Smart chemistry-based nanosized drug delivery systems for systemic applications: A comprehensive review.

The term "zwitterionic polymers" refers to polymers that bear a pair of oppositely charged groups in their repeating units. When these oppositely charged groups are equally distributed at the molecular level, the molecules exhibit an overall neutral charge with a strong hydration effect via ionic solvation. The strong hydration effect constitutes the foundation of a series of exceptional properties of zwitterionic materials, including resistance to protein adsorption, lubrication at interfaces, promotion of protein stabilities, antifreezing in solutions, etc. As a result, zwitterionic materials have drawn great attention in biomedical and engineering applications in recent years. In this review, we give a comprehensive and panoramic overview of zwitterionic materials, covering the fundamentals of hydration and nonfouling behaviors, different types of zwitterionic surfaces and polymers, and their biomedical applications.

Zwitterionic Biomaterials.

The cellular transport process of DNA is hampered by cell membrane barriers, and hence, a delivery vehicle is essential for realizing the potential benefits of gene therapy to combat a variety of genetic diseases. Virus-based vehicles are effective, although immunogenicity, toxicity and cancer formation are among the major limitations of this approach. Cationic polymers, such as polyethyleneimine are capable of condensing DNA to nanoparticles and facilitate gene delivery. Lack of biodegradation of polymeric gene delivery vehicles poses significant toxicity because of the accumulation of polymers in the tissue. Many attempts have been made to develop biodegradable polymers for gene delivery by modifying existing polymers and/or using natural biodegradable polymers. This review summarizes mechanistic aspects of gene delivery and the development of biodegradable polymers for gene delivery.

https://www.mdpi.com/1420-3049/24/20/3744/pdf

Biodegradable Polymers for Gene Delivery.

Biofouling is the undesirable accumulation of organisms such as bacteria, fungi, and barnacles on surfaces. It is a serious problem in many areas of our lives including health, food, water, and energy. For example, biofouling on medical devices causes hospital‐acquired infections. These infections caused by bacteria are often resistant to conventional antibiotics and therefore increase the number of deaths related to hospitalization. One of the solutions to avoid biofouling is to coat the surfaces with a material that resists biofouling by either killing the organisms (i.e., antimicrobial coating) or preventing their adhesion to the surface (i.e., antifouling coating). These coating solutions include the usage of biocidal agents, antibiotics, nanoparticles, polymers, and polycationic materials. Each of these solutions, however, has certain drawbacks. These include lack of long‐term stability, low biocompatibility, and high toxicity. In this context, peptide‐based materials gain considerable attention as antifouling and antimicrobial coatings. This is due to their biocompatibility, biodegradability, and low toxicity profile. Here, the various types of peptide‐based materials utilized as antifouling coatings are reviewed. Recent reports show the importance of these peptide‐based coatings for applications ranging from biomedical implants to biosensors.

Peptide-Based Approaches to Fight Biofouling

Application of dextran as nanoscale drug carriers.

Among various polymeric gene delivery systems, peptide-based vectors demonstrate great potential owing to their unique structure and properties, including flexibility; however, there is insufficient molecular understanding of the role and properties of amino acids as building blocks in gene delivery. In this work, we constructed a series of histidine (H)-containing peptide-grafted dextran (D-RxHy) vectors via a simple two-step reaction of dextran with five RxHyC peptides: R7H3C, R5H3C, R5H5C, R3H5C, and R3H7C. The gel electrophoresis study unveiled the DNA-binding ability of H residues. While all D-RxHy vectors possess similarly low cytotoxicity, D-R3H7 exhibited the highest gene transfection efficiency. Interestingly, at the low nitrogen to phosphate (N/P) ratio of 2, D-R3H7 displayed a 6–8-fold higher luciferase expression compared to the gold standard branched PEI (25k). D-R3H7 and D-R5H5 demonstrated favorable cell uptake rates. A chloroquine-treated transfection assay confirmed the key effect of the high buffering capacity of H-rich D-R3H7 on its high gene transfection efficiency, especially at low N/P ratios. The present work unveiled that histidine is critical for both DNA condensation and the accurate control of endosomal escape. The tunable D-RxHy platform not only demonstrates promising potential for therapeutic purposes but can also be used as a tool to elucidate the molecular mechanism of polymer-based transfection.

Peptide-grafted dextran vectors for efficient and high-loading gene delivery

Single stranded microRNAs and their antagomirs are unstable and polyanionic, which impedes efficient cellular uptake and reduces half-life. Therefore, effective delivery systems with low toxicity for microRNAs are urgently needed for the success of microRNA-based therapy. Here, a dextran–peptide hybrid, Dex10-R5H5(40%), was developed as a carrier to deliver microRNAs. Dex10-R5H5(40%) loaded with antagomir-149 could reduce the level of endogenous microRNA-149 by 76% and it is more effective than the commercially available transfection reagent, RNAiMAX, which leads to 67% reduction. Additionally, Dex10-R5H5(40%) exhibited no cytotoxicity to HepG2 cells. These results indicate that the dextran–peptide hybrid may be a promising delivery system for the safe and efficient microRNA-based therapy.

A naturally derived dextran–peptide vector for microRNA antagomir delivery

This research reports a synthetic amino acid based zwitterionic poly(histidine methacrylamide) (PHisMA), which possesses switchability among zwitterionic, anionic, and cationic states, pH-dependent antifouling properties, and chelation capability to multivalent metal ions. The PHisMA polymer brush surface shows good antifouling properties to resist protein adsorption and bacterial attachment in its zwitterionic state at pH 5. This study also demonstrates that the solution acidity significantly affects the mechanical properties of PHisMA hydrogels. PHisMA hydrogels show higher viscoelastic properties and lower swelling ratios in the zwitterionic state at pH 4 and pH 5, compared to higher or lower pH conditions. It was discovered that PHisMA can chelate multivalent metal ions, such as Ca2+, Mg2+, Cu2+, Ni2+ and Fe3+. This study provides us a better understanding of structure–property relationships of switchable zwitterionic polymers. PHisMA can potentially be adapted for a broad range of applications includ...

pH-Sensitive Poly(histidine methacrylamide)

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Peptide-grafted dextran vectors for efficient and high-loading gene delivery

A naturally derived dextran–peptide vector for microRNA antagomir delivery

pH-Sensitive Poly(histidine methacrylamide)