Computational and Experimental Studies on the Mechanism of Formation of Poly(hexahydrotriazine)s and Poly(hemiaminal)s from the Reactions of Amines with Formaldehyde

Combined experimental and computational studies have been performed on the mechanism of formation of poly­(hexa­hydro­triazine) and hemiaminal dynamic covalent network (PHT and HDCN) thermosetting polymers from the reactions of diamines with formaldehyde (Science 2014, 344, 732−735). Results suggest that these polymers are formed by a mechanism involving the water promoted stepwise addition of amines with formaldehyde in preference to dimerization or cyclotrimerization of imine intermediates or self-catalysis by the amine reagents. The predicted mechanism also explains experimentally observed electronic effects for hexahydrotriazine formation

Amidine-Mediated Zwitterionic Polymerization of Lactide

The ring-opening polymerization (ROP) of lactide with DBU (1,8-diazabicyclo[5.4.0] undec-7-ene) is described. Room temperature polymerization using the neutral amine catalyst DBU in the absence of any other initiator produces polymers with narrow polydispersities and shows a linear relationship between molecular weight and conversion. The resulting polymers were characterized and determined to be cyclic. DFT calculations support a mechanistic hypothesis involving a zwitterionic acyl amidinium intermediate

Injectable Biodegradable Hydrogels from Vitamin D‑Functionalized Polycarbonates for the Delivery of Avastin with Enhanced Therapeutic Efficiency against Metastatic Colorectal Cancer

Humanized vascular endothelial growth factor (VEGF) antibody (bevacizumab; Avastin) is a highly effective monoclonal antibody against metastatic colorectal cancer and several other advanced late stage cancers. However, limited aqueous solubility and short circulation half-life of the antibody result in long infusion time (30–90 min) and frequent injections. Such direful medical procedures often cause considerable patient inconvenience and prolonged pharmacy preparation. Subcutaneous delivery of Avastin using injectable hydrogels can continuously provide Avastin to treat the malignancy and mitigate antibody degradation. In this study, ABA triblock copolymers of vitamin D-functionalized polycarbonate and poly­(ethylene glycol), that is, VD_<i>m</i>-PEG-VD_<i>m</i> were synthesized and employed to form physically cross-linked injectable hydrogels for encapsulation and subcutaneous delivery of Avastin in a sustained fashion. Antitumor studies were performed using two different HCT116 xenograft mouse models: a subcutaneous and an intraperitoneal metastatic tumor models. The therapeutic efficacy of Avastin-loaded hydrogel injected subcutaneously (s.c.) was compared to an Avastin solution injected via either intravenous (i.v.) or intraperitoneal (i.p.) route. In the subcutaneous tumor model, the Avastin-loaded hydrogel resulted in greater tumor suppression as compared to i.v. and i.p. administration of Avastin solution. The biodistribution pattern of the hydrogel delivery system was also different from the other formulations as there was significantly higher accumulation in the tumor tissue and lesser accumulation within the liver and kidneys as compared to Avastin delivered through i.v. and i.p. administration. Furthermore, in vivo studies carried out on mice with peritoneal metastasis demonstrated that Avastin-loaded hydrogel and weekly administration of Avastin solution resulted in higher survival (87 and 77% over 62 days, respectively) when compared to the control, blank hydrogel and bolus Avastin solution (i.v.; 50–60%). The antimetastatic activity of Avastin delivered using a one-time injection of the hydrogel was as effective as that of 4× weekly injections (i.v.) of Avastin. The reduced injection frequency provided by the subcutaneous formulation may enhance patient convenience and compliance for metastatic cancer therapy

Self-Assembly and Dynamics Driven by Oligocarbonate–Fluorene End-Functionalized Poly(ethylene glycol) ABA Triblock Copolymers

