Search

Preparation and antitumor application of nanogels are presented. This study provides a promising strategy to improve the synergistic antitumor effect of drugs.

Developing multifunctional wound dressings, possessing not only skin-like mechanical properties and adaptability, long-lasting moisture, and temperature tolerance that maximally mimics the human skin but also on-demand adhesion without unnecessary bleeding and secondary damage upon peeling, is necessary but remains a challenge. Herein, a novel dual cross-linked and multifunctional hydrogel, termed PSNC hydrogel for polymerized sulfobetaine methacrylate (SBMA)

The imaging of hydrogel scaffolds by

The treatment of difficult-to-heal wounds remains a substantial clinical challenge due to deteriorative tissue microenvironment including the loss of extracellular matrix (ECM), excessive inflammation, impaired angiogenesis, and bacterial infection. Inspired by the chemical components, fibrous structure, and biological function of natural ECM, antibacterial and tissue environment-responsive glycopeptide hybrid hydrogel was developed for chronic wound healing. The hydrogel can facilitate the cell proliferation and macrophage polarization to M2 phenotype, and show potent antibacterial efficacy against both Gram-negative and Gram-positive bacteria. Significantly, the glycopeptide hydrogel accelerated the reconstruction of methicillin-resistant

The reconstruction of large cranial bone defects by bioactive materials without exogenous cells or growth factors remains a substantial clinical challenge. Here, synthetic fibrous glycopeptide hydrogel (GR

Titanium alloy has been widely used in orthopedic surgeries as bone defect filling. However, the regeneration of high-quality new bones is limited due to the pro-inflammatory microenvironment around implants, resulting in a high occurrence rate of implant loosening or failure in osteological therapy. In this study, extracellular matrix-mimetic polysaccharide hydrogel co-delivering BMP-2 and interleukin (IL)-4 was composited with 3D printed titanium alloy to promote the osseointegration and regulate macrophage response to create a pro-healing microenvironment in bone defect. Notably, it is discovered from the bioinformatics data that IL-4 and BMP-2 could affect each other through multiple signal pathways to achieve a synergistic effect toward osteogenesis. The composite scaffold significantly promoted the osteoblast differentiation and proliferation of human bone marrow mesenchyme stem cells (hBMSCs). The repair of large-scale femur defect in rat indicated that the dual-cytokine-delivered composite scaffold could manipulate a lower inflammatory level in situ by polarizing macrophages to M2 phenotype, resulting in superior efficacy of mature new bone regeneration over the treatment of native titanium alloy or that with an individual cytokine. Collectively, this work highlights the importance of M2-type macrophages-enriched immune-environment in bone healing. The biomimetic hydrogel–metal implant composite is a versatile and advanced scaffold for accelerating in vivo bone regeneration, holding great promise in treating orthopedic diseases.

The degradation behavior of hydrogel scaffolds is closely related to the controlled release of bioactive agents and matching with the proliferative demands of newly generated tissues. However, the current methods cannot provide precise localization and track the degradation of individual hydrogel scaffolds in vivo, despite superficial or volumetric information. Here, for the first time, we presented the use of 19F magnetic resonance imaging (19F MRI) to precisely monitor the localization and quantify the degradation rate of implantable or injectable hydrogels in a real-time and noninvasive manner, with no interference of endogenous background signals and limitation of penetration depth. The total voxel and content in the region of interest (ROI) were linearly correlated to the injection amount, providing exact three-dimensional (3D) stereoscopic and two-dimensional (2D) anatomical information in the meantime. Moreover, a computational algorithm was established to present the real-time degradation rate in vivo as a function of time, which was implemented directly from the 19F MRI dataset. In addition, labelling with a zwitterionic 19F contrast agent demonstrated a facile and general applicability for multiple types of materials with no influence on their original gelation properties as well as 19F NMR properties in the hydrogel matrix. Therefore, this 19F MRI method offers a new approach to non-invasively track the degradation rate of hydrogel scaffolds in vivo in a precise localization and accurate quantification way, which will suffice the need for the evaluation of implants at deep depths in large animals or human objects.

