Biocompatible Polymer Coated Paramagnetic Nanoparticles for Doxorubicin Delivery: Synthesis and Anticancer Effects Against Human Breast Cancer Cells

To increase the efficacy of doxorubicin in induction of apoptosis, pH-responsive nanocarriers with an average particle size of 20 nm by using chitosan-polymethacrylic acid (CTS-PMAA) shells and Fe₃O₄ cores via in situ polymerization approach were synthesized. Doxorubicin hydrochloride (DOX) was loaded effectively to nanocarrier through electrostatic interactions and strong hydrogen banding. The cumulative release of DOX-loaded nanoparticles was pH dependent with a maximum release rate at pH 5.8. In vitro cytotoxicity assay revealed the biocompatibility of blank nanocarrier and superior anticancer performance of DOX-loaded nanoparticles verified by DAPI staining and MTT assay tests.     

Graphene Oxide Hybrid Supramolecular Hydrogels with Self‐Healable,Bioadhesive and Stimuli‐Responsive Properties and Drug Delivery Application

Self‐healable hydrogels are promising soft materials with great potential in biomedical applications due to their autonomous self‐repairing capability. Although many attempts are made to develop new hydrogels with good self‐healing performance, to integrate this characteristic along with other responsive multifunctions into one hydrogel still remains difficult. Here, a self‐healable hybrid supramolecular hydrogel (HSH) with tunable bioadhesive and stimuli‐responsive properties is reported. The strategy is imparting graphene oxide (GO) nanosheets and quadruple hydrogen bonding ureido‐pyrimidinone (UPy) moieties into a thermoresponsive poly(N‐isopropylacrylamide) (PNIPAM) polymer matrix. The obtained GO–HSH hydrogel shows rapid self‐healing behavior and good adhesion to various surfaces from synthetic materials to biological tissue. In addition, doxorubicin hydrochloride (DOX) release profiles reveal the dual thermo‐ and pH‐responsiveness of the GO–HSH hydrogel. The DOX‐loaded hydrogel can further directly adhere to titanium substrate, and the released DOX from this thin hydrogel coating remains biologically active and has high capability to kill tumor cells.     

GSH-responsive polyglutamic acid nanocarriers for dual targeted cancer therapy

In order to reduce the toxic side effects of chemotherapeutic drugs and improve the targeting and efficiency of cancer treatment, the development of drug delivery system has received great attention. In this study, second generation polyglutamic acid dendrimers (G₂) are used as basic materials to produce porous nanoparticles through cross link by crosslinkers containing disulfide bonds. The crosslinked products (G₂)_n have negative electricity and abundant voids, which enable them to adsorb the electronegative anticancer drug DOX. At the same time, in order to transport DOX to the tumor site, we modified FA on DOX and encapsulated it in magnetic mesoporous silica (FA-DOX-MSNs). Therefore, the final nanoparticles (FA-DOX-MSNs/(G₂)_n) not only have dual targeting ability to transport DOX to the tumor site, but also have reductive responsiveness that can release drugs responsively in the tumor cells. In addition, it has good biocompatibility and endocytosis ability.     

A magnetic polypeptide nanocomposite with pH and near-infrared dual responsiveness for cancer therapy

A magnetic polypeptide nanocomposite with pH and near-infrared (NIR) dual responsiveness was developed as a drug carrier for cancer therapy, which was prepared through the self-assembly of Fe₃O₄ superparamagnetic nanoparticles, poly(aspartic acid) derivative (mPEG-g-PDAEAIM) and doxorubicin (DOX) in water. Fe₃O₄ nanoparticles were prepared to provide the superparamagnetic core of nanocomposites for tumor targeting via chemical co-precipitation. The protonable imidazole groups of mPEG-g-PDAEAIM with a pKa of ~7 were accountable for the pH-responsiveness of nanocomposites. The photothermal effect of nanocomposites under the irradiation of NIR laser was induced via the interactions between dopamine groups of mPEG-g-PDAEAIM and Fe₃O₄ superparamagnetic nanoparticles to trigger the drug release. NMR, FT-IR, TEM, hysteresis loop analysis and MRI were utilized to characterize the materials. The DOX loaded nanocomposites exhibited pH-responsive and NIR dependent on/off switchable release profiles. The nanocomposites without drug loading (Fe₃O₄@mPEG-g-PDAEAIM) showed excellent biocompatibility while DOX loaded nanocomposites caused MCF-7 cells’ apoptosis due to the photothermal/chemotherapy combination effects. Overall, the pH and near-infrared dual responsive magnetic nanocomposite had a great potential for cancer therapy.     

