Chuan Yang

Chemotherapy is one of the most effective treatments for cancer. However, toxicity and the development of drug resistance have become the major hurdles to the commonly used chemotherapeutics such as doxorubicin and paclitaxel. Antibiotics have also been used as anti-cancer drugs due to their anti-proliferative and cytotoxic effects. However, these anti-tumor antibiotics like ciprofloxacin face the similar resistance and toxicity issues. In this study, we used a quaternary ammonium-functionalized cationic polycarbonate to synergize with the existing chemotherapeutics and re-purpose antibiotics to address the resistance and toxicity issues. When used in combination with the drugs, the cationic polymer induced 2–3 fold more damage in the cancer cell membrane within 2 hours, thus enhancing the uptake of chemotherapeutics up to 2.5 fold more into the breast, liver and even chemotherapeutics-resistant cancer cells. On the other hand, the chemotherapeutics increased the cellular uptake of polymer. The combined effects resulted in 3–10 fold reduction in IC₅₀ of chemotherapy drugs and yielded therapeutic synergy at a clinically-relevant concentration range of drugs when treating multiple types of cancer cells, while the use of guanidinium-functionalized polymer capable of membrane translocation did not lead to a synergistic effect. Thus, the quaternary ammonium-functionalized cationic polymer can increase the therapeutic efficacies of existing drugs, mitigating toxicities by lowering required dosage and circumventing drug resistance via its membrane disruption mechanism. The findings of this study provide insights into designing future anticancer therapy.

The increasing emergence and spread of antimicrobial resistance are urgent and important global challenges today. The clinical pipeline is lacking in innovative drugs that avoid the development of drug resistance. Macromolecular antimicrobials kill bacteria and fungi through physical disruptions to the cell membrane, which is difficult for microbes to overcome. Recently, we reported antimicrobial polycarbonates that kill microbes via two different mechanisms. Polycarbonates functionalized with quaternary ammonium disrupted the lipid bilayer membrane of the microbes, while polycarbonates functionalized with guanidinium translocated the membrane and precipitated cytosolic components. We hypothesized that the combination of these two distinct mechanisms would result in a more than additive increase in antimicrobial efficacy. Block and random copolymers containing both cationic groups had similar minimum inhibitory concentrations (MICs) as the guanidinium homopolymer on 5 representatives of the ESKAPE pathogens. Interestingly, the random copolymer killed P. aeruginosa and A. baumannii more rapidly than the block copolymer and the guanidinium homopolymer with the same number of guanidinium groups. Like quaternary ammonium homopolymer, the copolymers killed the bacteria via a membrane-disruptive mechanism. Then, we simply mixed quaternary ammonium homopolymer and guanidinium homopolymer, and studied antimicrobial activity of the combination at various concentrations. Checkerboard assay results showed that the combination of the polymers, in general, achieved a synergistic or additive effect in inhibiting the growth of bacteria. At concentrations where it exibited a synergistic or additive effect in inhibiting bacterial growth, the combination killed the bacteria effectively (99%–99.9% killing efficiency) although the individual polymers at these concentrations did not exert bactericidal activity. Therefore, it is essential to have the two functional groups on separate molecules to provide synergism. This study provides a basic understanding of polymer design with different cationic groups.

In this study, cationic amphiphilic cyclic carbonates with varying hydrophobicity and structure were synthesized and grafted onto amine-containing silica surface via a ring-opening nucleophilic addition reaction to impart antimicrobial properties. The presence of the coated layer on silica surface was verified by X-ray photoelectron spectroscopy (XPS) and thermogravimetric analysis (TGA). The effects of the alkyl chain length and the cationic group structure of the surface-grafted carbonate on the antimicrobial efficacy against Gram-positive S. aureus, and Gram-negative E. coli and P. aeruginosa were examined to understand the structure–activity relationship of the surface-coated silica particles. Results indicated that an optimal chain length of the hydrophobic alkyl tail, and the position of the cationic center and benzyl group were crucial in imparting high antimicrobial efficacy especially against difficult-to-kill P. aeruginosa. These quaternary ammonium-functionalized silica particles have various potential antimicrobial applications.

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.

Adoptive T cell immunotherapy is a promising treatment strategy for epithelial ovarian cancer (EOC). However, programmed death ligand‐1 (PD‐L1), highly expressed on EOC cells, interacts with programmed death‐1 (PD‐1), expressed on T cells, causing immunosuppression. This study aims to block PD‐1/PD‐L1 interactions by delivering PD‐L1 siRNA, using various folic acid (FA)–functionalized polyethylenimine (PEI) polymers, to SKOV‐3‐Luc EOC cells, and investigate the sensitization of the EOC cells to T cell killing. To enhance siRNA uptake into EOC cells, which over express folate receptors, PEI is modified with FA or PEG–FA so that siRNA is complexed into nanoparticles with folate molecules on the surface. PEI modification with a single functional group lowers the polymer cytotoxicity compared to unmodified PEI. FA‐conjugated polymers increase siRNA uptake into SKOV‐3‐luc cells and decrease unspecific uptake into monocytes. All polymers result in 40% to 50% PD‐L1 protein knockdown. Importantly, SKOV‐3‐Luc cells treated with either PEI–FA or PEI– polyethylene glycol (PEG)–FA/PD‐L1 siRNA complexes are up to twofold more sensitive to T cell killing compared to scrambled siRNA treated controls. These findings are the first to demonstrate that PD‐L1 knockdown in EOC cells, via siRNA/FA‐targeted delivery, are able to sensitize cancer cells to T cell killing.

An antibacterial and antifouling surface is obtained by simple one-step immersion of a catheter surface with brush-like polycarbonates containing pendent adhesive dopamine, antifouling polyethylene glycol (PEG), and antibacterial cations. This coating demonstrates excellent antibacterial and antifouling activities against both Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria, proteins, and platelets, good stability under simulated blood-flow conditions, and no toxicity.

Polymeric micelles with and without galactose are synthesized to study liver targeting ability in an orthotopic HCC rat model. Micelles with galactose accumulate more in the healthy liver tissue instead of HCC, while micelles without galactose amass in HCC by the EPR effect. These micelles show great potential as drug delivery carriers to target either the liver or HCC.