Targeting Delivery of Oligodeoxynucleotides to Macrophages by Mannosylated Cationic Albumin for Immune Stimulation in Cancer Treatment.

To efficiently deliver CpG oligodeoxynucleotides (ODNs) to macrophages for the reversal of cancer-induced immunosuppression, nanoparticles ODN@MCBSA with mannosylated cationic albumin (MCBSA) as a macrophage targeting vector were constructed. Compared with ODN@CBSA with cationic albumin (CBSA) as a vector, ODN@MCBSA exhibited significantly improved cellular uptake mediated by mannose moieties, resulting in significantly enhanced secretion of proflammatory cytokines including IL-12, IL-6, TNF-α, and iNOS. The modulation of macrophages toward the favorable M1 phenotype was confirmed by the upregulated CD80 expression after being treated by ODN delivery systems. In addition to immune cells, the effects of the ODN delivery system on cancerous HeLa cells were also investigated. The results showed that ODN@MCBSA did not affect the overall tumor cell viability. However, enhanced NF-κB, p-Akt, PIK3R3, Fas, and FasL, as well as upregulated caspases were observed in tumor cells, implying the pleiotropic effects on tumor cells. Our study provides a more in-depth understanding on the immunotherapeutic effects of CpG ODNs and highlights the importance of macrophage targeting delivery to minimize the effects on tumor cells. These results indicate that MCBSA could serve as a promising delivery vector of CpG ODNs to macrophages for cancer immunotherapy.

A Dual-Targeting Delivery System for Effective Genome Editing and In Situ Detecting Related Protein Expression in Edited Cells.

One of critical steps in genome editing by CRISPR-Cas9 is to deliver the CRISPR-Cas9 system into targeted cells. In this study, we developed a dual-targeting delivery system based on polymer/inorganic hybrid nanoparticles to realize highly efficient genome editing in targeted tumor cells as well as in situ detection on the related protein expression in edited cells. The CRISPR-Cas9 plasmid for CDK11 knockout was encapsulated in the core of the delivery system composed of protamine sulfate, calcium carbonate, and calcium phosphate by coprecipitation, and functional derivatives of carboxymethyl chitosan (biotinylated carboxymethyl chitosan with biotin ligands and aptamer-incorporated carboxymethyl chitosan with AS1411 ligands) were decorated on the nanovector surface by electrostatic interactions to form the dual-targeting delivery system. On the basis of the tumor cell targeting capability of biotin and AS1411 ligands as well as the nuclear targeting of AS1411, the dual-targeting system can deliver the CRISPR-Cas9 plasmid into the nuclei of tumor cells to realize highly efficient genome editing, resulting in a dramatic decrease (>90%) in CDK11 protein together with the significant downregulation of other proteins involved in tumor development, including an ∼90% decrease in MMP-9, >40% decrease in VEGF, and ∼70% decrease in survivin. Using the same vector, molecular beacons can be easily delivered to edited cell nuclei to in situ detect the mRNA level of related proteins (p53 and survivin as typical examples) and mRNA distribution in subcellular organelles. Our strategy can realize effective genome editing and in situ detection on related protein expression simultaneously.

Tumor Targeting Synergistic Drug Delivery by Self-Assembled Hybrid Nanovesicles to Overcome Drug Resistance.

PURPOSE: To overcome multi-drug resistance (MDR) in tumor chemotherapy, a polymer/inorganic hybrid drug delivery platform with tumor targeting property and enhanced cell uptake efficiency was developed. METHOD: To evaluate the applicability of our delivery platform for the delivery of different drug resistance inhibitors, two kinds of dual-drug pairs (doxorubicin/buthionine sulfoximine and doxorubicin/tariquidar, respectively) were loaded in heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles to realize simultaneous delivery of an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells. RESULTS: Prepared by self-assembly, the drug loaded hybrid nanovesicles with a mean size less than 210 nm and a negative zeta potential exhibit good stability in serum contained aqueous media. The in vitro cytotoxicity evaluation indicates that hybrid nanovesicles with tumor targeting biotin moieties have an enhanced tumor cell inhibitory effect. In addition, dual-drug loaded hybrid nanovesicles exhibit significantly stronger cell growth inhibition as compared with doxorubicin (DOX) mono-drug loaded nanovesicles due to the reduced intracellular glutathione (GSH) content by buthionine sulfoximine (BSO) or the P-glycoprotein (P-gp) inhibition by tariquidar (TQR). CONCLUSIONS: The tumor targeting nanovesicles prepared in this study, which can simultaneously deliver multiple drugs and effectively reverse drug resistance, have promising applications in drug delivery for tumor treatments. The polymer/inorganic hybrid drug delivery platform developed in this study has good applicability for the co-delivery of different anti-tumor drug/drug resistance inhibitor pairs to overcome MDR. Graphical Abstract A polymer/inorganic hybrid drug delivery platform with enhanced cell uptake was developed for tumor targeting synergistic drug delivery. The heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles prepared in this study can deliver an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells simultaneously to overcome drug resistance efficiently.

