Abstract
This study is motivated by understanding and controlling the key physical properties underlying internalisation of nano drug delivery. We consider the internalisation of specific nanometre size delivery vehicles, comprised of self-assembling amphiphilic block copolymers, called polymersomes that have the potential to specifically deliver anticancer therapeutics to tumour cells. The possible benefits of targeted polymersome drug delivery include reduced off-target toxic effects in healthy tissue and increased drug uptake by diseased tissue. Through a combination of in vitro experimentation and mathematical modelling, we develop a validated model of nanoparticle uptake by cells via the clathrin-mediated endocytotic pathway, incorporating receptor binding, clustering and recycling. The model predicts how the characteristics of receptor targeting, and the size and concentration of polymersomes alter uptake by tumour cells. The number of receptors per cell was identified as being the dominant mechanism accounting for the difference between cell types in polymersome uptake rate. From the Clinical EditorThis article reports on a validated model developed through a combination of in vitro experimentation and mathematical modeling of nanoparticle uptake by cells via the clathrin-mediated endocytotic pathway. The model incorporates receptor binding, clustering, and recycling and predicts how the characteristics of receptor targeting, the size and concentration alter polymersome uptake by cancer cells.
Highlights
This study is motivated by understanding and controlling the key physical properties underlying internalisation of nano drug delivery
Cal[27] cells were routinely cultured in Dulbecco's modified Eagle's medium (DMEM), FaDu cells in RPMI-1640 both supplemented with 10% (v/v) fetal calf serum (FCS; BioSera, East Sussex, UK), 2 mM L-Glutamine, 100 IU/ml penicillin and 100 mg/ml streptomycin (Sigma, Poole, UK) and SCC4 in DMEM and Ham's F12 medium in a 1:1 (v/v) ratio supplemented with 10% (v/v) FCS and 5 mg/ml hydrocortisone
Our theoretical model could be applied to other nanoparticles and cell types where the uptake mechanism is clathrin-mediated endocytosis, with suitable experimental data required to appropriately parameterize the model
Summary
This study is motivated by understanding and controlling the key physical properties underlying internalisation of nano drug delivery. 2-(diisopropylamino)ethyl methacrylate (PDPA) block copolymers.[10,11,12] The PDPA block of the copolymer is pH sensitive creating amphiphilic copolymers which self-assemble at pH N 6.4 but disassemble when the pH drops below 6.4 Due to their amphiphilic nature, polymersomes can carry different therapeutic loads at the same time. Cisplatin-based chemotherapy and radiotherapy following surgery have become the standard of care, whilst cisplatin in combination with 5-Fluorouracil (5-FU) is the mainstay of treatment for patients with inoperable, recurrent or metastatic disease Taxanes such as paclitaxel, in combination with cisplatin and 5-FU have been shown to improve survival in patients with locally advanced HNSCC.[18] high systemically-delivered doses are required to achieve tumour killing and these lead to myelosuppression, mucositis and significant overall toxicity in patients. Polymersomes have been shown to target tumour cells through their ability to attach ligands or antibodies directed at tumour cell surface receptors, which may reduce off target toxicity further.[19]
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