Chang-Ming Dong

Supramolecular and Biomimetic Polypseudorotaxane/Glycopolymer Biohybrids : Synthesis, Glucose-Surfaced Nanoparticles, and Recognition with Lectin

A new class of supramolecular and biomimetic glycopolymer/poly(epsilon-caprolactone)-based polypseudorotaxane/glycopolymer triblock copolymers (poly(D-gluconamidoethyl methacrylate)-PPR-poly(D-gluconamidoethyl methacrylate), PGAMA-PPR-PGAMA), exhibiting controlled molecular weights and low polydispersities, was synthesized by the combination of ring-opening polymerization of epsilon-caprolactone, supramolecular inclusion reaction, and direct atom transfer radical polymerization (ATRP) of unprotected D-gluconamidoethyl methacrylate (GAMA) glycomonomer. The PPR macroinitiator for ATRP was prepared by the inclusion complexation of biodegradable poly(epsilon-caprolactone) (PCL) with alpha-cyclodextrin (alpha-CD), in which the crystalline PCL segments were included into the hydrophobic alpha-CD cavities and their crystallization was completely suppressed. Moreover, the self-assembled aggregates from these triblock copolymers have a hydrophilic glycopolymer shell and an oligosaccharide threaded polypseudorotaxane core, which changed from spherical micelles to vesicles with the decreasing weight fraction of glycopolymer segments. Furthermore, it was demonstrated that these triblock copolymers had specific biomolecular recognition with concanavalin A (Con A) in comparison with bovine serum albumin (BSA). To the best of our knowledge, this is the first report that describes the synthesis of supramolecular and biomimetic polypseudorotaxane/glycopolymer biohybrids and the fabrication of glucose-shelled and oligosaccharide-threaded polypseudorotaxane-cored aggregates. This hopefully provides a platform for targeted drug delivery and for studying the biomolecular recognition between sugar and lectin.

NIR-responsive and lectin-binding doxorubicin-loaded nanomedicine from Janus-type dendritic PAMAM amphiphiles.

Janus-type dendritic poly(amido amine) (PAMAM) amphiphiles Dm-Lac-D3DNQ were synthesized by connecting hydrophobic diazonaphthoquinone (DNQ)-decorated PAMAM dendron D3 (generation 3) and hydrophilic lactose (Lac)-decorated PAMAM dendrons Dm (generations 0-2, m = 0-2) via click chemistry. They self-assembled into the DNQ-cored micelles dangled by densely free Lac groups in aqueous solution. Irradiated by 808 nm laser and 365 nm lamp, both NIR- and UV-sensitivity of micelles were characterized by time-resolved UV-vis spectroscopy. The characteristic absorption intensity of DNQ progressively decreased and then leveled off. Moreover, the bigger the micelles, the more the irradiation time for finishing Wolff rearrangement of DNQ. TEM further confirmed that most of the micelles disassembled after 30 min of 808 nm laser irradiation. The Lac-coated micelles showed binding with RCA(120) lectin, as monitored by UV-vis and DLS. The apparent drug-release rate of doxorubicin (DOX) loaded nanomedicine nearly doubled after 10 min of 808 nm laser irradiation, presenting a NIR-triggered drug-release profile. Moreover, the DOX-loaded nanomedicine presented a phototriggered cytotoxicity that was close to free DOX, and they could quickly enter into HeLa cells, as evidenced by MTT assay, flow cytometry, and CLSM. Importantly, this work provides a versatile strategy for the fabrication of NIR-responsive and lectin-binding dendrimer nanomedicine, opening a new avenue for on-demand and spatiotemporal drug delivery.

Bioreducible micelles and hydrogels with tunable properties from multi-armed biodegradable copolymers

Multi-armed biodegradable block copolymers with a bioreducible core mPCL-b-PEO were for the first time synthesized by thiol-yne click chemistry. They self-assembled into bioreducible micelles and hydrogels in aqueous solution, which demonstrated tunable size, mechanical and drug-release properties.

Versatile Strategy for the Synthesis of Dendronlike Polypeptide/Linear Poly(ε-caprolactone) Block Copolymers via Click Chemistry

A new class of dendron-like polypeptide/linear poly(epsilon-caprolactone) block copolymers with asymmetrical topology (i.e., dendron-like poly(gamma-benzyl-l-glutamate)/linear PCL copolymers having 2(m) PBLG branches, m = 0, 1, 2, and 3; denoted as PCL-Dm-PBLG) was for the first time synthesized via the combination of controlled ring-opening polymerization (ROP) of epsilon-caprolactone, click chemistry, and the ROP of gamma-benzyl-l-glutamate N-carboxyanhydride (BLG-NCA). The linear hydroxyl-terminated PCL (PCL-OH) was synthesized by controlled ROP of epsilon-caprolactone and then transformed into clickable azide-terminated PCL (PCL-N(3)). The PCL-N(3) precursor was further click conjugated with propargyl focal point PAMAM-typed dendrons (i.e., Dm having 2(m) primary amine groups) to generate PCL-dendrons (PCL-Dm) using CuBr/PMDETA as catalyst in dimethylformamide solution at 35 degrees C. Finally, PCL-Dm was used as macroinitiator for the ROP of BLG-NCA monomer to produce the targeted PCL-Dm-PBLG block copolymers. Their molecular structures and physical properties were characterized in detail by FT-IR, NMR, matrix assisted laser desorption ionization time-of-flight mass spectrometry, gel permeation chromatography, differential scanning calorimetry, and wide-angle X-ray diffraction. To the best of our knowledge, this is the first report that describes the synthesis of dendron-like polypeptide/linear PCL block copolymers with asymmetrical topology via the combination of ROP and click chemistry. Consequently, this provides a versatile strategy for the synthesis of biodegradable and biomimetic dendron-like polypeptide-based biohybrids.

