (iRGD)‐modified ROS‐responsive paclitaxel (PTX)‐prodrug. iRGD could promote RLPA‐NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor‐mediated endocytosis, OA‐P(Asp‐API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA‐NPs escape from the endosome through the “proton sponge effect”. At the same time, the RLPA‐NPs micelle disassembles, releasing Lap and PTX‐prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA‐NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA‐NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.  相似文献   

12.
Small interfering RNA (siRNA) is an attractive therapeutic candidate for sequencespecific gene silencing to treat incurable diseases using small molecule drugs.However,its efficient intracellular delivery has remained a challenge.Here,we have developed a highly biocompatible fluorescent carbon dot (CD),and demonstrate a functional siRNA delivery system that induces efficient gene knockdown in vitro and in vivo.We found that CD nanoparticles (NPs) enhance the cellular uptake of siRNA,via endocytosis in tumor cells,with low cytotoxicity and unexpected immune responses.Real-time study of fluorescence imaging in live cells shows that CD NPs favorably localize in cytoplasm and successfully release siRNA within 12 h.Moreover,we demonstrate that CD NP-mediated siRNA delivery significantly silences green fluorescence protein (GFP) expression and inhibits tumor growth in a breast cancer cell xenograft mouse model of tumor-specific therapy.We have developed a multi functional siRNA delivery vehicle enabling simultaneous bioimaging and efficient downregulation of gene expression,that shows excellent potential for gene therapy.  相似文献   

13.
The preferred delivery systems for anticancer drugs would be the one which would have selective and effective destruction of cancer cells. In the present study etoposide (ETO) loaded nanoparticles (NP) were prepared using PLGA (ETO-PLGA NP), PLGA-MPEG block copolymer (ETO-PLGA-MPEG NP) and PLGA-Pluronic copolymer (ETO-PLGA-PLU NP) and they were evaluated for cytotoxicity and cellular uptake studies using two cancer cell lines, L1210 and DU145. The IC50 values for L1210 cells were 18.0, 6.2, 4.8 and 5.4 microM and for DU145 cells the IC50 values were 98.4, 75.1, 60.1 and 71.3 microM for ETO, ETO-PLGA NP, ETO-PLGA-MPEG NP and ETO-PLGA-PLU NP respectively. The increased cytotoxicities were attributed to increased uptake of the NPs by the cells. Moreover the ETO loaded PLGA-MPEG NP and PLGA-Pluronic NP showed a sustained cytotoxic effect till 5 days on both the cell lines. Results of the long term cytotoxicity study concluded that the drug loaded PLGA nanoparticulate formulations were efficient in decreasing the viability of the L1210 cells over a period of three days, whereas the pure drug exerted its maximum efficiency on the day one itself. Z-stack confocal images of NPs showed fluorescence activity in each section of DU 145 and L1210 cells indicating that the nanoparticles were internalized by the cells. The study concluded that ETO loaded PLGA NPs had higher cytotoxicity compared with that of the free drug and ETO-PLGA-MPEG NP and ETO-PLGA-PLU NP had higher cell uptake efficiency compared with that of ETO-PLGA NP. The developed PLGA based NPs shows promise to be used for cancer therapy.  相似文献   

14.
A nanocarrier system of d ‐a‐tocopheryl polyethylene glycol 1000 succinate (TPGS)‐functionalized polydopamine‐coated mesoporous silica nanoparticles (NPs) is developed for sustainable and pH‐responsive delivery of doxorubicin (DOX) as a model drug for the treatment of drug‐resistant nonsmall cell lung cancer. Such nanoparticles are of desired particle size, drug loading, and drug release profile. The surface morphology, surface charge, and surface chemical properties are also successfully characterized by a series of techniques such as transmission electron microscopy (TEM), X‐ray photoelectron spectroscopy (XPS), Brunauer‐Emmett‐Teller (BET) method, thermal gravimetric analysis (TGA), dynamic light scattering (DLS), and Fourier transform infrared spectroscopy (FTIR). The normal A549 cells and drug‐resistant A549 cells are employed to access the cytotoxicity and cellular uptake of the NPs. The therapeutic effects of TPGS‐conjugated nanoparticles are evaluated in vitro and in vivo. Compared with free DOX and DOX‐loaded NPs without TPGS ligand modification, MSNs‐DOX@PDA‐TPGS exhibits outstanding capacity to overcome multidrug resistance and shows better in vivo therapeutic efficacy. This splendid drug delivery platform can also be sued to deliver other hydrophilic and hydrophobic drugs.  相似文献   