We synthesized amino-modified poly(ε-caprolactone) PCN-b-PEG-b-PCN (PECN) triblock copolymers and studied the contribution of the introduced amino groups to the drug delivery efficiency of PECN nanoparticles (NPs) and their injectable thermosensitive hydrogels. PECN15 with an optimal amino group content was obtained. Firstly, the hydrophobic drug paclitaxel (PTX) was loaded into PECN15 up to 5.91% and formed PTX/PECN NPs 90 nm in size and with a slightly positive charge (7.3 mV). Furthermore, the injectable PTX/PECN NPs aqueous solution (25 wt%) at ambient temperature could undergo fast gelation at 37 °C and sustainedly release PTX/PECN NPs in 10 days. More importantly, compared with our previously reported PECT NPs, the PECN NPs without an increase in toxicity could improve the cell uptake and enhance intracellular drug release by responding to the acidic environment of the endosome. Thus, the PTX/PECN NPs presented a lower IC50 of 3.14 μg mL-1 than that of the PTX/PECT NPs (7.67 μg mL-1) and free PTX (4.65 μg mL-1). Moreover, through peritumoral injection, the PTX/PECNGel showed 94.27% inhibition rate of tumor growth on day 19, higher than PTX/PECTGel (72.28%) and Taxol® (47.03%). Therefore, the PECN NPs hydrogel provided a more effective injectable platform to enhance local cancer chemotherapy, and also provided the possibility of further functionalization by the reactive amino groups.

Poly(l-lactic acid) (PLLA) scaffolds have been used in regenerative medicine, however, they commonly suffer from low flexibility, restricting their application in the repair and reconstruction of soft tissues. In this study, poly(l-lactide-co-e-caprolactone) (PLCL) copolymers were examined to modulate the elasticity of PLLA with the random presence of CL units in PLLA. Thermodynamic analysis revealed that the introduction of PCL could significantly decrease the melting point and glass transition temperature of PLLA, benefiting the extrusion and printing of PLCL. Diverse scaffolds with designed architectures including porous cubes with or without large holes, cambered plates with holes and round tubes could be easily constructed by 3D printing. In the process of elastic deformation, the maximum elastic stress of the copolymer scaffold was obviously increased from 19.6 to 31.5 MPa when the relative content of PCL was increased to 70%, while the elongation at break was evidently increased from 388% to about 1974%. The Young's modulus of PLCL was also significantly decreased (P < 0.05) in comparison with that of PLLA. PLCL scaffolds have good platelet and endotheliocyte adhesion ability and no obvious hemolysis was observed. In vivo subcutaneous implantation of PLCL scaffolds demonstrated superior biocompatibility. Collectively, this work highlights that copolymerization of PCL segments into PLLA is an effective approach to tune the 3D printability and the stiffness and elasticity of PLLA scaffolds. PLCL scaffolds hold great promise for the regeneration of soft tissues including but not limited to cartilage, myocardium, muscle, tendon and nervous tissues.

Clinical wound management of radiation-induced skin injury (RSI) remains a great challenge due to acute injuries induced by excessive reactive oxygen species (ROS), and the concomitant repetitive inflammatory microenvironment caused by an imbalance in macrophage homeostasis. Herein, a cutaneous extracellular matrix (ECM)-inspired glycopeptide hydrogel (GK@TA

Radiotherapy (RT) combined with chemotherapy remains a dominant therapeutic manner in clinical tumor treatment, which is irreplaceable in a short term. To seek an intrinsic connection of combined chemoradiation therapy and maximize the antitumor efficacy, we developed a reactive oxygen species (ROS)-sensitive nanomicelle drug delivery system based on a self-assembled amphiphilic polymer, hyaluronic acid-graft-poly-(propylene sulfide) (HA-PPS). A chemical radiosensitizer, doxorubicin (DOX), was encapsulated into the core of HA-PPS nanomicelles, constituting the DOX-loaded nanomicelles (HA-PPS@DOX NMs) with a spherical structure of around 205.10 ± 11.33 nm diameter with a narrow polydispersity index (PDI) of 0.135 ± 0.01. When combined with RT, the ROS-sensitive HA-PPS@DOX NMs disintegrated and released great drug cargos, which further enhanced cytotoxicity. Meanwhile, as a radiosensitizer, the released DOX sensitized cancer cells to radiotherapy, which has been confirmed by an enhanced sensitizer enhancement ratio (SER) value of 1.78 contributing to the increased cytotoxicity of concurrent chemoradiation tumor therapy, as evidenced by the improvement of half maximal inhibitory concentration (IC50 value) of DOX from 2.316 to 0.8235 μg/mL. Moreover, in vivo studies revealed that HA-PPS@DOX NMs exhibited prolonged circulation time and improved tumor accumulation. Particularly, the released DOX triggered by radiation strengthened radiotherapy sensitization in return. Consequently, these superiorities of HA-PPS@DOX NMs shown by the concurrent chemoradiation tumor therapy resulted in an ideal tumor inhibition rate of 70.4%, thus providing a promising ROS-sensitive nanomedicine for cancer treatment.

