Self‐assembled nanoparticles from folate‐decorated maleilated pullulan–doxorubicin conjugate for improved drug delivery to cancer cells

The goal of this study was to develop doxorubicin conjugate nanoparticles with increased antitumor effects, reduced side effects and the ability to overcome multidrug resistance (MDR). In this regard, folate‐decorated maleilated pullulan–doxorubicin conjugate nanoparticles were developed as carriers for co‐delivery of pyrrolidinedithiocarbamate and doxorubicin (FA‐MP‐DOX/PDTC + DOX NPs). The resultant nanoparticles showed spherical geometry, with an average diameter of 152 nm. The two drugs were released from the nanoparticles in a slow, pH‐dependent sustained release. To test the efficacy of these nanoparticles, in vitro tests including cell viability and folate receptor‐mediated endocytosis were conducted against both A2780 cells and A2780/DOX^R cells. Compared to free DOX, the FA‐MP‐DOX/PDTC + DOX NPs showed effective but less potent cytotoxicity against A2780 cells. For A2780/DOX^R cells, they showed enhanced cellular uptake, increased targeting capacity and cytotoxicity. These results suggest that co‐delivery of PDTC and DOX may further overcome MDR by transporting an increased amount of DOX within cells in addition to the folate receptor‐mediated endocytosis process. © 2012 Society of Chemical Industry     

Enhanced loading of doxorubicin into polymeric micelles by a combination of ionic bonding and hydrophobic effect,and the pH-sensitive and ligand-mediated delivery of loaded drug

Folate-conjugated micelles were fabricated from amphiphilic diblock copolymers with poly(ethylene glycol) as the hydrophilic block and a random copolymer of n-butyl methacrylate and methacrylic acid as the hydrophobic block. Doxorubicin (DOX), a model drug that contains an amine group and hydrophobic moiety, was loaded with a high loading capacity into micelles by a combination of ionic bonding and hydrophobic effect. The combined interactions imparted a pH-sensitive delivery property to the system. The release rate of loaded DOX was slow at pH 7.4 (i.e., mimicking the plasma environment) but increased significantly at acidic pH (i.e., mimicking endosome/lysosome conditions). Acid-triggered drug release resulted from the carboxylate protonation of poly(methacrylic acid), which dissociated the ionic bonding between the micelles and DOX. Cellular uptake by folate receptor-overexpressing HeLa cells of the DOX-loaded folate-conjugated micelles was higher than that of micelles without folate conjugation. Thus, the DOX-loaded folate-conjugated micelles displayed higher cytotoxicity to HeLa cells.     

Fabrication of micelles from poly(butylene succinate) and poly(2‐methacryloyloxyethyl phosphorylcholine) copolymers as a potential drug carrier

A series of copolymers of poly(2‐methacryloyloxyethyl phosphorylcholine)‐b‐poly(butylene succinate)‐b‐poly(2‐methacryloyloxyethyl phosphorylcholine) (PMPC‐b‐PBS‐b‐PMPC) were synthesized by atom transfer radical polymerization. The structure of the polymers was characterized by ¹H NMR and infrared spectroscopy, and their thermal properties were described using TGA and DSC. In aqueous solutions, the PMPC‐b‐PBS‐b‐PMPC could form micelles with sizes ranging from 108 to 170 nm. In vitro release studies showed that acidic media and a longer PMPC chain benefited doxorubicin (DOX) release. 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assays indicated that the micelles had low cytotoxicity to HeLa and L929 cells. DOX‐loaded micelles exhibited high cytotoxicity to HeLa cells. Flow cytometry results demonstrated that DOX‐loaded micelles could be internalized by HeLa cells. The in vitro phagocytosis results showed 3.9‐fold and 5.5‐fold reductions compared with poly(lactic acid) (PLA) nanoparticles and PDS55 micelles. These results demonstrate that PMPC‐b‐PBS‐b‐PMPC block copolymer micelles have great promise for cancer therapy. © 2017 Society of Chemical Industry     