15.
Cell membrane coating has recently emerged as a promising biomimetic approach to engineering nanoparticles (NPs) for targeted drug delivery. However, simple cell membrane coating may not meet the need for efficient drug delivery to the brain. Here, a novel molecular engineering strategy to modify the surface of NPs with a cell membrane coating for enhanced brain penetration is reported. By using poly(lactic‐co‐glycolic) acid NPs as a model, it is shown that delivery of NPs to the ischemic brain is enhanced through surface coating with the membrane of neural stem cells (NSCs), and the delivery efficiency can be further increased using membrane isolated from NSCs engineered for overexpression of CXCR4. It is found that this enhancement is mediated by the chemotactic interaction of CXCR4 with SDF‐1, which is enriched in the ischemic microenvironment. It is demonstrated that the resulting CXCR4‐overexpressing membrane‐coated NPs, termed CMNPs, significantly augment the efficacy of glyburide, an anti‐edema agent, for stroke treatment. The study suggests a new approach to improving drug delivery to the ischemic brain and establishes a novel formulation of glyburide that can be potentially translated into clinical applications to improve management of human patients with stroke.  相似文献   

16.
Picroliv, a mixture of picroside I and kutkoside isolated from rhizome of Picrorrhiza kurroa has been reported for many pharmaceutical properties such as hepatoprotective, anticholestatic, antioxidant and immune‐modulating activity. However, picroliv possessed lesser efficacy due to its poor aqueous solubility and lesser bioavailability. To find solution, picroliv was loaded into biodegradable poly lactic acid nanoparticles (PLA NPs) using solvent evaporation method. The picroliv‐loaded PLA NPs were characterised by UV–vis spectroscopy, atomic force microscopy, transmission electron microscopy, Fourier transform infrared and Zeta sizer. The size of picroliv‐loaded PLA NPs was 182 ± 20 nm. Zeta potential of picroliv‐loaded PLA NPs was −23.5 mV, indicated their good stability. In vitro picroliv release from picroliv‐loaded PLA NPs showed an initial burst release followed by slow and sustained release. The efficacy of picroliv‐loaded PLA NPs was assessed against KB cell lines. Blank PLA NPs showed no cytotoxicity on KB cells. The picroliv‐loaded PLA NPs showed more cytotoxic activity on KB cells as compared to the pure drug. Hence, the developed picroliv nanoformulation would find potential application in pharma‐sector.Inspec keywords: drugs, nanomedicine, nanofabrication, biodegradable materials, nanoparticles, biomedical materials, evaporation, ultraviolet spectra, visible spectra, atomic force microscopy, transmission electron microscopy, Fourier transform infrared spectra, electrokinetic effects, drug delivery systems, cellular biophysics, toxicologyOther keywords: nanoformulation development, Picrorrhiza kurroa, picroside I‐kutkoside mixture, rhizome, pharmaceutical properties, hepatoprotective activity, anticholestatic activity, antioxidant activity, immune‐modulating activity, aqueous solubility, bioavailability, biodegradable poly lactic acid nanoparticles, solvent evaporation method, picroliv‐loaded PLA NPs, UV‐visible spectroscopy, atomic force microscopy, transmission electron microscopy, Fourier transform infrared spectra, zeta‐sizer, in vitro picroliv release, KB cell lines, initial burst release, cytotoxic activity, picroliv nanoformulation, pharma‐sector  相似文献   

17.
The aim of this study was to explore the possibility of obtaining nanoparticles (NPs) containing high amounts of cyclodextrin (CD) derivatives such as carboxymethyl-β-CD and sulphobutyl ether-β-CD. The rationale used was to combine the drug solubilizing and stabilizing properties of cyclodextrins (CDs) with the mucoadhesive properties of chitosan (CS) in a unique nanoparticulate drug delivery system. The size of the resulting NPs was affected by the nature of the CDs, ranging between 275 and 550?nm, whereas the zeta potential of the NPs was always positive and close to +35?mV. The positive zeta values, together with the results from NMR studies, suggest that CS is the major compound on the surface of the NPs, while CD molecules are strongly associated with the NP matrix. The empirical composition of the NPs was quantified by elemental analysis and the results indicated that the amount of CD associated with the NPs was strictly dependent on its electrostatic charge. Finally, in vitro stability studies indicated that the presence of CDs in the NP structure can prevent the aggregation of this nanometric carrier system in simulated intestinal fluid. Overall, this new type of NP represents an attractive drug delivery platform of particular interest for the oral administration of drugs with low bioavailability.  相似文献   