Water-soluble photoluminescent fullerene capped mesoporous silica for pH-responsive drug delivery and bioimaging.

In this paper, a biocompatible and water-soluble fluorescent fullerene (C60-TEG-COOH) coated mesoporous silica nanoparticle (MSN) was successfully fabricated for pH-sensitive drug release and fluorescent cell imaging. The MSN was first reacted with 3-aminopropyltriethoxysilane to obtain an amino-modified MSN, and then the water-soluble C60 with a carboxyl group was used to cover the surface of the MSN through electrostatic interaction with the amino group in PBS solution (pH = 7.4). The release of doxorubicin hydrochloride (DOX) could be triggered under a mild acidic environment (lysosome, pH = 5.0) due to the protonation of C60-TEG-COO-, which induced the dissociation of the C60-TEG-COOH modified MSN (MSN@C60). Furthermore, the uptake of nanoparticles by cells could be tracked because of the green fluorescent property of the C60-modified MSN. In an in vitro study, the prepared materials showed excellent biocompatibility and the DOX-loaded nanocarrier exhibited efficient anticancer ability. This work offered a simple method for designing a simultaneous pH-responsive drug delivery and bioimaging system.

Dual-pH Sensitive Charge-Reversal Polypeptide Micelles for Tumor-Triggered Targeting Uptake and Nuclear Drug Delivery.

A novel dual-pH sensitive charge-reversal strategy is designed to deliver antitumor drugs targeting to tumor cells and to further promote the nuclei internalization by a stepwise response to the mildly acidic extracellular pH (≈6.5) of a tumor and endo/lysosome pH (≈5.0). Poly(L-lysine)-block-poly(L-leucine) diblock copolymer is synthesized and the lysine amino residues are amidated by 2,3-dimethylmaleic anhydride to form ß-carboxylic amide, making the polypeptides self-assemble into negatively charged micelles. The amide can be hydrolyzed when exposed to the mildly acidic tumor extracellular environment, which makes the micelles switch to positively charged and they are then readily internalized by tumor cells. A nuclear targeting Tat peptide is further conjugated to the polypeptide via a click reaction. The Tat is amidated by succinyl chloride to mask its positive charge and cell-penetrating function and thus to inhibit nonspecific cellular uptake. After the nanoparticles are internalized into the more acidic intracellular endo/lysosomes, the Tat succinyl amide is hydrolyzed to reactivate the Tat nuclear targeting function, promoting nanoparticle delivery into cell nuclei. This polypeptide nanocarrier facilitates tumor targeting and nuclear delivery simultaneously by simply modifying the lysine amino residues of polylysine and Tat into two different pH-sensitive ß-carboxylic amides.

Self-assembled polymer/inorganic hybrid nanovesicles for multiple drug delivery to overcome drug resistance in cancer chemotherapy.

With the aim to develop a facile strategy to prepare functional drug carriers to overcome multidrug resistance (MDR), we prepared heparin/protamine/calcium carbonate (HP/PS/CaCO3) hybrid nanovesicles with enhanced cell internalization, good serum stability, and pH sensitivity for drug delivery. All the functional components including protamine to improve the cell uptake, heparin to enhance the stability, and CaCO3 to improve drug loading and endow the system with pH sensitivity were introduced to the nanovesicles by self-assembly in an aqueous medium. An antitumor drug (doxorubicin, DOX) and a drug resistance inhibitor (tariquidar, TQR) were coloaded in the nanovesicles during self-assembly preparation of the nanovesicles. The drug loaded nanovesicles, which had a mean size less than 200 nm, exhibited a pH-sensitive drug release behavior. In vitro study was carried out in both nonresistant cells (HeLa and MCF-7) and drug-resistant cancer cells (MCF-7/ADR). Because of the enhanced intracellular and nuclear drug accumulation through effective inhibition of the P-gp efflux transporter, DOX/TQR coloaded nanovesicles showed significantly improved tumor cell inhibitory efficiency, especially for drug-resistant cells. These results suggest the self-assembled nanovesicles have promising applications in multidrug delivery to overcome drug resistance in tumor treatments.