The use of polyethylenimine-modified graphene oxide as a nanocarrier for transferring hydrophobic nanocrystals into water to produce water-dispersible hybrids for use in drug delivery

In order to produce water-dispersible nanocrystals, including upconversion nanoparticles (UCNPs) which are the new generation fluorophores and magnetic nanoparticles (Fe₃O₄), a polyethylenimine-modified graphene oxide (PEI-GO) was used as a nanocarrier of nanocrystals, and PEI-GO-nanocrystal hybrids were prepared by transferring hydrophobic nanocrystals from an organic phase to water. Nanocrystals were anchored onto the hydrophobic plane of PEI-GO, which was confirmed by atomic force microscopy and electron microscopy. Molecular dynamics simulation further showed that hydrophobic interaction between PEI-GO and oleic acid molecules coated on the surface of the nanocrystals was the major driving force in the transfer process. The resulting hybrids had high stability in both water and physiological solutions, and combined the functionalities of the nanocrystals and PEI-GO, such as luminescence, superparamagnetism and drug delivery capability. Through π–π stacking interaction between PEI-GO-UCNP and an aromatic drug, PEI-GO-UCNP was able to load a water-insoluble anticancer drug, doxorubicin (DOX), with a superior loading capacity of 100 wt.%. In addition, PEI-GO-UCNP did not exhibit toxicity on the human endothelial cells and PEI-GO-UCNP-DOX showed a high potency of killing cancer cells in vitro.     

TPE‐conjugated biomimetic and biodegradable polymeric micelle for AIE active cell imaging and cancer therapy

Smart nanocarrier for simultaneous drug delivery and cellular imaging is ideal for both cancer therapy and diagnosis. In this work, polymeric micelles based on the tetraphenylethene (TPE) conjugated poly(N6‐carbobenzyloxy‐l ‐lysine)‐block‐poly(2‐methacryloyloxyethyl phosphorylcholine) (TPE‐PLys‐b‐PMPC) copolymer are successfully prepared. Such biomimetic and biodegradable TPE‐PLys‐b‐PMPC micelles exhibit remarkable aggregation‐induced emission (AIE) feature and great biocompatibility, showing great potential for bioimaging application. In addition, anticancer drug doxorubicin (DOX) can be incorporated into the core of micelles and the intracellular release of DOX can be furthermore traced through the fluorescent imaging of these AIE micelles. As expected, this DOX‐loading polymeric micelle shows significant growth inhibition against HeLa cells and 4T1 cells and such TPE‐PLys‐b‐PMPC micelles would be a promising drug carrier for potential cancer therapy and bioimaging. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 45651.     

Effect of graphene oxide on the pH-responsive drug release from supramolecular hydrogels

Polypseudorotaxane (PPR) hydrogels formed by inclusion complexes between poly(ethylene glycol) (PEG) and α-cyclodextrin (α-CD) are highlighted as promising biomaterial for drug delivery. Here, we report a novel injectable PPR hydrogel containing graphene oxide (GO) for pH-responsive controlled release of doxorubicin hydrochloride (DOX). Our results showed that the gelation rates of the PEG/α-CD supramolecular structures could be tailored depending on the reagent concentrations. The formation of PEG/α-CD inclusion complexes was confirmed by TEM and XRD, the latter further confirming that GO restricts their formation. The supramolecular hydrogels were easily loaded with DOX by simple addition into the PEG solution before the complex formation with the α-CD solution. Noteworthy, disruption of ionic interactions between DOX and GO in the nanocomposite at pH = 5.5 resulted in higher DOX release than under physiological conditions (pH = 7.4). This pH dependence was barely observed in pure PPR hydrogel. These findings introduce DOX-loaded supramolecular hydrogels nanocomposites as promising carriers for pH-responsive and therefore localized, drug delivery systems.     

