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Optimisation and feature selection of poly-beta-amino-ester as a drug delivery system for cartilage.

ABSTRACT: Drug localisation is still one of the main challenges in treating pathologies affecting cartilage; poly-beta-amino-esters (PBAEs) drug conjugates are a possible solution; however, their efficacy highly depends on the polymer structure hence the full potential of this delivery system is still unknown. For the purpose of optimising the delivery system design, a large library of PBAEs was synthesised and dexamethasone (DEX) uptake in cartilage was determined. All three components of PBAE (amine, acrylate and end-capping) impacted the outcome. The most effective PBAE identified enhanced DEX uptake by 8 folds compared to an equivalent dose of the commercial formulation and also prevented, through delivery of DEX, the cartilage degradation caused by IL-1α (interleukine1α). A chemometrics based predictive model was constructed and PBAEs properties most affecting the performance of the drug delivery systems were identified. This model will allow further computer based PBAEs optimisation and fast track the bench to market process for this delivery system.

SUBMITTER: Perni S

PROVIDER: S-EPMC7412864 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Optimisation and feature selection of poly-beta-amino-ester as a drug delivery system for cartilage.

Perni Stefano S Prokopovich Polina P

Journal of materials chemistry. B 20200601 23

Drug localisation is still one of the main challenges in treating pathologies affecting cartilage; poly-beta-amino-esters (PBAEs) drug conjugates are a possible solution; however, their efficacy highly depends on the polymer structure hence the full potential of this delivery system is still unknown. For the purpose of optimising the delivery system design, a large library of PBAEs was synthesised and dexamethasone (DEX) uptake in cartilage was determined. All three components of PBAE (amine, ac ...[more]

PMID: 32412019

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Project description:Recently, biomaterials have been designed to contain redox-sensitive moieties, such as thiols and disulfides, to impart responsive degradation and/or controlled release. However, due to the high sensitivity of cellular redox-based systems which maintain free-radical homeostasis (e.g. glutathione/glutathione disulfide), if these biomaterials modify the cellular redox environment, they may inadvertently affect cellular compatibility and/or oxidative stress defenses. In this work, we hypothesize that the degradation products of a poly(β-amino ester) (PBAE) hydrogel formed with redox sensitive disulfide (cystamine) crosslinking could serve as a supplement to the environmental cellular antioxidant defenses. Upon introduction into a reducing environment, these disulfide-containing hydrogels cleave to present bound-thiol groups, yet remain in the bulk form at up to 66 mol% cystamine of the total amines. By controlling the molar fraction of cystamine, it was apparent that the thiol content varied human umbilical vein endothelial cell (HUVEC) viability IC50 values across an order of magnitude. Further, upon introduction of an enzymatic oxidative stress generator to the cell culture (HX/XO), pre-incubated thiolated hydrogel degradation products conferred cellular and mitochondrial protection from acute oxidative stress, whereas non-reduced disulfide-containing degradation products offered no protection. This polymer may be an advantageous implantable drug delivery system for use in acute oxidative stress prophylaxis and/or chronic oxidative stress cell therapies due to its solid/liquid reversibility in a redox environment, controlled thiolation, high loading capacity through covalent drug-addition, and simple post-synthesis modification which bound-thiols introduce.Statement of significanceIn this work, we demonstrate a unique property of disulfide containing degradable biomaterials. By changing the redox state of the degradation products (from oxidized to reduced), it is possible to increase the IC50 of the material by an order of magnitude. This dramatic shift is linked directly to the oxidative stress response of the cells and suggests a possible mechanism by which one can tune the cellular response to degradable biomaterials.

Dataset Information

Optimisation and feature selection of poly-beta-amino-ester as a drug delivery system for cartilage.

Publications

Optimisation and feature selection of poly-beta-amino-ester as a drug delivery system for cartilage.

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