A dual-responsive mesoporous silica nanoparticle for tumor-triggered targeting drug delivery.

A novel pH- and redox- dual-responsive tumor-triggered targeting mesoporous silica nanoparticle (TTTMSN) is designed as a drug carrier. The peptide RGDFFFFC is anchored on the surface of mesoporous silica nanoparticles via disulfide bonds, which are redox-responsive, as a gatekeeper as well as a tumor-targeting ligand. PEGylated technology is employed to protect the anchored peptide ligands. The peptide and monomethoxypolyethylene glycol (MPEG) with benzoic-imine bond, which is pH-sensitive, are then connected via "click" chemistry to obtain TTTMSN. In vitro cell research demonstrates that the targeting property of TTTMSN is switched off in normal tissues with neutral pH condition, and switched on in tumor tissues with acidic pH condition after removing the MPEG segment by hydrolysis of benzoic-imine bond under acidic conditions. After deshielding of the MPEG segment, the drug-loaded nanoparticles are easily taken up by tumor cells due to the exposed peptide targeting ligand, and subsequently the redox signal glutathione in tumor cells induces rapid drug release intracellularly after the cleavage of disulfide bond. This novel intelligent TTTMSN drug delivery system has great potential for cancer therapy.

Theranostic GO-based nanohybrid for tumor induced imaging and potential combinational tumor therapy.

Graphene oxide (GO)-based theranostic nanohybrid is designed for tumor induced imaging and potential combinational tumor therapy. The anti-tumor drug, Doxorubicin (DOX) is chemically conjugated to the poly(ethylenimine)-co-poly(ethylene glycol) (PEI-PEG) grafted GO via a MMP2-cleavable PLGLAG peptide linkage. The therapeutic efficacy of DOX is chemically locked and its intrinsic fluorescence is quenched by GO under normal physiological condition. Once stimulated by the MMP2 enzyme over-expressed in tumor tissues, the resulting peptide cleavage permits the unloading of DOX for tumor therapy and concurrent fluorescence recovery of DOX for in situ tumor cell imaging. Attractively, this PEI-bearing nanohybrid can mediate efficient DNA transfection and shows great potential for combinational drug/gene therapy. This tumor induced imaging and potential combinational therapy will open a window for tumor treatment by offering a unique theranostic approach through merging the diagnostic capability and pathology-responsive therapeutic function.

Multifunctional envelope-type mesoporous silica nanoparticles for tumor-triggered targeting drug delivery.

A novel type of cellular-uptake-shielding multifunctional envelope-type mesoporous silica nanoparticle (MEMSN) was designed for tumor-triggered targeting drug delivery to cancerous cells. ß-Cyclodextrin (ß-CD) was anchored on the surface of mesoporous silica nanoparticles via disulfide linking for glutathione-induced intracellular drug release. Then a peptide sequence containing Arg-Gly-Asp (RGD) motif and matrix metalloproteinase (MMP) substrate peptide Pro-Leu-Gly-Val-Arg (PLGVR) was introduced onto the surface of the nanoparticles via host-guest interaction. To protect the targeting ligand and prevent the nanoparticles from being uptaken by normal cells, the nanoparticles were further decorated with poly(aspartic acid) (PASP) to obtain MEMSN. In vitro study demonstrated that MEMSN was shielded against normal cells. After reaching the tumor cells, the targeting property could be switched on by removing the PASP protection layer via hydrolyzation of PLGVR at the MMP-rich tumor cells, which enabled the easy uptake of drug-loaded nanoparticles by tumor cells and subsequent glutathione-induced drug release intracellularly.

A peptide nanofibrous indicator for eye-detectable cancer cell identification.

A unique peptide nanofibrous indicator (NFI) is fabricated by mixing a borono-peptide with alizarin red S, followed by subsequent binding and self-assembly. The NFI thus obtained exhibits an intense response to sialyl Lewis X tetrasaccharide, which is overexpressed in human hepatocellular carcinoma cell lines. Importantly, this NFI has the capability of specifically recognizing human hepatocellular liver carcinoma (HepG2) cells through the eye-detectable color change resulting from strong binding-induced displacement. This novel technique for cancer cell identification through direct unaided eye judgment will open up an innovative platform for cancer cell detection.