Acid and light dual- stimuli-cleavable polymeric micelles

In this study, acid and light dual- stimuli-responsive amphiphilic AB-type methoxy poly(ethylene glycol)-acetal-ONB-poly(4-substituted-ε-caprolactone) (MPEG-a-ONB-PXCL) diblock copolymers were synthesized using ring-opening polymerization and nucleophilic substitution reactions. The prepared copolymer features an acid-cleavable acetal group and photocleavable o-nitrobenzyl linkage between the hydrophilic MPEG and hydrophobic PXCL blocks. The design enables the diblock copolymers to respond to both acid and ultraviolet (UV) light while ensuring the minimum number of stimuli-reactive moieties in the copolymer structure. The disruption of the copolymeric micelles in aqueous solution was examined under the action of pH or UV light alone or under the combined stimulation pH and UV light. Under the combined stimulation of UV irradiation and pH, the micellar nanoparticles could dissociate; therefore, the loaded molecules could be released from the assemblies more efficiently than under either stimulus alone. The nanoparticles exhibited nonsignificant toxicity against human cervical cancer (HeLa) cells at concentrations ≤300 μg mL^?1. Doxorubicin (DOX)-loaded micelles facilitated the uptake of DOX by the HeLa cells at the initial stage. The dual stimuli-cleavable polymeric micelles show promising potential as new nanocarrier for precisely controlled release of encapsulated drug.     

Doxorubicin loaded silica nanorattles actively seek tumors with improved anti-tumor effects

Silica nanorattles (SNs) have proven to be promising vehicles for drug delivery. In order to further enhance efficacy and minimize adverse effects, active targeted delivery to tumors is necessary. In this work, SNs modified with a tumor specific targeting ligand, folic acid (FA), was used as carrier of doxorubicin (DOX) (DOX-FA-SNs). Drug loading, cytotoxicity and cellular uptake of DOX-FA-SNs in vitro in human cervical carcinoma cells (HeLa cells) were evaluated. DOX-FA-SNs showed a higher cytotoxicity in human cervical carcinoma cells (HeLa cells) than DOX loaded carboxyl (-COOH) and poly(ethylene glycol) (PEG) modified SNs (DOX-COOH-SNs and DOX-PEG-SNs, respectively). However, DOX-FA-SNs showed lower cytotoxicity in folate receptor negative normal mouse fibroblast cells (L929 cells) compared with free DOX. In vivo tumor-targeted fluorescence imaging indicated specific tumor targeting and uptake of FA-SNs in nude mice bearing subcutaneous HeLa cell-derived xenograft tumors. In vivo anti-tumor experiments demonstrated that DOX-FA-SNs (10 mg kg(-1) of DOX) significantly regressed the tumor growth and reduced toxicity compared with free DOX. These results have great significance in developing and optimizing SNs as effective intracellular delivery and specific tumor targeting vehicles.     

Synthesis and characterization of PEG–PCL–PEG triblock copolymers as carriers of doxorubicin for the treatment of breast cancer

Triblock copolymers of monomethoxy poly(ethylene glycol) (mPEG) and ε‐caprolactone (CL) were prepared with varying lengths of poly(ε‐caprolactone) (PCL) compositions and a fixed length of mPEG segment. The molecular characteristics of triblock copolymers were characterized by ¹H NMR, gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FT‐IR), X‐ray diffraction (XRD), and differential scanning calorimetry (DSC). These amphiphilic linear copolymers based on PCL hydrophobic chain and hydrophilic mPEG ending, which can self‐assemble into nanoscopic micelles with their hydrophobic cores, encapsulated doxorubicin (DOX) in an aqueous solution. The particle size of prepared micelles was around 40–92 nm. The DOX loading content and DOX loading efficiency were from 3.7–7.4% to 26–49%, respectively. DOX‐released profile was pH‐dependent and faster at pH 5.4 than pH 7.4. Additionally, the cytotoxicity of DOX‐loaded micelles was found to be similar with free DOX in drug‐resistant cells (MCF‐7/adr). The great amounts of DOX and fast uptake accumulated into the MCF‐7/adr cells from DOX‐loaded micelles suggest a potential application in cancer chemotherapy. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Hyaluronic acid conjugated graphene oxide for targeted drug delivery

Nano-sized graphene oxide (GO) is functionalized with adipic acid dihydrazide to introduce amine groups, and then hyaluronic acid (HA) is covalently conjugated to GO by the formation of amide bonds. The resulting HA-grafted GO (GO–HA) has negligible hemolytic activity and very low cytotoxicity towards HeLa and L929 cells, and it can be effectively taken up by cancer cells through receptor-mediated endocytosis. The histological, hematological and biochemical analysis results suggest no perceptible toxicity of GO–HA in mice at a high exposure level of 10 mg kg⁻¹ and at an exposure time of up to 10 days. Doxorubicin (DOX) can be efficiently loaded on the GO–HA, and the resulting GO–HA/DOX exhibits notable cytotoxicity to HeLa cells. The in vivo drug delivery capability of GO–HA is demonstrated by following the tumor growth in mice after intravenous administration of GO–HA/DOX. The results indicate that GO–HA can efficaciously deliver DOX to the tumors and suppress tumor growth.     

