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Amplify antimicrobial photo dynamic therapy efficacy with poly-beta-amino esters (PBAEs).

ABSTRACT: Light-activated antimicrobial agents (photosensitisers) are promising alternatives to antibiotics for the treatment of skin infections and wounds through antimicrobial photo dynamic therapy (aPDT); utilisation of this technique is still restricted by general low efficacy requiring long exposure time (in the order of tens of minutes) that make the treatment very resource intensive. We report for the first time the possibility of harvesting the cell penetrating properties of poly-beta-amino esters (PBAEs) in combination with toluidine blue O (TBO) to shorten aPDT exposure time. Candidates capable of inactivation rates 30 times quicker than pure TBO were discovered and further improvements through PBAE backbone optimisation could be foreseen. Efficacy of the complexes was PBAE-dependent on a combination of TBO uptake and a newly discovered and unexpected role of PBAEs on reactive species production. Chemometric approach of partial least square regression was employed to assess the critical PBAE properties involved in this newly observed phenomenon in order to elicit a possible mechanism. The superior antimicrobial performance of this new approach benefits from the use of well established, low-cost and safe dye (TBO) coupled with inexpensive, widely tested and biodegradable polymers also known to be safe. Moreover, no adverse cytotoxic effects of the PBAEs adjuvated TBO delivery have been observed on a skin cells in vitro model demonstrating the safety profile of this new technology.

SUBMITTER: Perni S

PROVIDER: S-EPMC8012660 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PβAE polymers have emerged as highly promising candidates for biomedical and drug delivery applications owing to their tunable, degradable and pH sensitive properties. These polymeric systems can serve as prodrug carriers for the delivery of bioactive compounds which suffer from poor aqueous solubility, low bioavailability and are biologically unstable, such as the antioxidant, quercetin. Using acrylate functionalized quercetin, it is possible to incorporate the polyphenol into the backbone of the polymer matrix, permitting slow release of the intact molecule which is perfectly timed with the polymer degradation. While formulating these quercetin conjugated PβAE matrix into nanocarriers would allow for multiple delivery routes (oral, intravenous, inhalation etc.), well known oil-water nano-emulsion formulation methods are not amenable to the crosslinked hydrolytically sensitive nanoparticle/nanogel. In this work, a single-phase reaction-precipitation method was developed to formulate quercetin conjugated PβAE nanogels (QNG) via reaction of acrylated quercetin (4-5 acrylate groups) with a secondary diamine under dilute conditions using acetonitrile as the reaction medium, resulting in a self-stabilized suspension. The proposed approach permits the post synthesis modification of the spherical nanogels with a PEGylated coating, enhancing their aqueous stability and stealth characteristics. Nanogel size was controlled by varying feed reactant concentrations, achieving drug loadings of 25-38wt%. Uniform release of quercetin over 45-48h was observed upon PβAE ester hydrolysis under physiological conditions with its retained antioxidant activity over the extended times.Statement of significanceHere we present the first demonstration of using poly(beta amino ester) chemistry to form nanogels composed of a bioactive polyphenol for the control of cellular oxidative stress. Previous nanogel and nanoparticle approaches, which use a water phase, are not readily amenable to PBAE chemistry due to their hydrolytic sensitivity. Here we demonstrate a simple approach to control particle size, modify surface chemistry and achieve highly regulated controlled release of active antioxidants, which can protect cells against external oxidative stress signals. This work has importance in the area of controlling material biocompatibility through augmenting the antioxidant status of cells.

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Amplify antimicrobial photo dynamic therapy efficacy with poly-beta-amino esters (PBAEs).

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