The precise locoregional co-delivery of multi-agents is an attractive strategy for combination cancer therapy, with the imperative requirement of an ideal injectable hydrogel platform with immense adaptability and multicomponent compatibility to achieve synergetic therapeutic efficiency. Herein, the methoxy poly(ethylene glycol)-b-poly(e-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (mPECT) diblock copolymer was empolyed to prepare mPECT-modified gold nanorods (AuNR-PECT) and paclitaxel-loaded mPECT nanoparticles (PTX/mPECT NPs). Then, an injectable nanocomposite hydrogel (AuNR/PTXmPECTgel) was fabricated by the host-guest inclusion between AuNR-PECT, PTX/mPECT NPs and α-cyclodextrin. A single local injection of AuNR/PTXmPECTgel could deposit abundant PTX/mPECT NPs (20% w/w) and AuNRs at the target location, which then sustainedly released PTX/mPECT NPs at a constant rate for two weeks and exhibited outstanding photothermal effects by near-infrared radiation. As a result, complete tumor regression after peritumoral injection of AuNR/PTXmPECTgel and effective inhibition of tumor recurrence after injection of AuNR/PTXmPECTgel in the postoperative cavity were observed in breast cancer mouse models; this can be attributed to the in situ synergetic chemo-photothermal anticancer efficiencies of AuNR and the PTX/mPECT NPs. Remarkably, this injectable hydrogel platform constructed by supramolecular assembly of multi-nanoagents can be facilely extended to local combination therapies of different therapeutic agents.

Brachytherapy is considered to be an unparalleled form of conformal radiation therapy, which involves the delivery of radiation directly to tumor lesions or the postoperative cavity. With the development of specific applicators, the exploitation of in situ drug-delivery platform introduces opportunities for the synchronous administration of radiosensitizers. In this study, an iodine-131 (I131)-labeled injectable thermosensitive methoxy poly(ethylene glycol)-b-poly(tyrosine) hydrogel (denoted as PETyr-I131) was developed via a facile method. The radioactive source of I131 was immobilized at the subcutaneous injection site and monitored via single-photon emission computed tomography in real time, and hematological and histopathological analyses revealed no obvious side effects. Additionally, the SmacN7 peptide conjugated with cell membrane-permeable oligosarginine (denoted as SmacN7-R9) was used to enhance the radiosensitivity of cancer cells, as confirmed by the results of reactive oxygen species detection, DNA damage assay, cell apoptosis assay, and clonogenic evaluation. Importantly, a synergistic brachytherapy treatment effect on tumor-bearing nude mice was achieved. The proposed thermosensitive supramolecular hydrogel platform, which conformally immobilizes radionuclides and delivers radiosensitizers by virtue of its proximity to the site of the primary tumor or the postoperative cavity, has great potential for achieving synergistic treatment outcomes with reduced radiation-related side effects. STATEMENT OF SIGNIFICANCE: In this work, a kind of radioiodinated thermosensitive supramolecular hydrogel was developed, which was facilely used as the radioactive source for brachytherapy. Meanwhile, SmacN7-R9 peptide was combined as a model radiosensitizer to facilitate the activation of tumor cell apoptosis pathways and promotion of radiation-induced cytotoxicity. Synergistic brachytherapy outcomes were achieved from the in vitro and in vivo evaluations. Therefore, from the practical standpoint, this thermosensitive supramolecular hydrogel platform holds great potential for the 3D-conformally immobilizing radionuclide and delivering radiosensitizer by virtue of its proximity to the site of primary tumor lesions or postoperative cavity, resulting in synergetic treatment outcomes with reduced radiation associated side effects.