Intracellular pH‐sensitive dextran‐based micelles as efficient drug delivery platforms

As drug delivery systems, stimuli‐responsive polymer micelles hold great potential in cancer chemotherapeutics to improve therapeutic efficiency and eliminate organism adverse effects. Here, pH‐sensitive polymeric micelles based on dextran‐g‐benzimidazole were designed and used for intracellular anticancer drug delivery. The anticancer drug doxorubicin (DOX) was effectively loaded into the micelles via hydrophobic interactions. In vitro release studies demonstrated that the release of loaded DOX was greater and faster under acid conditions such as in carcinomatous areas (pH < 6.8) than in physiological conditions (pH 7.4). MTT assays and flow cytometric analyses showed that DOX‐loaded micelles had higher cellular proliferation inhibition towards HeLa and HepG2 cells than pH‐insensitive controls. These pH‐sensitive micelles with significant efficiency for intracellular drug release will be beneficial to the future of in vivo biomedical applications. © 2014 Society of Chemical Industry     

Synthesis of glycopoly(pseudo amino acid)s and their interaction with lectins

In this study, we developed a novel bioeliminable amphiphilic glycopoly(pseudo amino acid), which was synthesized by the condensation polymerization of N-benzyloxycarbonyl-4-hydroxyl-l-proline (NZHpr) followed by the coupling of an alkynyl-functional sugar derivative to the azido-end group, P(NZHpr)_n. The glycosylated P(NZHpr)_n polymers formed micelles in the aqueous phase. Selective lectin binding experiments confirmed that the glycosylated P(NZHpr)_n can be used in biorecognition applications. The DOX-loaded micelles facilitated improved uptake of DOX by HeLa cells within 2 h and were primarily retained in the cytoplasm, whereas free DOX tended to accumulate in the nuclei. The DOX-loaded glucosylated P(NZHpr)_n micelles exhibited a substantially lower cytotoxicity compared to free DOX.     

Thermosensitive biotinylated hydroxypropyl cellulose-based polymer micelles as a nano-carrier for cancer-targeted drug delivery

In this article, we report the synthesis of a novel amphiphilic hydroxypropyl cellulose-based polymer (HPC-PEG-Chol) that contained poly (ethylene glycol) and cholesterol-containing moieties with specific degrees of substitution. The resulting polymer was subsequently converted to a biotin conjugate (HPC-PEG-Chol-biotin), to develop a new potential cancer-targeted drug delivery system. The biotin conjugate was used to prepare micelles via the dialysis method. The polymeric micelles in aqueous solution presented a lower critical solution temperature (LCST) of 39.8 ^oC. The critical micelle concentration (CMC) values of the polymeric micelles at 25 and 45 °C were evaluated to be about 0.32 and 0. 25 g/L, respectively. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses of the micelles revealed the spherical shapes of the micelles, with 84 nm mean diameters that increased with the increase of the temperature above LCST. The hydrophobic anticancer drug paclitaxel (PTX) was loaded in the micelles and the in vitro release behaviors of PTX were investigated at different temperatures. The release profile of PTX from the polymeric micelles revealed a thermosensitivity, since its release rate was higher at 41 °C than at 37 °C. Fluorescent microscopy analyses confirm that the PTX-loaded HPC-PEG-Chol-biotin is superior in cellular uptake, with very strong adsorption to both HeLa and MDA-MB-231 cancer cell lines. MTT assay in normal cells indicated that HPC-PEG-Chol-biotin micelles have great potential to be safely used in tumor-targeting chemotherapy.     

