Synthetic lipo-polylysine with anti-cancer activity.

Development of novel therapeutic agents that possess different anticancer mechanisms from the traditional antitumor drugs is highly attractive as no medication can cure all types of cancers. Herein, we report a rational design of antitumor lipo-polylysine polymers as synthetic mimics of biosynthetic lipopeptide surfactants featuring antimicrobial or cytotoxic activities for cancer therapy. The optimal polymer shows a wide range of anticancer activities against multiple cancer cells, including highly metastatic and drug-resistant ones, but low toxicity to normal cells. Mechanism studies show that the optimal polymer can interact with the membrane of cancer cells and induce cell necrosis by triggering cell membrane perforation, which is different from the therapeutic mechanisms of traditional anticancer drugs. In vivo studies imply that the optimal polymer efficiently inhibits tumor growth without causing obvious side effects on a C26 graft tumor model. Overall, the lipopeptide-mimicking lipo-polylysine with the advantages of easy synthesis and low cost provides a new anticancer strategy with high efficacy and biocompatibility.

Photosensitizer-Polypeptide Conjugate for Effective Elimination of Candida albicans Biofilm.

Persistent fungal infections caused by biofilms seriously endanger human health. In this study, a photosensitizer-polypeptide conjugate (PPa-cP) comprising a photosensitizer, pyropheophorbide a (PPa), and a cationic polypeptide (cP) is readily synthesized for effective antifungal and antibiofilm treatment. Compared with free PPa, the cationic PPa-cP shows enhanced binding ability to the negatively charged surface of Candida albicans (C. albicans) through electrostatic interactions. As a result, PPa-cP exhibits effective antifungal efficiency against both C. albicans and fluconazole-resistant C. albicans in vitro under light irradiation. The minimum inhibitory concentration (MIC) of PPa-cP for both C. albicans and fluconazole-resistant C. albicans is 1 µm. In addition, PPa-cP also shows improved penetration in a C. albicans biofilm, thus effectively eliminating the C. albicans biofilm by photodynamic effects. More importantly, PPa-cP demonstrats significantly enhanced therapeutic effects in a fluconazole-resistant C. albicans-infected rat model with minimal side effects. In conclusion, the current work presents an effective strategy to combat biofilm infections associated with biomedical equipment.

Photosensitizer-Polypeptide Conjugate with Synergistic Antibacterial Efficacy.

Recently, continuous emergence of resistant bacteria has appeared as one of the most serious threats to human health. Therefore, systematic exploration of new antibacterial materials is of guiding significance. In this study, a series of photosensitizer-polypeptide conjugate (PPa-cP) is readily synthesized through simple ring-opening reactions to realize the synergistic antibacterial effects on Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA) under light irradiation. Compared with free PPa, the cationic PPa-cP shows enhanced binding ability with the negative surface of S. aureus through electrostatic interaction, exhibiting effective antibacterial activity against both S. aureus and MRSA in vitro under light irradiation. Among the synthesized PPa-cP, PPa-cP5 with the degree of polymerization of 37 and modified with a 1-methylimidazole side group exhibits the best antibacterial activity with a minimum inhibitory concentration value of 2 µm without light irradiation and 0.25 µm with light irradiation. Moreover, PPa-cP5 shows good hemocompatibility. The above-mentioned results elucidate that the positively charged PPa-cP5 can significantly increase the efficiency of photodynamic therapy and effectively eradicate S. aureus biofilm due to its potent penetration ability into S. aureus biofilms. Overall, the present study establishes an efficient strategy for the treatment of S. aureus and S. aureus biofilm infections.

Cationic Amphiphilic Dendrons with Anticancer Activity.

Cancer has become the leading cause of human death worldwide, and there is an urgent need to design and develop new oncology drugs. In this study, we report series of cationic amphiphilic dendrons with different hydrophobic alkyl chains (Cn) and different generations (Gx) and demonstrate their use for anticancer applications. The results revealed that lower-generation dendrons (G1) with a longer hydrophobic alkyl chain (C12 and C18) have stronger antitumor activity. Among these dendrons, a lead candidate C12-G1 was identified that demonstrated excellent broad-spectrum antitumor activity in 7 cancer cell lines including highly metastatic tumor cells, while simultaneously, hemolysis was negligible. Mechanistic studies showed that C12-G1 could lead to cytoplasmic leakage and induce cancer cell necrosis through membrane disruption. In addition, C12-G1 showed potent inhibition of tumor growth in a B16-F10 melanoma model. In conclusion, these findings demonstrate that the cationic amphiphilic dendron might be a promising agent for anticancer application.