Stimuli-responsive Supra-biomolecular Nanoassemblies of Cucurbit[7]uril with Bovine Serum Albumin: Drug Delivery and Sensor Applications

Construction and characterization of stimuli-responsive supra-biomolecular nanoassembly between cucurbit[7]uril (CB7) and bovine serum albumin (BSA), uptake and release of doxorubicin (DOX) in live cells, the enhanced sensitivity of brilliant green (BG) and the metal ion-induced relocation of neutral red (NR) dye to BSA have been discussed in this review. The fluorescence intensity of DOX is largely quenched in the presence of nanoassembly which recovers with adamantylamine or by changing the pH of the solution, indicating the significant uptake and release of DOX. Whereas, the interaction of BG with CB7-BSA assembly leads to a huge fluorescence enhancement ∼350-fold through ternary complex formation. In another study, the supramolecular pK_a tuning of nanoassembly encapsulated NR dye with metal ion and the consequent relocation of NR from CB7 cavity to the hydrophobic pocket of BSA have been demonstrated. All these studies show promising applications in drug delivery and on-off sensor.     

Biodegradable vesicular nanocarriers based on poly(?-caprolactone)-block-poly(ethyl ethylene phosphate) for drug delivery

Biodegradable polymer vesicle for drug delivery is reported. Poly(?-caprolactone)-block-poly(ethyl ethylene phosphate) with well-defined structure (PCL₁₅₀-b-PEEP₃₀) has been prepared by ring-opening polymerization. It forms vesicles in aqueous solution using the thin-film hydration method and further exclusion of the as-formed vesicles results in vesicles at nano-size, demonstrated by confocal laser scanning microscope (CLSM) and transmission electron microscopy observations. Doxorubicin (DOX) has been loaded into the vesicles with a loading content of 4.38% using an acid gradient method. The release of DOX from the vesicles is accelerated in the presence of an enzyme phosphodiesterase I that is known to catalyze the degradation of polyphosphoester, achieving 83.8% release of total loaded DOX in 140 h. The DOX-loaded vesicles can be successfully internalized by A549 cells, and it results in enhanced inhibition to A549 cell proliferation, likely owning to the sustained intracellular release of DOX as observed by CLSM. With these properties, the vesicles based on the block copolymer of PCL and PEEP are attractive as drug carriers for pharmaceutical application.     

Facile synthesis of novel fluorescent phenol formaldehyde resin nanospheres for drug release

A highly-efficient nano-medical carrier system was constructed for drug release based on a facile synthesis, excellent fluorescence, and structure of phenol formaldehyde resin (PFR). The PFR was easily synthesized through a simple one-step hydrothermal reaction, reduction and etching process, and a silane coupling agent modification process. The multiple functionalized drug delivery system, defined as PFR-NH₂@DOX was constructed by loading Adriamycin (DOX) into PFR. Drug release results in vitro displayed a DOX content of 145 mg g⁻¹ prodrug nanosphere has excellent pH-triggered drug release (about 84.71%) within 72 h at pH 5 solution. The fluorescence recovery of PFR after DOX release indicates the potential application in fluorescence imaging and controlled drug release.     

F3-functionalized nanoscale metal–organic frameworks for tumor-targeting combined chemotherapy and chemodynamic therapy

Nanoscale metal–organic frameworks (nMOFs) have attracted much attention as emerging porous materials as drug delivery carriers. Appropriate surface modification of them can greatly improve stability and introduce biocompatibility and cancer targeting functionality into drug delivery systems. Herein, we prepared nano-sized MIL-101(Fe)-N₃ and loaded anticancer drug doxorubicin (DOX) into it. The synthetic polymer layer Alkyne-PLA-PEG was then attached to the F3 peptide (labeled as Alkyne-PLA-PEG-F3), and the surface of DOX/MIL-101(Fe)-N₃ was covalently modified with it to obtain DOX/MIL-101-PLA-PEG-F3. Nano-sized MIL-101(Fe)-N₃ has high drug loading capacity and the modification of MIL-101(Fe)-N₃ by polymer Alkyne-PLA-PEG not only improved the dispersion, but also avoided the sudden release of the drugs and increased the biocompatibility of nanocarriers. The F3 peptide introduced into the nanocarriers also enabled it to specifically target tumor tissues and achieved active targeted drug delivery. As a nucleolin-mediated endocytosis drug delivery system, DOX/MIL-101-PLA-PEG-F3 can not only deliver anticancer drugs to tumors accurately, but also participate in Fenton-like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy (CDT), thus enabling combination therapy. It holds great promise as drug candidates to reduce systemic toxicity and improve the efficacy of cancer treatment.     

