Comparative Analysis of Nucleic Acid-Binding Polymers as Potential Anti-Inflammatory Nanocarriers.

Conventionally, nanocarriers are used to regulate the controlled release of therapeutic payloads. Increasingly, they can also be designed to have an intrinsic therapeutic effect. For example, a positively charged nanocarrier can bind damage-associated molecular patterns, inhibiting toll-like receptor (TLR) pathway activation and thus modulating inflammation. These nucleic acid-binding nanomaterials (NABNs), which scavenge pro-inflammatory stimuli, exist in diverse forms, ranging from soluble polymers to nanoparticles and 2D nanosheets. Unlike conventional drugs that primarily address inflammation symptoms, these NABPs target the upstream inflammation initiation pathway by removing the agonists responsible for inflammation. Many NABNs have demonstrated effectiveness in murine models of inflammatory diseases. However, these scavengers have not been systematically studied and compared within a single setting. Herein, we screen a subset of the most potent NABNs to define their relative efficiency in scavenging cell-free nucleic acids and inhibiting various TLR pathways. This study helps interpret existing in vivo results and provides insights into the future design of anti-inflammatory nanocarriers.

Therapeutic Nanocarriers Inhibit Chemotherapy-Induced Breast Cancer Metastasis.

Chemotherapy, although effective against primary tumors, may promote metastasis by causing the release of proinflammatory factors from damaged cells. Here, polymeric nanoparticles that deliver chemotherapeutics and scavenge proinflammatory factors simultaneously to inhibit chemotherapy-induced breast cancer metastasis are developed. The cationic nanoparticles can adsorb cell-free nucleic acids (cfNAs) based on charge-charge interaction, which downregulates the expression of Toll-like receptors and then reduces the secretion of inflammatory cytokines. Through in vitro structural optimization, cationic polyamidoamine (PAMAM) dendrimers modified with drug-binding dodecyl groups and diethylethanolamine surface groups (PAMAM-G3-C125 -DEEA20 ) exhibit the most desirable combination of nanoparticle size (≈140 nm), drug loading, cytotoxicity, cfNA binding, and anti-inflammatory activity. In the mouse models of breast cancer metastasis, paclitaxel-loaded nanoparticles reduce serum levels of cfNAs and inflammatory cytokines compared with paclitaxel treatment alone and inhibit both primary tumor growth and tumor metastasis. Additionally, no significant side effects are detected in the serum or major organs. These results provide a strategy to deliver chemotherapeutics to primary tumors while reducing the prometastatic effects of chemotherapy.

Drug delivery carriers with therapeutic functions.

Design of micro- or nanocarriers for drug delivery has primarily been focused on properties such as hydrophobicity, biodegradability, size, shape, surface charge, and toxicity, so that they can achieve optimal delivery with respect to drug loading, release kinetics, biodistribution, cellular uptake, and biocompatibility. Incorporation of stimulus-sensitive moieties into the carriers would lead to "smart" delivery systems. A further evolution would be to endow the carrier with a therapeutic function such that it no longer serves as a mere passive entity to release the drug at the target tissue but can be viewed as a therapeutic agent in itself. In this review, we will discuss recent and ongoing efforts over the past decade to design therapeutic drug carriers that confer a biological benefit, including ROS scavenging or generating, pro- or anti-inflammatory, and immuno-evasive properties, to enhance the overall therapeutic efficacy of the delivery systems.