构建pH响应性中空介孔硅纳米复合材料用于肿瘤联合治疗

以正硅酸四乙酯为原料,合成直径约为100 nm的中空介孔二氧化硅纳米颗粒(HMSN)作为药物载体,采用物理包埋法和原位还原KMnO4生成二氧化锰的方法实现对化疗药物阿霉素(DOX)和MnO2的有效负载.此外,利用肿瘤靶向性功能肽(PEG-R7-RGDS)末端的氨基与醛基修饰的HMSN(HMSN-CHO)形成席夫碱,合成pH响应性纳米载药系统(DOX/MnO2@HMSN-imide-PEG-R7-RGDS).通过TEM、激光粒度仪、FTIR和XRD对合成材料形貌、粒径、结构和组成等进行表征.结果表明,合成的HMSN呈球形中空结构.DOX/MnO2@HMSN-imide-PEG-R7-RGDS在模拟的肿瘤酸性环境(pH 5.0)中具有明显快于在模拟生理环境(pH 7.4)下的药物释放行为.此外,体外细胞实验结果表明,DOX/MnO2@HMSN-imide-PEG-R7-RGDS可以靶向进入宫颈癌细胞(HeLa)并快速释放DOX.与此同时,纳米载药颗粒中的MnO2和肿瘤细胞中高浓度谷胱甘肽(GSH)反应产生具有类芬顿反应效果的Mn2+.Mn2+与肿瘤细胞内过表达的H2O2反应生成?OH,发挥增强的化学动力学治疗.细胞毒性实验证明,化学动力学治疗与化疗相结合能对HeLa细胞产生很高的细胞毒性.     

PEG and PEG-peptide based doxorubicin delivery systems containing hydrazone bond

mPEG and mPEG-peptide based drug delivery systems were prepared by conjugating doxorubicin (DOX) to these carrier molecules via hydrazone bond. The peptide, AT1, with a sequence of CG₃H₆G₃E served as mPEG and doxorubicin attachment site. Histidines were incorporated to the sequence to improve pH responsiveness of the carrier molecule. Hydrodynamic diameters (mean sizes) of mPEG-based drug delivery system (mPEG-HYD-DOX) were measured as 9?±?0.5 and 7?±?0.5 nm at pH 7.4 and pH 5.0, respectively. Mean size of the aggregates of the peptide containing drug delivery system, mPEG-AT1-DOX, was determined as 12?±?2 nm at neutral pH. At pH 5.0, on the other hand, mPEG-AT1-DOX exhibited a size distribution between 20 and 100 nm centered at about 40 nm. Comparison of % DOX release values of the drug delivery systems obtained at pH 7.4 and pH 5.0 indicated that mPEG-AT1-DOX has enhanced pH sensitivity. DOX equivalent absolute IC₅₀ values were obtained as 0.96?±?0.51, 21.9?±?5.9, and 5.55?±?0.75 μg/mL for free DOX, mPEG-HYD-DOX, and mPEG-AT1-DOX, respectively. Considering more pronounced pH sensitivity and cytotoxicity of mPEG-AT1-DOX, the use of both pH responsive functional groups and acid cleavable chemical bond between the carrier molecule and drug can be a promising approach in the design of drug delivery systems for cancer therapy.     

PEGylated polylysine derived copolymers with reduction‐responsive side chains for anticancer drug delivery

Reduction‐responsive drug delivery systems have recently gained intense attention in intracellular delivery of anticancer drugs. In this study, we developed a PEGylated polypeptide, poly(ethylene glycol)‐block‐poly(?‐propargyloxycarbonyl‐l ‐lysine) (PEG₁₁₃‐b‐PPAL), as a novel clickable substrate for conjugation of reduction‐responsive side chains for antineoplastic drug delivery. PEG₁₁₃‐b‐PPAL was synthesized through ring‐opening polymerization of alkyne‐containing N‐carboxyanhydride monomers. A designed disulfide‐containing side chain was introduced onto the PEGylated polypeptide by click reaction. The obtained copolymer PEG₁₁₃‐b‐P(Lys‐DSA) formed micelles by self‐assembly, which exhibited reduction‐responsive behavior under the stimulus of 10 mmol L^–1 glutathione (GSH) in water. A small molecule intermediate, compound 2 , was used as a model to investigate the thiol reduction mechanism of PEG₁₁₃‐b‐P(Lys‐DSA) copolymers. The anticancer drug doxorubicin (DOX) was then loaded into the micelles with a drug loading content of 6.73 wt% and a loading efficiency of 40.3%. Both the blank and the drug‐loaded micelles (DOX‐loaded polylysine derived polymeric micelles (LMs/DOX)) adopted a spherical morphology, with average diameters of 48.0 ± 13.1 and 63.8 ± 20.0 nm, respectively. The in vitro drug release results indicated that DOX could be released faster from the micelles by the trigger of GSH in phosphate buffered saline. Confocal laser scanning microscopy and flow cytometer analysis further proved the intracellular delivery of DOX by LMs/DOX and their GSH‐sensitive release behavior. A 3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay showed that the polymers exhibited negligible cytotoxicity towards normal L929 cells or cancer MCF‐7 cells with a treated concentration up to 1.0 mg mL^–1. In conclusion, our synthesized biocompatible and biodegradable PEGylated polypeptides hold great promise for intracellular antineoplastic drug delivery. © 2019 Society of Chemical Industry     