Peptide-based vector of VEGF plasmid for efficient gene delivery in vitro and vessel formation in vivo.

Critical limb ischemia is regarded as a potentially lethal disease, and the treatment effects of existing therapies are limited. Here, in order to develop a potential approach to improve the therapy effects, we designed a peptide of TAT-PKKKRKV as the vector for VEGF165 plasmid to facilitate in vivo angiogenesis. In in vitro studies, TAT-PKKKRKV with low cytotoxicity exhibited efficient transfection ability either with or without serum. Additionally, application of TAT-PKKKRKV/VEGF165 complexes in hindlimb ischemia rats obviously promoted the expression of VEGF protein, which further enhanced effective angiogenesis. The results indicated that TAT-PKKKRKV is an efficient gene vector with low toxicity both in vitro and in vivo, which has great potential for clinical gene therapy.

Avidin-biotin interaction mediated peptide assemblies as efficient gene delivery vectors for cancer therapy.

Gene therapy offers a bright future for the treatment of cancers. One of the research highlights focuses on smart gene delivery vectors with good biocompatibility and tumor-targeting ability. Here, a novel gene vector self-assembled through avidin-biotin interaction with optimized targeting functionality, biotinylated tumor-targeting peptide/avidin/biotinylated cell-penetrating peptide (TAC), was designed and prepared to mediate the in vitro and in vivo delivery of p53 gene. TAC exhibited efficient DNA-binding ability and low cytotoxicity. In in vitro transfection assay, TAC/p53 complexes showed higher transfection efficiency and expression amount of p53 protein in MCF-7 cells as compared with 293T and HeLa cells, primarily due to the specific recognition between tumor-targeting peptides and receptors on MCF-7 cells. Additionally, by in situ administration of TAC/p53 complexes into tumor-bearing mice, the expression of p53 gene was obviously upregulated in tumor cells, and the tumor growth was significantly suppressed. This study provides an alternative and unique strategy to assemble functionalized peptides, and the novel self-assembled vector TAC developed is a promising gene vector for cancer therapy.

Controlled arrays of self-assembled peptide nanostructures in solution and at interface.

Controlling the formation of large and homogeneous arrays of bionanostructures through the self-assembly approach is still a great challenge. Here, we report the spontaneous formation of highly ordered arrays based on aligned peptide nanostructures in a solution as well as at an interface by self-assembly. By controlling the time and temperature of self-assembly in the solution, parallel fibrous alignments and more sophisticated two-dimensional "knitted" fibrous arrays could be formed from aligned rod-like fibers. During the formation of such arrays, the "disorder-to-order" transitions are controlled by the temperature-responsible motile short hydrophobic tails of the gemini-like amphiphilic peptides (GAPs) with asymmetric molecular conformation. In addition, the resulting long-range-ordered "knitted" fibrous arrays are able to direct mineralization of calcium phosphate to form organic-inorganic composite materials. In this study, the self-assembly behavior of these peptide building blocks at an interface was also studied. Highly ordered spatial arrays with vertically or horizontally aligned nanostructures such as nanofibers, microfibers, and microtubes could be formed through interfacial assembly. The regular structures and their alignments on the interface are controlled by the alkyl chain length of building blocks and the hydrophilicity/hydrophobicity property of the interface.

Graphene-based anticancer nanosystem and its biosafety evaluation using a zebrafish model.

In this paper, a facile strategy to develop graphene-based delivery nanosystems for effective drug loading and sustained drug release was proposed and validated. Specifically, biocompatible naphthalene-terminated PEG (NP) and anticancer drugs (curcumin or doxorubicin (DOX)) were simultaneously integrated onto oxidized graphene (GO), leading to self-assembled, nanosized complexes. It was found that the oxidation degree of GO had a significant impact on the drug-loading efficiency and the structural stability of nanosystems. Interestingly, the nanoassemblies resulted in more effective cellular entry of DOX in comparison with free DOX or DOX-loaded PEG-polyester micelles at equivalent DOX dose, as demonstrated by confocal microscopy studies. Moreover, the nanoassemblies not only exhibited a sustained drug release pattern without an initial burst release, but also significantly improved the stability of formulations which were resistant to drug leaking even in the presence of strong surfactants such as aromatic sodium benzenesulfonate (SBen) and aliphatic sodium dodecylsulfonate (SDS). In addition, the nanoassemblies without DOX loading showed negligible in vitro cytotoxicity, whereas DOX-loaded counterparts led to considerable toxicity against HeLa cells. The DOX-mediated cytotoxicity of the graphene-based formulation was around 20 folds lower than that of free DOX, most likely due to the slow DOX release from complexes. A zebrafish model was established to assess the in vivo safety profile of curcumin-loaded nanosystems. The results showed they were able to excrete from the zebrafish body rapidly and had nearly no influence on the zebrafish upgrowth. Those encouraging results may prompt the advance of graphene-based nanotherapeutics for biomedical applications.