The closed assembly transition from polymers to micelles and open assembly to clusters are induced by supramolecular π–π stacking in model oligocarbonate–fluorene (F-TMC) end-group telechelic polymers. The critical micelle concentration (CMC) depends on the F-TMC degree of polymerization that further controls the weak micelle association and strong clustering of micelles regimes. Clustering follows a multistep equilibria model with average size scaling with concentration reduced by the CMC as <i>R</i> ∼ (<i>c</i>/CMC)^1/4. The F-TMC packing that drives the supramolecular self-assembly from polymers to micelles stabilizes these larger clusters. The clusters are characterized by internal relaxations by dynamic light scattering. This signifies that while F-TMC groups drive the clustering, the micelles interconnected via F-TMC bridging interactions remain coupled to the extent that the clusters relax via Rouse–Zimm dynamics, reminiscent of microgels

Fabrication and Characterization of Hybrid Stealth Liposomes

Next-generation liposome systems for anticancer and therapeutic delivery require the precise insertion of stabilizing polymers and targeting ligands. Many of these functional macromolecules may be lost to micellization as a competing self-assembly landscape. Here, hybrid stealth liposomes, which utilize novel cholesteryl-functionalized block copolymers as the molecular stabilizer, are explored as a scalable platform to address this limitation. The employed block copolymers offer resistance to micellization through multiple liposome insertion moieties per molecule. A combination of thermodynamic and structural investigations for a series of hybrid stealth liposome systems suggests that a critical number of cholesteryl moieties per molecule defines whether the copolymer will or will not insert into the liposome bilayer. Colloidal stability of formed hybrid stealth liposomes further corroborates the critical copolymer architecture value

Tetra‑<i>n</i>‑butylammonium Fluoride as an Efficient Transesterification Catalyst for Functionalizing Cyclic Carbonates and Aliphatic Polycarbonates

We have developed a general method for the functionalization of cyclic carbonate monomers having a pentafluorophenyl ester substituent at the 5-position (MTC-OC₆F₅), as well as the postpolymerization modification of the subsequent polymer, poly­(MTC-OC₆F₅), with alcohols. The transesterifications are achieved under mild conditions using catalytic tetra-<i>n</i>-butylammonium fluoride (TBAF) as the nucleophilic acyl transfer agent. As an organic-soluble form of fluoride, TBAF loadings as low as 5 mol % were sufficient in bringing about high conversions at room temperature. The mild reaction conditions preserved the integrity of the sensitive carbonate moieties even without the use of Schlenk techniques. In addition to commercial TBAF solutions, we also found solid-supported forms of TBAF to be effective for transesterification, thus enabling facile postreaction workup and purification. More importantly, with only minor adjustments to the reaction conditions, we show that TBAF also promotes the postpolymerization modification of poly­(MTC-OC₆F₅), whereby fluoride-mediated transesterification with various alcohols proceeded quantitatively across the pendant pentafluorophenyl esters. Synthesizing a series of pendant ester-functionalized polycarbonates from a common precursor polymer was previously unattainable with existing methods, an issue that is now resolved by the current work

Organocatalytic Synthesis of Quinine-Functionalized Poly(carbonate)s

The ring-opening polymerization of substituted cyclic carbonates with 1-(3,5-bis-trifluoromethyl-phenyl)-3-cyclohexyl-thiourea (TU)/1,8-diazabicyclo[5.4.0]­undec-7-ene (DBU) organocatalysts afford highly functionalized oligocarbonates. The fluorescent alkaloid quinine can be readily incorporated into the oligocarbonates either by initiation from quinine or by ring-opening polymerization of a quinine-functionalized cyclic carbonate (MTC-Q). Copolymerization of MTC-Q with a boc-protected guanidinium cyclic carbonate affords, after deprotection, highly water-soluble cationic copolymers functionalized with both quinine and pendant guanidinium groups. When multiple quinine groups are attached to the oligomers, they exhibit minimal fluorescence due to self-quenching. Upon hydrolysis, the fluorescence intensity increases, providing a potential strategy for monitoring the hydrolysis rates in real time

Accurate Location and Manipulation of Nanoscaled Objects Buried under Spin-Coated Films

