Bioinspired polydopamine (PDA) has served as a universal coating to nanoparticles (NPs) for various biomedical applications. However, one remaining critical question is whether the PDA shell on NPs is stable in vivo. In this study, we modified gold nanoparticles (GNPs) with finely controlled PDA nanolayers to form uniform core/shell nanostructures (GNP@PDA). In vitro study showed that the PDA-coated GNPs had low cytotoxicity and could smoothly translocate to cancer cells. Transmission electron microscopy (TEM) analysis demonstrated that the PDA nanoshells were intact within cells after 24 h incubation. Notably, we found the GNP@PDA could partially escape from the endosomes/lysosomes to cytosol and locate close to the nucleus. Furthermore, we observed that the PDA-coated NPs have very different uptake behavior in two important organs of the liver and spleen: GNP@PDA in the liver were mainly uptaken by the Kupffer cells, while the GNP@PDA in the spleen were uptaken by a variety of cells. Importantly, we proved the PDA nanoshells were stable within cells of the liver and spleen for at least six weeks, and GNP@PDA did not show notable histological toxicity to main organs of mice in a long time. These results provided the direct evidence to support that the PDA surface modification can serve as an effective strategy to form ultrastable coatings on NPs in vivo, which can improve the intracellular delivery capacity and biocompatibility of NPs for biomedical application.
Biofilms that contribute to the persistent bacterial infections pose serious threats to global public health, mainly due to their resistance to antibiotics penetration and escaping innate immune attacks by phagocytes. Here, we report a kind of surface-adaptive gold nanoparticles (AuNPs) exhibiting (1) a self-adaptive target to the acidic microenvironment of biofilm, (2) an enhanced photothermal ablation of methicillin-resistant Staphylococcus aureus (MRSA) biofilm under near-infrared (NIR) light irradiation, and (3) no damage to the healthy tissues around the biofilm. Originally, AuNPs were readily prepared by surface modification with pH-responsive mixed charged zwitterionic self-assembled monolayers consisting of weak electrolytic 11-mercaptoundecanoic acid (HS-C-COOH) and strong electrolytic (10-mercaptodecyl)trimethylammonium bromide (HS-C-N). The mixed charged zwitterion-modified AuNPs showed fast pH-responsive transition from negative charge to positive charge, which enabled the AuNPs to disperse well in healthy tissues (pH ∼7.4), while quickly presenting strong adherence to negatively charged bacteria surfaces in MRSA biofilm (pH ∼5.5). Simultaneous AuNP aggregation within the MRSA biofilm enhanced the photothermal ablation of MRSA biofilm under NIR light irradiation. The surrounding healthy tissues showed no damage because the dispersed AuNPs had no photothermal effect under NIR light. In view of the above advantages as well as the straightforward preparation, AuNPs developed in this work may find potential applications as a useful antibacterial agent in the areas of healthcare.
Biofilm has resulted in numerous obstinate clinical infections, posing severe threats to public health. It is urgent to develop original antibacterial strategies for eradicating biofilms. Herein, we develop a surface charge switchable supramolecular nanocarrier exhibiting pHresponsive penetration into an acidic biofilm for nitric oxide (NO) synergistic photodynamic eradication of the methicillin-resistant Staphylococcus aureus (MRSA) biofilm with negligible damage to healthy tissues under laser irradiation. Originally, by integrating the glutathione (GSH)-sensitive α-cyclodextrin (α-CD) conjugated nitric oxide (NO) prodrug (α-CD-NO) and chlorin e6 (Ce6) prodrug (α-CD-Ce6) into the pH-sensitive poly(ethylene glycol) (PEG) block polypeptide copolymer (PEG-(KLAKLAK) 2 -DA) via host−guest interaction, the supramolecular nanocarrier α-CD-Ce6-NO-DA was finely prepared. The supramolecular nanocarrier shows complete surface charge reversal from negative charge at physiological pH (7.4) to positive charge at acidic biofilm pH (5.5), promoting efficient penetration into the biofilm. Once infiltrated into the biofilm, the nanocarrier exhibits rapid NO release triggered by the overexpressed GSH in the biofilm, which not only produces abundant NO for killing bacteria but also reduces the biofilm GSH level to improve photodynamic therapy (PDT) efficiency. On the other hand, NO can react with reactive oxygen species (ROS) to produce reactive nitrogen species (RNS), further improving the PDT efficiency. Due to the effective penetration into the biofilm and depletion of biofilm GSH, the surface charge switchable GSH-sensitive NO nanocarrier can greatly improve the PDT efficiency at a low photosensitizer dose and laser intensity and cause negligible side effect to healthy tissues. Considering the above advantages, the strategy developed in this work may offer great possibilities to fight against biofilm infections.