One pot preparation of polyurethane-based GSH-responsive core-shell nanogels for controlled drug delivery

In this work, we present a new type of glutathione (GSH)-responsive polyurethane-based core‑shell nanogels (RS-CS-PUNGs) with hydrophilic methoxypolyethylene glycols (mPEG) shell, which was prepared by a one-pot synthetic method. The obtained RS-CS-PUNGs not only show a good size distribution with the hydrodynamic radii around of 20 nm, but also exhibit good stability in the organic solvent. The results demonstrate that GSH (10 mM) trigger the nanogel swelling and accelerate the loaded drug release in PBS (pH = 7.4). Although the RS-CS-PUNGs loaded with DOX show a slower cellular uptake behavior than the free doxorubicin (DOX), which is likely caused by the controlled drug release property of the nanocarrier, the enhanced cellular uptake fluorescence intensity of RS-CS-PUNGs loaded with DOX is still observed compared to the control group. Both MTT and CCK-8 assay indicate that although an obvious lower initial cytotoxicity is observed compared to free DOX at 24 h postincubation, the cytotoxicity of the RS-CS-PUNGs loaded with DOX is obvious enhanced after treated 72 h, which stayed at the similar level with free DOX. Attributing to the easy preparation progress and GSH-responsive property, RS-CS-PUNGs maybe hold the potential for further application in the field of drug delivery. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48473.     

Photo-Responsive Supramolecular Micelles for Controlled Drug Release and Improved Chemotherapy

Development of stimuli-responsive supramolecular micelles that enable high levels of well-controlled drug release in cancer cells remains a grand challenge. Here, we encapsulated the antitumor drug doxorubicin (DOX) and pro-photosensitizer 5-aminolevulinic acid (5-ALA) within adenine-functionalized supramolecular micelles (A-PPG), in order to achieve effective drug delivery combined with photo-chemotherapy. The resulting DOX/5-ALA-loaded micelles exhibited excellent light and pH-responsive behavior in aqueous solution and high drug-entrapment stability in serum-rich media. A short duration (1–2 min) of laser irradiation with visible light induced the dissociation of the DOX/5-ALA complexes within the micelles, which disrupted micellular stability and resulted in rapid, immediate release of the physically entrapped drug from the micelles. In addition, in vitro assays of cellular reactive oxygen species generation and cellular internalization confirmed the drug-loaded micelles exhibited significantly enhanced cellular uptake after visible light irradiation, and that the light-triggered disassembly of micellar structures rapidly increased the production of reactive oxygen species within the cells. Importantly, flow cytometric analysis demonstrated that laser irradiation of cancer cells incubated with DOX/5-ALA-loaded A-PPG micelles effectively induced apoptotic cell death via endocytosis. Thus, this newly developed supramolecular system may offer a potential route towards improving the efficacy of synergistic chemotherapeutic approaches for cancer.     

黏膜粘附性缺氧响应型壳聚糖胶束的制备与性能

以2-硝基咪唑和6-溴己酸乙酯为原料，合成了缺氧响应型6-(2-硝基咪唑)己酸（NIHA），将其接枝改性壳聚糖合成了取代度分别为3.9%、6.3%和8.9%的两亲性壳聚糖-g-6-(2-硝基咪唑)己酰胺衍生物（CS-NID）。利用1HNMR、UV和FTIR表征了CS-NID的化学结构。CS-NID在水中能自组装形成纳米胶束，并采用DLS、Zeta电位和UV对胶束进行了表征。结果表明，CS-NID胶束的平均粒径为165~190 nm，粒径随NIHA取代度增加而减小。胶束具有优良的储存稳定性、黏膜粘附性、pH响应性和缺氧响应性。阿霉素（DOX）通过疏水相互作用被装载进胶束内，最大载药率（DLC）可达13.3%，最大包封率（DLE）可达44.3%。体外药物释放研究表明，CS-NID胶束具有明显的缺氧响应的药物释放行为，在正常生理环境（常氧，pH 7.4）中24h最大药物释放量仅为42%，而在缺氧的酸性（pH 5.4）条件下，2h内药物释放量高达65%，24h内药物释放量超过92%。     

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.     