Bioreducible polypeptide containing cell-penetrating sequence for efficient gene delivery.

PURPOSE: To design excellent polypeptide-based gene vectors and determine the gene delivery efficiency. METHODS: Polypeptides (designated as xPolyK6, xPolyK6-R81 and xPolyK6-R82), comprising the DNA condensing and buffering peptide HK6H as well as cell penetrating peptide (CPP) R8 were obtained by the oxidative polymerization of CHK6HC and CR8C at different molar ratios in 4 mL phosphate-buffered saline (PBS) containing 30% (v/v) DMSO at room temperature for 96 h. The cytotoxicity of vectors was studied by MTT assay. Moreover, particle size, zeta potential and morphology along with the in vitro transfection efficiency and cellular uptake of vector/plasmid DNA (pDNA) complexes were characterized at various w/w ratios to determine their potential in gene therapy. RESULTS: All the vectors presented excellent ability of binding and condensing pDNA, additionally with low cytotoxicity. Simultaneously, transfection efficiency of the vectors appeared apparent dependence on the vector composition. The distinct correlation between the content of CR8C with the transfection efficiency demonstrated the effective improvement in transfection efficacy by the oxidative polymerization. Particularly, xPolyK6-R82 possessed the highest transfection efficiency at a w/w ratio of 50. Furthermore, xPolyK6-R82 also presented the best cellular uptake capability demonstrated by confocal microscopy and flow cytometry. CONCLUSIONS: Bioreducible polypeptides incorporating with proper amount of CPP are promising as effective non-viral gene vectors in gene therapy.

Enhanced nuclear import and transfection efficiency of TAT peptide-based gene delivery systems modified by additional nuclear localization signals.

Cellular uptake and nuclear localization are two major barriers in gene delivery. In order to evaluate whether additional nuclear localization signals (NLSs) can improve gene transfection efficiency, we introduced different kinds of NLSs to TAT-based gene delivery systems to form three kinds of complexes, including TAT-PV/DNA, TAT/DNA/PV, and TAT/DNA/HMGB1. The DNA binding ability of different vectors was evaluated by agarose gel electrophoresis. The in vitro transfections mediated by different complexes under different conditions were carried out. The cells treated by different complexes were observed by confocal microscopy. The MTT assay showed that all complexes did not exhibit apparent cytotoxicity in both HeLa and Cos7 cell lines even at high N/P ratios. The luciferase reporter gene expression mediated by TAT-PV/DNA complexes exhibited about 200-fold enhancement as compared with TAT/DNA complexes. Confocal study showed that, except TAT/DNA/PV, all other complexes exhibited enhanced nuclear accumulation and cellular uptake in both HeLa and Cos7 cell lines. These results indicated that the introduction of nuclear localization signals could enhance the transfection efficacy of TAT-based peptides, implying that the TAT peptide-based vectors demonstrated here have promising potential in gene delivery.

Synthesis of thermo- and pH-sensitive polyion complex micelles for fluorescent imaging.

Two thermo- and pH-sensitive polypeptide-based copolymers, poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide)-b-poly(L-lysine) (P(NIPAAm-co-HMAAm)-b-PLL, P1) and poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide)-b-poly(glutamic acid) (P(NIPAAm-co-HMAAm)-b-PGA, P2), have been designed and synthesized by the ring-opening anionic polymerization of N-carboxyanhydrides (NCA) with amino-terminated P(NIPAAm-co-HMAAm). It was found that the block copolymers exhibit good biocompatibility and low toxicity. As a result of electrostatic interactions between the positively charged PLL and negatively charged PGA, P1 and P2 formed polyion complex (PIC) micelles consisting of polyelectrolyte complex cores and P(NIPAAm-co-HMAAm) shells in aqueous solution. The thermo- and pH-sensitivity of the PIC micelles were studied by UV/Vis spectrophotometry, dynamic light scattering (DLS), and transmission electron microscopy (TEM). Moreover, fluorescent PIC micelles were achieved by introducing two fluorescent molecules with different colors. Photographs and confocal laser scanning microscopy (CLSM) showed that the fluorescence-labeled PIC micelles exhibit thermo- and pH-dependent fluorescence, which may find wide applications in bioimaging in complicated microenvironments.