Multi‐Responsive Polypeptidosome: Characterization, Morphology Transformation, and Triggered Drug Delivery

The biodegradable polymeric nanomedicines that may be integrated with multi-stimuli-sensitivity to achieve triggered or on-demand drug release kinetics are challenging for polymer therapeutics and drug delivery systems. By controlling the structure transformation of one polypeptide-b-PEO copolymer, a novel multi-responsive polypeptide-based vesicle (polypeptidosome) presents the combined sensitivity of multiple physiological and clinic-related stimuli, and both morphology and size of the polypeptidosome are changed during the triggered process. The designer polypeptide has unique structures composed of 1) light-responsive o-nitrobenzyl groups, 2) oxidizable thioether linkers, 3) photo-caged redox thiol groups on parent poly(L-cysteine), and 4) tunable conformation, which enable the polypeptidosome to have a peculiar multi-response. The anticancer drug doxorubicin can be released in a controlled or on-off manner. The combination stimuli of UV irradiation and H2 O2 oxidation induces a large effect and a lower IC50 of 3.80 μg doxorubicin (DOX) equiv/mL compared to 5.28 μg DOX equiv/mL of individual H2 O2 trigger.

Light-responsive linear-dendritic amphiphiles and their nanomedicines for NIR-triggered drug release

Both ultraviolet (UV) and near-infrared (NIR) light-responsive linear-dendritic amphiphiles, PEO-D3DNQ, were click conjugated by connecting the diazonaphthoquinone (DNQ)-decorated poly(amido amine) dendron D3 (generation 3) and linear poly(ethylene oxide) (PEO) with molecular weights of 2 or 5 kDa. They self-assembled into spherical micelles with a hydrophobic DNQ core stabilized by a hydrophilic PEO corona in aqueous solution. As characterized by time-resolved UV-vis spectroscopy, dynamic light scattering and TEM, these micelles showed both UV- and NIR-sensitivity in phosphate buffer solution. Under 365 nm UV irradiation, the characteristic absorption intensity of DNQ progressively decreased and then leveled off within 8 minutes, suggesting the completion of the Wolff rearrangement of DNQ, while it took a longer time of 40–60 minutes to complete the Wolff rearrangement of DNQ under 808 nm NIR irradiation. Most of the micelles were disrupted after 30 minutes of 808 nm irradiation, and the apparent drug-release rate of the doxorubicin (DOX)-loaded micelles showed a nearly 8-fold increase, presenting a NIR-triggered drug-release profile. The DOX-loaded micelles could quickly enter into HeLa cells, release DOX inside the cells, and then kill the cells in a NIR-triggered manner, as evidenced by flow cytometry, confocal laser scanning microscopy, and MTT assay.

A Sweet Polydopamine Nanoplatform for Synergistic Combination of Targeted Chemo-Photothermal Therapy

Inspired by sweet or sugar-coated bullets that are used for medications in clinics and the structure and function of biological melanin, a novel kind of sweet polydopamine nanoparticles and their anticancer drug doxorubicin loaded counterparts are prepared, which integrate an active targeting function, photothermal therapy, and chemotherapy into one polymeric nanocarrier. The oxidative polymerization of lactosylated dopamine and/or with dopamine are performed under mild conditions and the resulting sweet nanoparticles are thoroughly characterized. When exposed to an 808 nm continuous-wave diode laser, the magnitude of temperature elevation not only increases with the concentration of nanoparticles, but can also be tuned by the laser power density. The nanoparticles possess strong near infrared light absorption, high photothermal conversion efficiency, and good photostability. The nanoparticles present tunable binding with RCA120 lectin and a targeting effect to HepG2 cells, confirmed by dynamic light scattering, turbidity analysis, MTT assay, and flow cytometry. Importantly, the sweet nanoparticles give the lowest IC50 value of 11.67 μg mL(-1) for chemo-photothermal therapy compared with 43.19 μg mL(-1) for single chemotherapy and 67.38 μg mL(-1) for photothermal therapy alone, demonstrating a good synergistic effect for the combination therapy.