Low-Molecular-Weight Polylysines with Excellent Antibacterial Properties and Low Hemolysis.

The steady development of bacterial resistance has become a global public health issue, and new antibacterial agents that are active against drug-resistant bacteria and less susceptible to bacterial resistance are urgently needed. Here, a series of low-molecular-weight cationic polylysines (Cx-PLLn) with different hydrophobic end groups (Cx) and degrees of polymerization (PLLn) was synthesized and used in antibacterial applications. All the obtained Cx-PLLn have antibacterial activity. Among them, C6-PLL13 displays the best antibacterial effect for Gram-positive bacteria, that is, Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA), and highest selectivity against Gram-positive bacteria. A mechanistic study revealed that the C6-PLL13 destroys the integrity of the bacterial cell membrane and causes effective bacterial death. Owing to this membrane-disrupting property, C6-PLL13 showed rapid bacterial killing kinetics and was not likely to develop resistance after repeat treatment (up to 13 generations). Moreover, C6-PLL13 demonstrated a significant therapeutic effect on an MRSA infection mouse model, which further proved that this synthetic polymer could be used as an effective weapon against bacterial infections.

Cationic amphiphilic dendrons with effective antibacterial performance.

Bacterial infections and antibiotic resistance have become a global healthcare crisis. Herein, we designed and synthesized a series of cationic amphiphilic dendrons with cationic dendrons and hydrophobic alkyl chains for potential antibacterial applications. Our results showed that the antimicrobial activities of the cationic amphiphilic dendrons were highly dependent upon the length of the hydrophobic alkyl chain, whereas the number of cationic charges was less important. Among these cationic amphiphilic dendrons, a prime candidate was identified, which possessed excellent antimicrobial activity against various pathogens (minimum inhibitory concentrations of 9, 3, and 3 µg mL-1 for Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus, respectively). Scanning electron microscopy and fluorescence microscopy analyses showed that it could disrupt the integrity of a pathogen's membrane, leading to cell lysis and death. In addition, in vitro bacteria-killing kinetics showed that it had rapid bactericidal efficiency. It also had excellent antimicrobial activities against MRSA in vivo and promoted wound healing. In general, the synthesized cationic amphiphilic dendrons, which exhibited rapid and broad-spectrum bactericidal activity, may have great potential in antimicrobial applications.

Monomer Controlled Switchable Copolymerization: A Feasible Route for the Functionalization of Poly(lactide).

Switchable polymerization is an attractive strategy to enable the sequential selectivity of multi-block polyesters. Besides, these well-defined multi-block polyesters could enable further modification for wider applications. Herein, based on the reversible insertion of CO2 by Salen-MnIII , a new monomer controlled self-switchable polymerization route was developed. Chemoselective ring opening copolymerization of O-carboxyanhydrides (OCAs) and lactide (LA) was explored without cocatalyst. The sequential conversion of OCAs and LA into the polymer chain could form multi-block polyesters. Based on this strategy, a series of multi-block polyesters with different pendant groups were synthesized. Furthermore, by modifying the propargyl-containing copolymers with quaternary ammonium groups, we have realized antibacterial functionalization of PLA. These results imply the potential application of this strategy for the fabrication of functional polymers for biomedical applications.

Antineoplastic Drug-Free Anticancer Strategy Enabled by Host-Defense-Peptides-Mimicking Synthetic Polypeptides.

An antineoplastic drug-free anticancer strategy enabled by host defense peptides (HDPs)-mimicking synthetic polypeptides is reported. The polypeptide exhibits a broad spectrum of anticancer activity in 12 cancer cell lines, including drug-resistant and highly metastatic tumor cells. Detailed mechanistic studies reveal that the cationic anticancer polypeptide (ACPP) can directly induce rapid necrosis of cancer cells within minutes through a membrane-lytic mechanism. Moreover, a pH-sensitive zwitterionic derivative of ACPP (DA-ACPP) is prepared for in vivo application. DA-ACPP shows negligible hemolysis under neutral physiological conditions, and can be converted back to ACPP in slightly acidic tumor environments, resulting in selective killing of cancer cells. Consequently, DA-ACPP shows an effective inhibition of tumor growth in both 4T1 orthotopic breast tumor models and B16-F10 melanoma pulmonary metastatic models. Overall, these findings demonstrate that synthetic HDPs-mimicking polypeptides represent safe and effective antineoplastic agents, which sheds new light on the development of drug-free synthetic polymers for cancer therapy.