Alginate/CaCO3 hybrid nanoparticles for efficient codelivery of antitumor gene and drug.

In this study, a facile strategy for efficient codelivery of gene and drug was developed. Using a coprecipitation method, doxorubicin hydrochloride (DOX), an antitumor drug, and p53 expression plasmid were encapsulated in alginate/CaCO(3)/DNA/DOX nanoparticles with high encapsulation efficiency. The in vitro cell inhibition effect of the alginate/CaCO(3)/DNA/DOX nanoparticles was evaluated by MTT assay in HeLa cells. The alginate/CaCO(3)/DNA/DOX nanoparticles exhibited a high cell inhibition rate about 80%, indicating that the alginate/CaCO(3)/DNA/DOX nanoparticles could effectively mediate gene transfection and deliver the drug to the cells. Compared with the codelivery of gene and drug, the treatments by alginate/CaCO(3)/DOX nanoparticles and alginate/CaCO(3)/DNA nanoparticles separately led to much lower cell inhibition rates. Compared with the CaCO(3)/DNA/DOX nanoparticles without alginate modification, the alginate/CaCO(3)/DNA/DOX nanoparticles with a decreased particle size exhibited enhanced delivery efficiency. The alginate/CaCO(3)/DNA/DOX nanoparticles have promising applications in cancer treatments.

Morphology transformation via pH-triggered self-assembly of peptides.

Three flexible peptides (P1: (C(17)H(35)CO-NH-GRGDG)(2)KG; P2: (Fmoc-GRGDG)(2)KG; P3: (CH(3)CO-NH-GRGDG)(2)KG) self-assembled to form a variety of morphologically distinct assemblies at different pHs. P1 formed nanofibers at pH 3, then self-assembled into nanospheres with pH up to 6 and further changed to lamellar structures when the pH value was further increased to 10. P2 aggregated into an entwined network structure at pH 3, and then self-assembled into well-defined nanospheres, lamellar structures, and vesicles via adjusting the pH value. However, P3 did not self-assemble into well-ordered nanostructures, presumably due to the absence of a large hydrophobic group. The varying self-assembly behaviors of the peptides at different pHs are attributed to molecular conformational changes. These self-assembled supramolecular materials might contribute to the development of new peptide-based biomaterials.

PEG-stabilized micellar system with positively charged polyester core for fast pH-responsive drug release.

PURPOSE: To design functional drug carriers for fast pH-responsive drug release. METHODS: Functional diblock terpolymers of monomethoxy poly(ethylene glycol)-block- copoly(6,14-dimethyl-1,3,9,11-tetraoxa-6,14-diaza-cyclohexadecane-2,10-dione-co-ε-caprolactone) [mPEG-b-poly(ADMC-co-CL)] were fabricated via biosynthetic pathway. The self-assembled nanosphere and drug-loaded micelles of the copolymers were further prepared by dialysis method. The pH-tunable morphology variation and drug release pattern were observed at different pH. RESULTS: A collection of three PEGylated terpolymers with varied compositions in poly(ADMC-co-CL) block was designed with high cell-biocompatibility. The copolymers could readily self-assemble into nanoscale micelles (~ 100 nm) in aqueous medium and exhibit high stability over 80-h incubation in different mediums including deionized water, neutral NaCl solution, and heparin sodium solution. Due to the protonation-deprotonation of tertiary amine groups in ADMC units, acid-induced structural deformation of micelles was disclosed in terms of the variation in CAC value and hydrodynamic size at different pH. Drug loading efficiency was comparable to that of reported PEG-polyester micelles with specifically designed structures purposed for drug-loading improvement. Remarkably accelerated drug release triggered by acidity was distinctly detected for ibuprofen-loaded mPEG-b-poly(ADMC-co-CL) micelle system, suggesting a fast pH-responsive characteristic. CONCLUSION: Functional PEG-stabilized micellar carriers with positively charged polyester core were successfully developed for fast pH-responsive drug release.