Detection and precise localization of nanoscale structures buried beneath spin-coated films are highly valuable additions to nanofabrication technology. In principle, the topography of the final film contains information about the location of the buried features. However, it is generally believed that the relation is masked by flow effects, which lead to an upstream shift of the dry film’s topography and render precise localization impossible. Here we demonstrate, theoretically and experimentally, that the flow-shift paradigm does not apply at the submicrometer scale. Specifically, we show that the resist topography is accurately obtained from a convolution operation with a symmetric Gaussian kernel whose parameters solely depend on the resist characteristics. We exploit this finding for a 3 nm precise overlay fabrication of metal contacts to an InAs nanowire with a diameter of 27 nm using thermal scanning probe lithography

Broad-Spectrum Antimicrobial/Antifouling Soft Material Coatings Using Poly(ethylenimine) as a Tailorable Scaffold

Microbial colonization and biofilm formation is the leading cause of contact lens-related keratitis. Treatment of the condition remains a challenge because of the need for prolonged therapeutic course and high doses of antimicrobial agents especially for biofilm eradication. The development of strategies to prepare nonfouling contact lens surfaces is a more practical way to ensure users’ safety and relieve the excessive public healthcare burden. In this study, we report a series of polymers that were modified to introduce functionality designed to facilitate coating adhesion, antimicrobial and antifouling properties. Cyclic carbonate monomers having different functional groups including adhesive catechol, antifouling poly­(ethylene glycol) (PEG), and hydrophobic urea/ethyl were conjugated onto branched poly­(ethylenimine) (bPEI, 25 kDa) at various degrees in a facile and well-controlled manner using a simple one step, atom economical approach. Immersion of contact lenses into an aqueous solution of the catechol-functionalized polymers at room temperature resulted in robust and stable coating on the lens surfaces, which survived the harsh condition of autoclaving and remained on the surface for a typical device application lifetime (7 days). The deposition of the polymer was unambiguously confirmed by static contact angle measurement and X-ray photoelectron spectroscopy (XPS). Polymer coating did not change light transmission significantly. Combinatorial optimization demonstrated that lenses coated with bPEI functionalized with catechol, PEG (5 kDa) and urea groups at 1:12:3:23 molar ratio for 18 h provided the highest antifouling effect against four types of keratitis-causing pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Fusarium solani, after 7 days of incubation. The polymer coating also inhibited protein adsorption onto the contact lens surfaces after exposure to bovine serum albumin solution for up to 24 h, owing to the flexible and large PEG constituent. Notably, all the polymer coatings used in this study were biocompatible, achieving ≥90% cell viability following direct contact with human corneal epithelial cells for 24 h. Hence, these polymer coatings are envisaged to be promising for the prevention of contact lens-related keratitis

Antimicrobial/Antifouling Polycarbonate Coatings: Role of Block Copolymer Architecture

The high prevalence of catheter-associated infections accounts for more than 3 billion dollars annually in hospitals, and antimicrobial polymer coatings on catheter surface may serve as an attractive weapon to mitigate infections. Triblock polycarbonate polymers consisting of three critical components including antifouling poly­(ethylene glycol) (PEG), antimicrobial cationic polycarbonate, and a tethering or adhesive functional block were synthesized. In this study, the block topology or placement of the distinctive blocks was varied and their efficacy as antimicrobial and antifouling agents investigated on coated surfaces. The individual blocks were designed to have comparable lengths that were subsequently grafted onto a prefunctionalized catheter surface through covalent bonding under mild conditions. The anchoring/adhesive functional moiety based on a maleimide functional carbonate was positioned at either the center or end of the polymer block and subsequently tethered to the surface via Michael addition chemistry. The placement of the adhesive block was investigated in terms of its effect on antimicrobial and antifouling properties. The surface coated with the polymer containing the center-positioned tethering block (2.4k-V) was unable to prevent bacteria fouling, even though demonstrated higher bacteria killing efficacy in solution as compared to the surface coated with the polymer containing the end-positioned tethering block (2.4k-S). In contrast, the 2.4k-S coating resisted fouling of both Gram-positive <i>S. aureus</i> and Gram-negative <i>E. coli</i> effectively under conditions that simulate the device lifetime (1 week). Moreover, the coating prevented protein fouling and platelet adhesion without inducing significant hemolysis. Consequently, this antibacterial and antifouling polymer coating is an interesting candidate to prevent catheter-associated bloodstream infections