18.
In the present study, we have aimed to produce nanoparticles (NPs) possessing the capability of carrying both of the hydrophobic and hydrophilic drugs and reveal significant release for both drug types. Poly(ε-caprolactone) (PCL) grafted poly(vinyl alcohol) (PVA) copolymer (PCL-g-PVA) has been prepared and shaped in nano-particulate form to be adequate for carrying the drugs. Stannous octoate (Sn(II)Oct2) was used to catalyze PVA and ε-caprolactone monomer to chemically bond. Moreover, this catalyst enhanced side chain polymerization reaction for the utilized ε-caprolactone monomer to form poly(ε-caprolactone) (PCL). The formed PCL was attached as branches with PVA backbone. 1H NMR has confirmed formation of PCL and grafting of PVA by this new polymer. Moreover, the vibration modes in the functional groups of PCL-g-PVA have been detected by FT-IR. The thermal alteration in the grafted polymer was checked by TGA analysis. The successfully synthesized grafted copolymer was able to self-aggregate into NPs by direct dialysis method. The size, morphology and charges associated with the obtained NPs were analyzed by DLS, TEM and ELS, respectively. PCL-g-PVA NPs were investigated as drug carrier models for hydrophobic and hydrophilic anti cancer drugs; paclitaxel and doxorubicin. In vitro drug release experiments were conducted; the loaded NPs reveal continuous and sustained release form for both drugs, up to 20 and 15 days for paclitaxel and doxorubicin, respectively. However, in a case of using pure drugs only, both drugs completely released within 1–2 h. The overall obtained results strongly recommend the use these novel NPs in future drug delivery systems.  相似文献   

19.
Chondroitin (Chn) sulphate composed of N‐acetyl galactoseamine units was chosen to target doxorubicin (DOX) to asialoglycoprotein receptors (ASGPRs) overexpressed in HepG2 cells of hepatocellular carcinoma (HCC). Two different ways of targeting the drug to the receptors were compared with each other; (i) by polyelectrolyte complex formation of DOX and Chn (DC), (ii) by loading the drug in gelatin nanoparticles (NPs) and then coating them by Chn. The characteristics of DC complexes were determined by Fourier transform infrared spectroscopy, differential scanning calorimetry and CHN analysis. The complexes and Chn coated NPs were characterised for their particles size, zeta potential, drug loading and release efficiency. The morphology of NPs was studied by transmission electron microscopy. The cytotoxicity of DC complex and Chn coated NPs were compared on HepG2 cells by MTT assay. The results showed that the cytotoxicity of both Chn coated gelatin NPs and DC complexes were significantly increased in comparison with free DOX. However, the presence of Chn did not have significant effect on the cytotoxicity of DOX loaded NPs. It was concluded that polyelectrolyte complex of DC could successfully target the drug to the hepatic ASGPRs and may be a simple promising way for targeted drug delivery in HCC.Inspec keywords: drug delivery systems, drugs, polymer electrolytes, electrokinetic effects, nanoparticles, particle size, cellular biophysics, nanocomposites, nanofabrication, molecular biophysics, cancer, gelatin, coatings, Fourier transform infrared spectra, differential scanning calorimetry, filled polymers, transmission electron microscopy, toxicology, nanomedicine, biomedical materialsOther keywords: chondroitin‐doxorubicin nanoparticulate polyelectrolyte complex, HepG2 cells, N‐acetyl galactoseamine units, chondroitin sulphate, asialoglycoprotein receptors, hepatocellular carcinoma, drug targeted delivery, receptors, polyelectrolyte complex formation, gelatin nanoparticles, DC complexes, Fourier transform infrared spectroscopy, differential scanning calorimetry, CHN analysis, Chn coated NPs, particle size, zeta potential, drug loading, drug release efficiency, morphology, transmission electron microscopy, cytotoxicity, MTT assay, hepatic ASGPRs  相似文献   

20.
As non-phagocytic eukaryotic cells can internalize particles < 1 microm in size, small size (25 to 110 nm) lipid nanocapsules (LNC) are proposed for the intracellular drug delivery of anticancer drugs to cancer cells. LNC of different diameters were loaded with etoposide or paclitaxel and subsequently tested for drug release kinetics and their efficiency to reduce cancer cell growth in cell culture. Relative high drug loads could be achieved and sustained drug release can be provided over a period of several days (etoposide) up to a few weeks (paclitaxel). While particle size exhibited only minor influences on the release kinetics, higher initial drug load led to a distinctly lower burst release. In a cancer cell culture model, etoposide or paclitaxel LNC showed a 4-fold or 40-fold higher efficiency, respectively than the drug solution while blank LNC were found to be less toxic than the pure drug at equivalent concentrations. The uptake and intracellular accumulation of LNC was confirmed by confocal laser scanning microscopy after fluorescence labeling of the nanocarriers. This nanoparticulate system is able to achieve efficient intracellular drug concentrations and seems to be therefore a promising therapeutic approach in cancer treatment.  相似文献   

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