Poly(methyl methacrylate)/poly(ethylene glycol)/poly(ethylene glycol dimethacrylate) micelles: Preparation,characterization, and application as doxorubicin carriers

A crosslinked amphiphilic copolymer [poly(ethylene glycol) (PEG)–poly(methyl methacrylate) (PMMA)–ethylene glycol dimethacrylate (EGDM)] composed of PMMA, PEG, and crosslinking units (EGDM) was synthesized by atom transfer radical polymerization to develop micelles as carriers for hydrophobic drugs. By adjusting the molar ratio of methyl methacrylate and EGDM, three block copolymer samples (P0, P1, and P2) were prepared. The measurement of gel permeation chromatography and ¹H‐NMR indicated the formation of crosslinked structures for P1 and P2. Fluorescence spectroscopy measurement indicated that PEG–PMMA–EGDM could self‐assemble to form micelles, and the critical micelle concentration values of the crosslinked polymer were lower than those of linear ones. The prepared PEG–PMMA–EGDM micelles were used to load doxorubicin (DOX). The drug‐loading efficiencies of P1 and P2 were higher than that of P0 because the crosslinking units enhanced the micelles' stability. With increasing drug‐loading contents, DOX release from the micelles in vitro was decreased, and in the crosslinked formulations, the release rate was also slower. An in vitro release study indicated that DOX release from the micelles for the linear samples was faster than that for crosslinked micelles. The drug feeding amount increased and resulted in an increase in the drug‐loading content, and the loading efficiency decreased. These PEG–PMMA–EGDM micelles did not show toxicity in vitro and could reduce the cytotoxicity of DOX in the micelles; this suggested that they are good candidates as stable drug carriers. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39623.     

Synthesis,and characterization folate-conjugated photocleavable poly(4-substituted-ε-caprolactone) polymers for drug delivery

Abstract

Photo-cleavable polymers containing 5-hydroxy-2-nitrobenzyl alcohol (ONB) junction point between the target molecule of folic acid (FA) and the hydrophobic poly(4-substituted-?-caprolactone) (PXCL_n) chain were synthesized. FA –terminated ONB-PXCL_n polymers formed micelles with critical micelle concentration (CMC) 1.2 – 64.3?mg L^?1. Fluorescence emission spectroscopy indicated the release of Nile red encapsulated FA-ONB-PXCL_n micelles in response to irradiation. Light-triggered bursts released were observed for drug-loaded FA-ONB-PXCL_n micelles. The nanoparticles exhibited nonsignificant toxicity at concentrations up to 300?µg mL^?1. Flow cytometry revealed that the uptake of folate-targeted doxorubicin (DOX) -encapsulated micelles by HeLa cells was faster than that of free DOX.     

Novel amphiphilic dextran copolymers nanoparticles for delivery of doxorubicin

In this work, a novel biodegradable amphiphilic copolymer based on dextran and 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphoethanolamine (DPPE) was successfully prepared. The amphiphilic copolymer may self‐assemble into polymeric micelles in an aqueous solution. Fluorescence spectroscopy, dynamic light scattering (DLS), and a transmission electron microscope (TEM) method confirmed the formation of copolymeric micelles. To estimate the feasibility as novel drug carriers, doxorubicin (DOX) was incorporated into polymeric nanoparticles. The DOX‐loaded nanoparticles exhibited greater antitumor effect than free DOX for HeLa celles, suggesting that the dextran/DPPE nanoparticles have great potential as a tumor targeting drug carrier. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Temperature,pH, and reduction triple‐stimuli‐responsive inner‐layer crosslinked micelles as nanocarriers for controlled release

Temperature, pH, and reduction triple‐stimuli‐responsive inner‐layer crosslinked micelles as nanocarriers for drug delivery and release are designed. The well‐defined tetrablock copolymer poly(polyethylene glycol methacrylate)–poly[2‐(dimethylamino) ethyl methacrylate]–poly(N‐isopropylacrylamide)–poly(methylacrylic acid) (PPEGMA‐PDMAEMA‐PNIPAM‐PMAA) is synthesized via atom transfer radical polymerization, click chemistry, and esterolysis reaction. The tetrablock copolymer self‐assembles into noncrosslinked micelles in acidic aqueous solution. The core‐crosslinked micelles, shell‐crosslinked micelles, and shell–core dilayer‐crosslinked micelles are prepared via quaternization reaction or carbodiimide chemistry reaction. The crosslinked micelles are used as drug carriers to load doxorubicin (DOX), and the drug encapsulation efficiency with 20% feed ratio reached 59.2%, 73.1%, and 86.1%, respectively. The cumulative release rate of DOX is accelerated by single or combined stimulations. The MTT (3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay verifies that the inner‐layer crosslinked micelles show excellent cytocompatibility, and DOX‐loaded micelles exhibit significantly higher inhibition for HepG2 cell proliferation. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46714.     

