Bruce M. Novak

Amphiphilic helical polycarbodiimides bearing side chains with terminal alkyne groups provide a unique platform for construction of polymeric micelles. Incorporation of propargyl pendants into polyguanidine backbone allowed post‐polymerization modification with azide terminated, random coil, poly(N‐isopropylacrylamide), PNIPAM_15K and poly(ethyleneglycol), PEG_2K moieties using copper‐catalyzed click reaction (CuAAC). Thus, four new amphiphilic brush copolymers with varying grafting density were synthesized and their self‐assembly behavior in aqueous medium was studied by combination of TEM, SEM, AFM, and optical microscopy techniques. It was shown the formation of micellar structures at critical micelle concentration (CMC) ranging from 1.58 × 10⁻⁵ to 1.05 × 10⁻³mg mL⁻¹. A hydrophobic drug doxorubicin (DOX) was then encapsulated successfully into these micellar structures with encapsulation efficiency (EE) falling in the range from 16% to 27%. Further, the cellular uptake studies were carried out by using HeLa cells and the cytotoxic activity of DOX‐loaded micelles was determined to be less than 65% of cell viability at a concentration of 0.250 mg mL⁻¹. Fluorescence microscopy imaging revealed importing the micelles into the cells by endocytosis and internalization of the DOX into nucleus of the HeLa cells.

We have successfully synthesized water-soluble neutral and polyelectrolyte helical polycarbodiimides and studied their biological properties. These polymers were prepared by decorating carbodiimide backbones with non-ionic, hydrophilic functional groups such as dimethylamine, piperazine, and morpholine. Additionally, the 3° amines present in these functional groups were quaternized using methyl iodide as the alkylating agent to produce their ionic analogs. Polycarbodiimides were chosen as the base polymer used because of their facile chemical modification, pH tolerance in terms of both their helical conformations and degradation behaviors, and tunable helical inversion barriers. Hydrophilic side groups, such as morpholine, dimethylamine, and piperazine, can be used to balance the amphiphilic architecture of the polycarbodiimides along with lipophilic groups, such as alkyl side chains. A chiral R or S BINOL Ti(IV) isopropoxide catalyst was used to control the handedness of the polycarbodiimide helices in these studies. These ionic and neutral polycarbodiimides were subsequently studied for potential antimicrobial and cytotoxic properties. Poly[N-methyl-N’-2-morpholinoethylcarbodiimide], as an example, exhibited significant antifungal properties against C. albicans. Also, Poly[N-methyl-N’-2-morpholinoethylcarbodiimide] showed significant inhibition of biofilm formation. This suggests that the polymer is a promising candidate for antifungal biomedical applications. Measuring cytotoxicity against urinary bladder cancer cells, poly[N-[3-(dimethylamino)propyl)]-N’-[3-(morpholino)propyl]carbodiimide] (S-cat) and Poly[N-[3-(dimethylamino)propyl)]-N’-[3-(morpholino)propyl]carbodiimide]-MeI (S-cat) showed significantly low IC₅₀ values. The IC₅₀ values of poly[N-[3-(dimethylamino)propyl)]-N’-[3-(morpholino)propyl]carbodiimide] (S-cat) and Poly[N-[3-(dimethylamino)propyl)]-N’-[3-(morpholino)propyl]carbodiimide]-MeI (S-cat) are 3.50 μM and 1.27 μM respectively. The significantly low cancer cell growth inhibition concentration implies the highest cytotoxicity of the polymers, suggesting potential applications as cancer therapeutics. These results also showed that the functionalization and chirality of polycarbodiimides modulate their anticancer and antifungal activity.

A series of helical rigid-rod (R)- and (S)-polycarbodiimides having PEG2K, 10K, and 20K groups attached to aromatic or aliphatic side chains have been successfully synthesized from the respective alkyne polycarbodiimide precursors using the CuI-catalyzed azide/alkyne cycloaddition (CuAAC) reaction. The AFM, TEM and SEM studies of this series revealed the formation of different types of aggregated morphologies, i.e., micro- and nanospheres, fiber-like crystallites, and porous aggregates, which can be tailored with the hydrophilic PEG segments in the polymer structure. In general, heavily PEGylated scaffolds comprising ∼44 ethylene oxide segments are prone to form round-shaped secondary structures, especially in the bulk, as evident by SEM measurements. AFM data suggested that spherical aggregates are the preferred motifs in a wide range of concentrations. Moreover, polycarbodiimide-graft-PEG(2K) random copolymers were shown to efficiently suspend SWCNTs in water, leading to novel neutral photoluminescent nanocomposite materials. Overall, these extensive self-assembly studies on various polycarbodiimide platforms featuring a hydrophobic rigid rod main chain and a flexible hydrophilic periphery may provide a basic layout for prospective biomedical applications, such as controlled drug delivery and enhanced dispersibility properties of SWCNTs.