Flexible electronics is booming and attracts considerable interest in monitoring physiological activities and health conditions. The development of human-friend flexible electronics with both excellent human movement monitoring and flexible electrode functions at a wide working range remains highly challenging. Herein, we report a biomimetic double-layered multifunctional flexible electronic device composed of a stretchable, tough elastomer covalently coupled with a conductive, double-network hydrogel for monitoring physiological motions. The introduction of optimal physical crosslinking including hydrogen bond and metal coordination in the covalently cross-linked polyurethane elastomer effectively provides favorable flexibility and stretchability. The elastomer-hydrogel integration (EHI) shows ultra-fast responsiveness (10 ms) and resilience (246 ms) as a skin sensor and could effectively detect diverse muscle and joint movements in a highly sensitive and signal waveform-interpreting manner. Further, such a polymer integration with skin shape-adaptive hydrogel and low contact impedance enables real-time high-quality detection of electrocardiogram (ECG) by serving as flexible electrode compared to commercial Ag/AgCl electrodes, and was successfully applied to measure electrooculogram (EOG) and electromyogram (EMG). EHI-based electrodes were feasible and effective for electroencephalogram (EEG) signal detection in brain-computer interfaces (BCI) system. Altogether, this biomimetic EHI electronic device provides an advanced platform for the design of next-generation flexible healthcare diagnostic monitors and soft robots.

In recent years, photodynamic therapy (PDT) was considered to be a promising cancer treatment modality, however, the therapeutic efficiency was often attenuated by the intrinsic antioxidant defense systems. Herein, a kind of novel glutathione-induced amino-activatable micelle was designed, which was expected to weaken the antioxidant capacity and in the meantime release the photosensitizer by the exhaustion of intracellular glutathione (GSH). The amphiphilic poly(ethylene glycol)-(2-((2,4-dinitro-N-(ethyl) phenyl)sulfonamido) ethyl methacrylate) copolymers were synthesized and assembled into a core-shell nano structure in aqueous media. The nano structure demonstrated high sensitivity and selectivity to bio-thiols in vitro and in vivo. Subsequently, pheophorbide a (PhA) was encapsulated as the model photosensitizer. Upon internalization by HepG2 cells, the strongly electron-withdrawing 2,4-dinitrobenzenesulfonyl groups on the PADEE segments were readily cleaved by GSH, during which time the secondary amino groups (pKb = 11.32) were recovered and completely protonated, leading to disassembly of the micelles and rapid release of PhA. Importantly, the consumption of GSH weakened the intracellular antioxidant capacity, resulting in the synergetic accumulation of reactive oxygen species (ROS) under laser irradiation. As a result, this micellar photosensitization system could overcome the antioxidant capacity of advanced stage tumors through a simultaneous extrinsic and intrinsic strategy, facilitating therapeutic efficiency. These results demonstrate that the as-designed micelles provide a versatile photosensitization platform for on-demand PDT.

Immunotherapy in solid tumors is limited by the poor immunogenicity of tumors and limited T-cell immune response, resulting in low patient response rate. To increase the efficiency of cancer immunotherapy, a unique synergistic combination cancer immunotherapy by co-localized delivery of cancer nanomedicine for enhancing the tumor immunogenicity and nanovaccine for augmenting the antitumor T-cell immunity was developed for post-surgical tumor treatment. The thermo-responsive, curcumin-loaded polymer nanoparticles (nanomedicine)-assembled hydrogel enabled the complete coverage of the surgical bed of primary tumor and the spatio-temporal delivery of cognate nanomedicines and encapsulated nanovaccines. Importantly, the nanomedicine efficiently induced the immunogenic cell death (ICD) of residual cancer cells, and consequently enhanced the tumor immunogenicity and sensitized the tumor to antitumor T-cell immunity. The cancer nanovaccine composed of antigenic peptide, CpG-ODN and cationic polymer nanoparticle significantly triggered the maturation of dendritic cells (DCs) and elicited potent vaccine-specific T-cell immune responses. Using highly malignant postoperative breast carcinoma 4T1 models, we found that the combination immunotherapy strategy strikingly amplified the level of systemic host T-cell immunity, promoted the infiltration of CD8+ T lymphocytes in tumor, and thus efficaciously attenuated the local tumor recurrence and pulmonary metastasis. Collectively, this work provided an advanced synergistic combination approach for post-surgical tumor immunotherapy. The self-assembled hydrogel should enable a broader combination of immunomodulating nanomedicines and vaccines for cancer immunotherapy.