pH‐sensitive hydroxyethyl starch–doxorubicin conjugates as antitumor prodrugs with enhanced anticancer efficacy

Doxorubicin (DOX) is a widely used chemotherapeutic drug for the treatment of several types of cancers, which has limitation in clinical applications because of severe heart toxicity. Herein, to reduce the fast clearance from the blood system and the severe systemic toxicity caused by the nonspecific protein adsorption, a pH‐sensitive drug delivery system with higher drug conjugated content was prepared by conjugating DOX onto hydroxyethyl starch (HES) with a pH‐sensitive hydrazone bond. In normal physiological environment, the release of DOX conjugated onto HES was slight which could be neglected without any side effect. However, in an acidic environment mimicking the tumor microenvironment, this pH‐sensitive hydrazone linkage provided a controlled and sustained release of DOX over a period of more than 3 days. The conjugates had good biocompatibility, long circulation, and lower cytotoxicity, which could efficiently be transferred into HeLa and HepG2 cells and release the conjugated drug. Based on these promising properties, these HES–DOX conjugates outline the significant potential for future biomedical application in the controlled release of antitumor drugs. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42778.     

透明质酸自组装聚合物胶束的制备及表征

为了增强抗肿瘤药物的靶向性与抗肿瘤活性,本文制备了透明质酸-十八烷聚合物,用其对阿霉素进行包载,考察其理化性质及体外细胞毒性。合成两亲性透明质酸-十八烷聚合物,利用核磁对其结构进行确证。选择超声法制备载阿霉素的聚合物胶束,考察胶束的粒径、电位、包封率、载药量以及体外释放行为。选择乳腺癌细胞MCF-7为肿瘤细胞模型,考察载药胶束的体外抗肿瘤活性。成功合成了透明质酸-十八烷聚合物。制备的空白胶束和载药的胶束的粒径分别为（180.7±1.25）nm和（178.3±2.24）nm,Zeta电位分别为（-21.3±0.25）mV和（-18.1±0.31）mV。载阿霉素聚合物胶束的包封率为（96.1%±0.72%）,载药量为16.1%±1.18%,体外释放行为表明在72h的累计药物释放率仅为40%左右,具有明显的缓释行为。体外细胞毒性结果表明,空白聚合物胶束对肿瘤细胞几乎没有毒性,而载阿霉素的聚合物胶束具有较好的抗肿瘤活性。结论：透明质酸-十八烷聚合物胶束可以有效地包载抗肿瘤药物阿霉素,具有良好的缓释特性和抗肿瘤活性。     

Influence of polyethylene glycol molecular weight on the anticancer drug delivery of pH-sensitive polymeric micelle

Polyethylene glycol (PEG) and pH-sensitive polymers have been widely utilized in anticancer drug delivery systems due to their characteristics of prolonging circulation time and tumor-responsive drug release. However, the effect of PEG molecular weight on the delivery of anticancer drug-encapsulating pH-sensitive polymer micelles has been poorly studied. Therefore, a simple method was used to prepare pH-sensitive doxorubicin (DOX)-loaded micelles (DOX/POD) based on polyethylene glycol-2-(octadecyloxy)-1, 3-dioxan-5-amine (POD) polymers, and the influence of PEG molecular weights (1 K, 2 K, and 5 K) on in vitro drug release and antitumor effect was further studied. Interestingly, as the molecular weight increased, the release amount of DOX was augmented. While the cytotoxicity and cellular uptake were increased, the molecular weight was decreased. It is reasonable to speculate that the high molecular weight of PEG may promote the dissolution rate of DOX, and their micelles with uncompact structure are being prone to disassembly in an acid environment. However, the low molecular weight of PEG may contribute to the formation of compact POD micelles, which make it easier to be uptaken by tumor cells resulting in the enhanced antitumor effect. Taken together, the results indicate that pH-sensitive POD micelles with low molecular weight can achieve the efficient delivery of drugs, and PEG molecular weight in pH-sensitive nanocarriers may influence the antitumor effect. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47854.