NIR-responsive polypeptide copolymer upconversion composite nanoparticles for triggered drug release and enhanced cytotoxicity

Near infrared (NIR) light-responsive polymeric nanomedicines might achieve spatiotemporal, pulsatile, and on-demand drug release profiles and are appealing as a noninvasive technology for various clinical therapies. Polypeptide copolymer composite nanoparticles with different amounts of upconversion nanoparticles (UCNPs) were successfully fabricated in aqueous solution, and the NIR sensitivity of the composite nanoparticles was characterized by time-resolved UV-vis spectroscopy, on-line dynamic light scattering, and transmission electron microscopy. The composite nanoparticles disassembled with the help of UCNPs converting NIR light into UV light, and the NIR-responsive time can be tuned by both the loaded amount of UCNPs and the polypeptide chain length. The composite nanoparticles loaded with the anticancer drug doxorubicin (DOX) can release DOX in a controllable and/or pulsatile manner, and the drug release profile can be manipulated by NIR light. The DOX-loaded composite nanoparticles can be quickly internalized by HeLa cells and then release DOX inside the cells, as evidenced by flow cytometry and confocal laser scanning microscopy. After 5 or 10 min of NIR irradiation, the half maximal inhibitory concentration (IC50) for the DOX-loaded composite nanoparticles dropped to 5.08 μg DOX equiv. mL−1 or 2.95 μg DOX equiv. mL−1, respectively, compared to 8.26 μg DOX equiv. mL−1 for the non-irradiated sample, demonstrating a tunable NIR-triggered cytotoxicity. This work provides a versatile platform for the fabrication of NIR-responsive polypeptide copolymer nanomedicines with the potential for on-demand drug delivery and cancer therapy.

Comb-like poly(L-cysteine) derivatives with different side groups: synthesis via photochemistry and click chemistry, multi-responsive nanostructures, triggered drug release and cytotoxicity

A series of comb-like graft polypeptides having different side groups and tunable grafting ratios were prepared by sequential photocleavage reactions and Michael-type thiol–ene addition, as fully characterized by 1H NMR, gel permeation chromatography, FT-IR, and circular dichroism spectroscopy. The grafting ratio of the resulting polypeptides was close to the photolysis ratio of o-nitrobenzyl derived poly(L-cysteine) precursors. Both electrolytic acrylic acid (AA) and 2-(dimethylamino) ethyl acrylate (DMAEA) produced a larger disturbance on the ordered conformations than neutral poly(ethylene glycol) (PEG) methyl ether acrylate although the molecular weight and size of AA and DMAEA are much smaller than those of PEG. The polypeptide vesicles and micelles with a neutral or electrolytic corona could be facilely fabricated from these side group modified poly(L-cysteine)s, and the polypeptide vesicles exhibited both light- and redox-sensitivity in aqueous solution. As characterized by the MTT assay, flow cytometry, and CLSM, the anticancer drug doxorubicin (DOX) loaded nanoparticles quickly entered into HeLa cells and presented photo- and reduction-triggered cytotoxicity. The half maximal inhibitory concentration of HeLa cells (IC50) for the irradiated nanoparticles dropped to 0.40 μg DOX equiv. per mL compared to 1.27 μg DOX equiv. per mL for the non-irradiated sample; however, the IC50 for the irradiated sample increased about 1.5-fold after the BSO inhibitor treatment. Importantly, this work not only establishes a facile method for the preparation of comb-like graft polypeptides by the combination of photochemistry and thiol–ene click chemistry, but also provides a promising platform for on-demand nanomedicine and cancer therapy.

Biomimetic PAMAM-poly(benzyl L-glutamate) amphiphiles with multi-armed architecture: synthesis, physical properties and self-assembled nanoparticles.

Biomimetic poly(amidoamine)-poly(benzyl L-glutamate) (PAMAM-PBLG) amphiphiles with multi-armed architecture were synthesized by the ring-opening polymerization (ROP) of beta-benzyl-L-glutamate N-carboxyanhydride (BLG-NCA) using primary amine-terminated PAMAM dendrimer as the macroinitiator. Both (1)H NMR and (13)C NMR demonstrated that all the primary amines of PAMAM participated in initiating the ROP of BLG-NCA monomer, and the chain length of PBLG can be adjusted linearly by the molar ratio of BLG-NCA monomer to PAMAM. These multi-armed PAMAM-PBLG amphiphiles exhibited both alpha-helix and beta-sheet conformations similar to linear analogues, while their multi-armed architecture could enhance the secondary conformation content of PBLG segments. Meanwhile, the PAMAM-PBLG amphiphiles showed weaker liquid crystalline textures than the linear analogues. Moreover, spherical nanoparticles could be generated by direct injection of these PAMAM-PBLG solutions into distilled water, and their average size (38 - 275 nm) could be adjusted through the multi-armed architecture, the PBLG composition, and the concentration of the amphiphiles. These nanoparticles were stable in aqueous solution for up to 64 days at room temperature and 16 days at 37 degrees C. Consequently, this will provide a convenient method not only to synthesize multi-armed polypeptides amphiphiles, but also to generate biodegradable and biocompatible nanoparticles with adjustable size for drug/gene release.