Clinical wound management remains a major challenge due to massive bleeding, bacterial infection, and difficult wound healing after tissue trauma. To simultaneously address these issues, composite polymer sponges for accelerating drug-resistant bacterial infected wound healing are fabricated by facilely mixing sodium polyacrylate (PAAS), double quaternary ammonium salts-conjugated chitosan (QAS-CS), and collagen (COL) in aqueous solution, followed by lyophilization. Composite sponges (PAAS/QAS-CS/COL, PQC) show highly porous microstructures (porosity ≈90%) with moderate compress modulus (≈0.3 MPa), tensile strength (0.004 MPa), and high swelling ratio (≈3500%). Importantly, PQC sponge demonstrates superior hemostasis ability over commercially available CS sponge by inducing rapid hemagglutination, and exhibits significantly better antibacterial activity against both methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli by destroying cell membrane and causing the leakage of bioactive components such as potassium ion and β-galactosidase from treated bacterial. Furthermore, PQC sponge can efficiently promote cell proliferation. Significantly, the sponge greatly expedites the regeneration of MRSA-infected full-thickness skin wound in rabbit by successfully eradicating bacterial infection, and reducing inflammation. PQC sponge also improves both early angiogenesis and blood vessel maturation at the wound site. Overall, this multifunctional sponge is a promising wound dressing for clinical use and holds great potential for rapid clinical translation.

A novel injectable and high-solid-content drug-loaded supramolecular hydrogel (PTX-mPECT NP/α-CDgel) was prepared by self-assembly of inclusion complexes based on PTX-loaded mPECT (methoxy poly(ethylene glycol)-b-poly(e-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-un-decanone)) nanoparticles (PTX-mPECT NPs) and α-cyclodextrin (α-CD). Paclitaxel (PTX) was chosen as a hydrophobic drug encapsulated into mPECT NPs. Then, gelation occurred when the aqueous solution of α-CD was added to the PTX-mPECT NPs aqueous dispersion within several seconds after stirring. Importantly, with the erosion of the hydrogel, PTX-loaded NPs could be released again and then PTX released further. Rheological studies showed that PTX-mPECT NP/α-CDgel with good injectability underwent a shear-induced sol-gel transition. The results of in vitro drug-release studies demonstrated a sustained-release profile, and the cumulative release of PTX was ≈35% after 20 days. The results of cell-uptake studies and in vitro cytotoxicity studies indicated that the PTX-loaded NPs have been efficiently delivered to cells and killed tumor cells. Higher suppression of tumor growth demonstrated the remarkable anticancer effect of PTX-mPECT NP/α-CDgel upon peritumoral injection. These results showed that high-solid-content PTX-mPECT NP/α-CDgel based on in situ systems could be a promising candidate for local and sustained drug delivery.

The redox status of cancer cells is well regulated by the balance between the reactive oxygen species (ROS) generation and elimination. Thus, the overall elevation of ROS level above the cellular tolerability threshold would lead to apoptotic or necrotic cell death. Herein, cinnamaldehyde (CA), a kind of oxidative stress amplified agent, was combined with photosensitizer pheophorbide A (PA) to promote the generation of ROS though synergistically endogenous and exogenous pathways. Firstly, acid-responsive polygalactose-co-polycinnamaldehyde polyprodrug (termed as PGCA) was synthesized, which could self-assemble into stable nanoparticles for the delivery of PA (termed as PGCA@PA NPs). The abundant expression of galactose receptor on tumor cells facilitated the positive targeting and cellular uptake efficiency of PGCA@PA NPs, after which PA could be synchronously released in company with the intracellular disassembly of PGCA NPs, due to the detaching of CA moieties under acidic microenvironment in endo/lysosomal compartment. Significantly increased ROS level was induced by the combined action of CA and PA with light irradiation, resulting in dramatically enhanced apoptosis of cancer cells. Importantly, intravenous injection of PGCA@PA NPs potently inhibited the tumor growth in hepatocellular carcinoma with negligible adverse effects. Moreover, combined with anti-programmed cell death protein 1 (anti-PD-1) therapy, PGCA@PA NPs treatment elicited anti-melanoma T-cell immune response and significantly promoted T cells infiltration in tumors. Hence, this novel polyprodrug nano delivery system was able to target and modulate the unique redox regulatory mechanisms of cancer cells through endogenous and exogenous pathways, providing a feasible approach to achieve synergetic therapeutic activity and selectivity.