Antitumor efficacy of doxorubicin encapsulated within PEGylated poly(amidoamine) dendrimers

We report here a general approach to using poly(amidoamine) (PAMAM) dendrimers modified with polyethylene glycol (PEG) as a platform to encapsulate an anticancer drug doxorubicin (DOX) for in vitro cancer therapy applications. In this approach, PEGylated PAMAM dendrimers were synthesized by conjugating monomethoxypolyethylene glycol with carboxylic acid end group (mPEG‐COOH) onto the surface of generation 5 amine‐terminated PAMAM dendrimer (G5.NH₂), followed by acetylation of the remaining dendrimer terminal amines. By varying the molar ratios of mPEG‐COOH/G5.NH₂, G5.NHAc‐mPEG_n (n = 5, 10, 20, and 40, respectively) with different PEGylation degrees were obtained. We show that the PEGylated dendrimers are able to encapsulate DOX with approximately similar loading capacity regardless of the PEGylation degree. The formed dendrimer/DOX complexes are water soluble and stable. In vitro release studies show that DOX complexed with the PEGylated dendrimers can be released in a sustained manner. Further cell viability assay in conjunction with cell morphology observation demonstrates that the G5.NHAc‐mPEG_n/DOX complexes display effective antitumor activity, and the DOX molecules encapsulated within complexes can be internalized into the cell nucleus, similar to the free DOX drug. Findings from this study suggest that PEGylated dendrimers may be used as a general drug carrier to encapsulate various hydrophobic drugs for different therapeutic applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40358.     

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.     

Synthesis of hollow maghemite (-Fe2O3) particles for magnetic field and pH-responsive drug delivery and lung cancer treatment

The development of smart stimuli-responsive materials for drug delivery offers new opportunities for precise drug release and cancer chemotherapy. A combination of more than one stimuli is highly desirable to further maximize the therapy by taking the advantages of various unique merits. Herein, we employed polyethylene glycol (PEG) functionalized γ-Fe₂O₃ particles (γ-Fe₂O₃/PEG) as a novel magnetic drug carrier for doxorubicin (DOX) delivery. The results showed that the γ-Fe₂O₃/PEG exhibited excellent thermal effects under alternating magnetic field (AMF), high magneto-thermal stability, and large DOX loading capacity. Furthermore, the effects of pH and AMF on the DOX drug release were studied. It was discovered that DOX loaded γ-Fe₂O₃/PEG carriers were highly responsive to both AMF and pH, resulting in significantly improved cancer cell killing capability over a single stimulus. The magnetic and pH responsive drug delivery system provided a new opportunity to minimize the side effects and maximize the therapeutic efficiency of lung cancer treatment.     

In-situ self-assembly of sandwich-like Ti3C2 MXene/gold nanorods nanosheets for synergistically enhanced near-infrared responsive drug delivery

As a novel two-dimensional material, Ti₃C₂ MXenes has attracted lots of attention in biomedical filed for its large surface area and excellent near-infrared (NIR) responsiveness. In this paper, an in-situ growth and self-assembly approach was employed to combine gold nanorods (GNRs) with Ti₃C₂ nanosheets to prepare intelligent sandwich-like Ti₃C₂@GNRs/PDA/Ti₃C₂ nanohybrids. Compared with Ti₃C₂ nanosheets, in-situ growth Ti₃C₂@GNRs possessed excellent photothermal conversion efficiency (45.89%), caused by the distinguished photothermal synergy between GNRs and Ti₃C₂ nanosheets. Moreover, the high specific surface area of Ti₃C₂ MXene and outstanding adhesion performance of PDA endowed Ti₃C₂@GNRs/PDA/Ti₃C₂ nanohybrids with superior drug loading ability for doxorubicin hydrochloride (DOX) (95.88%). Besides, Ti₃C₂@GNRs/PDA/Ti₃C₂ nanohybrids displayed distinct pH/NIR responsive drug release properties upon NIR irradiation owing to the strong π-π stacking interaction between Ti₃C₂@GNRs/PDA/Ti₃C₂ and DOX, along with the excellent NIR-responsiveness of Ti₃C₂@GNRs/PDA/Ti₃C₂. This paper offers a practicable method to prepare Ti₃C₂ MXene-based nanoplatform with synergistically enhanced NIR drug release behavior, brilliant biocompatibility and high drug loading efficiency, which is expected to be applied in remote 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