Effective accumulation of nanoparticles (NPs) in tumors is crucial for NP-assisted cancer diagnosis and treatment. With the hypothesis that aggregation of NPs stimulated by tumor microenvironment can be utilized to enhance retention and cellular uptake of NPs in tumors, we designed a smart NP system to evaluate the effect of aggregation on NPs' accumulation in tumor tissue. Gold nanoparticles (AuNPs, ~16 nm) were facilely prepared by surface modification with mixed-charge zwitterionic self-assembled monolayers, which can be stable at the pH of blood and normal tissues but aggregate instantly in response to the acidic extracellular pH of solid tumors. The zwitterionic AuNPs exhibited fast, ultrasensitive, and reversible response to the pH change from pH 7.4 to pH 6.5, which enabled the AuNPs to be well dispersed at pH 7.4 with excellent stealth ability to resist uptake by macrophages, while quickly aggregating at pH 6.5, leading to greatly enhanced uptake by cancer cells. An in vivo study demonstrated that the zwitterionic AuNPs had a considerable blood half-life with much higher tumor accumulation, retention, and cellular internalization than nonsensitive PEGylated AuNPs. A preliminary photothermal tumor ablation evaluation suggested the aggregation of AuNPs can be applied to cancer NIR photothermal therapy. These results suggest that controlled aggregation of NPs sensitive to tumor microenvironment can serve as a universal strategy to enhance the retention and cellular uptake of inorganic NPs in tumors, and modifying NPs with a mixed-charge zwitterionic surface can provide an easy way to obtain stealth properties and pH-sensitivity at the same time.
Chronic lung infection caused by bacterial biofilms is an extremely serious clinical problem, which can lead to the failure of antibiotic therapy. Although nanoparticles have shown great potential in the treatment of biofilms, the efficient penetration and retention of nanoparticles in biofilms is still a big challenge. To address this issue, we herein fabricate size and charge adaptive azithromycin (AZM)-conjugated clustered nanoparticles (denoted as AZM-DA NPs) as therapeutic agents for treating biofilms. The AZM-DA NPs are prepared by electrostatic complexation between AZM conjugated amino-ended poly(amidoamine) dendrimer (PAMAM) and 2,3-dimethyl maleic anhydride (DA) modified poly(ethylene glycol)-block-polylysine (PEG-b-PLys). It is noteworthy that the AZM-DA NPs can disassemble in an acidic biofilm microenvironment (pH 6.0), leading to the release of secondary AZM-conjugated PAMAM nanoparticles (PAMAM-AZM NPs). PAMAM-AZM NPs with small size and positive charge are beneficial for improved penetration and retention inside biofilms, enhanced permeabilization of the bacterial membrane, and increased internalization of AZM, thus exhibiting excellent antibiofilm activities. AZM-DA NPs are also favorable as long-term antibacterial agents due to the reduced occurrence of drug resistance. In vivo therapeutic performance is confirmed by the reduced bacterial burden and the alleviated inflammation in the chronic lung infection model. This research not only develops an innovative strategy for antibiotic delivery in vivo but also provides an effective way for the management of biofilm-associated infections, including chronic lung infection.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.