19F magnetic resonance imaging (19F MRI), a kind of non-invasive and non-radioactive diagnostic technique with no endogenous background signals, opens up new research avenues for accurate molecular imaging studies. However, 19F MRI is manily limited by the performance of contrast agents. Here, for the first time, we presented the zwitterionic fluorinated polymer and nanogel as new types of superhydrophilic, sensitive and ultra-stable 19F MRI contrast agents. The superhydrophilicity of carboxybetaine zwitterionic structure completely overcame the hydrophobic aggregation-induced signal attenuation associated with amphiphilic fluorinated polymer-based nanoprobes. In addition, the superhydrophilic contrast agent exhibited distinct advantages, including high 19F-content (19.1 wt%), superior resistance to protein adsorption, constant MR properties and 19F MRS-based quantitative determination in complex biological fluids, and intense 19F MRI signals in the whole-body images after intravenous injection. In combination with angiogenesis targeting ligand, the superhydrophilic contrast agent was applied for the unambiguous detection of tumor. Importantly, computational algorithm was established for the directly quantitative determination of bioavailability and tumor-to-whole body ratio (TBR) from the in vivo 19F MRI dataset, providing real-time information with non-invasive manner. Finally, crosslinked nanogels were developed with significantly prolonged systemic circulation, of which intense 19F MRI signals nonspecifically distributed in the aortaventralis and blood-rich organs, instead of being trapped steadily in liver as with the state-of-the-art superhydrophobic perfluocarbon nanoemulsions. Overall, this kind of superhydrophilic, zwitterionic fluorinated polymer and nanogel could be defined as a new generation of high-performance 19F MRI contrast agents, which hold great potential for image-based unambiguous disease detection and computational quantification.

Wenlei Chen,1 Min Zhi,1 Zujian Feng,2 Pengfei Gao,1 Yuan Yuan,1 Congcong Zhang,1 Yonglan Wang,1 Anjie Dong2 1Department of Periodontology, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, People’s Republic of China; 2Department of Polymer Science and Technology and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin, People’s Republic of China Objective: The aims of this study were to 1) encapsulate ibuprofen (IBU) and basic fibroblast growth factor (bFGF) in a thermosensitive micellar hydrogel, 2) test the biological properties of this in situ drug delivery system, and 3) study the effect of hydrogel in promoting soft tissue healing after implant surgery and its anti-inflammatory function as an early local treatment of peri-implantitis.Materials and methods: A thermosensitive micellar hydrogel was prepared from amphiphilic copolymer poly(ε-caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(ε-caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undecanone) (PECT) nanoparticles and tested in vitro using a scanning electron microscope, rheometer, UV spectrophotometer, HPLC, and transmission electron microscope.Results: The bFGF + IBU/PECT hydrogel formed a stable, water-dispersible nanoparticle core shell that was injectable at room temperature, hydrogel in situ at body temperature, and provided sustained release of both hydrophilic and hydrophobic drugs. The hydrogel promoted the proliferation and adhesion of human gingival fibroblasts, upregulated the expression of adhesion factors such as vinculin proteins, and showed anti-inflammatory properties.Conclusion: In situ preparation of IBU- and bFGF-loaded PECT hydrogel represents a promising drug delivery system with the potential to provide early local treatment for peri-implantitis. Keywords: thermosensitive hydrogel, nanoparticles, dual drugs, peri-implantitis &nbsp

The ability to tune the degradation rate of a biodegradable polymer, which can achieve precise spatiotemporal control of drug delivery, is of considerable interest for biomedical applications. In this study, a series of amphiphilic copolymers, methoxy poly(ethyleneglycol)-b-poly((2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate)-co-2-(diisopropylamino)ethyl methacrylate) (mPEG-b-P(TTMA-co-DPA), PETD) with different numbers of DPA units, were synthesized by Reversible Addition Fragmentation Chain Transfer (RAFT) copolymerization, in which DPA containing tertiary amines were introduced to adjust the hydrolysis behavior of cyclic benzylidene acetals (CBAs). The molecular structure and the chemical composition of PETD were characterized by 1H NMR and gel permeation chromatography (GPC). PETD could self-assemble into stable nanoparticles with well-defined spherical morphology and displayed high drug loading capacity with doxorubicin (DOX) as the drug model. The hydrolysis behavior of CBAs in the PETD NPs was investigated by UV/vis spectroscopy under different pH values. Compared with PETD-0 bearing no DPA unit, the hydrolysis rate of PETD-3 with more DPA was faster, while PETD-1 with less DPA hydrolyzed much slower, which indicated that the introduction of DPA had an amphoteric effect on the hydrolysis behavior of CBAs under acidic conditions. In addition, the in vitro release of DOX was also investigated under different pH conditions and the result was in accordance with the hydrolysis result. Furthermore, the results of fluorescence microscopy demonstrated improved internalization of DOX-loaded PETD-3 NPs in HepG-2 cells with rapid DOX release intracellularly, which showed considerable cytotoxicity against HepG-2 cells.