Targeted delivery of hexametaphosphate to prevent and treat pathological calcifications

Robinson, Thomas Edward ORCID: 0000-0002-0003-2286 (2021). Targeted delivery of hexametaphosphate to prevent and treat pathological calcifications. University of Birmingham. Ph.D.

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Abstract

Pathological calcification is the localised formation of hard tissue where it should not exist. Some of these conditions, such as heterotopic ossification (HO), have complex biological pathways leading to the ordered, cellular laydown of bone, while others, such as kidney stones, are driven primarily by material chemistry. Regardless of aetiology, all such conditions lead to mineral formation in ectopic locations, causing pain and a range of disabling effects. In this thesis, hexametaphosphate (HMP), a potent multivalent cation chelator, is investigated as a potential new therapy that targets the final, mineral formation step of these conditions. This approach may be used prophylactically, but can also dissolve mineral once formed, offering a previously absent medicinal alternative to surgery. HMP, whose structure is controversial, was found to be a linear polyphosphate with an average chain length of around 15 phosphate tetrahedra, rather than a six membered ring as often stated, with the ability to chelate one divalent cation for each pair of phosphates. Colloidal alginate could be loaded with up to 0.2 M HMP for targeted delivery, and formulations exhibited shear thinning with immediate viscosity recovery. These formulations were then investigated in an Achilles tenotomy model of HO. Neither inflammation nor accumulation of HMP or alginate was observed in the treated legs or filter organs. The ability of the formulations to reduce HO was less clear, and it was found that injection of fluid increased HO, apparently regardless of composition, though the needle itself did not. HMP was also investigated as a new therapy for kidney stones, where it was found to be over 16 fold more effective at dissolving calcium stones than citrate. Further, HMP was found to impart a strong negative charge on the particles, preventing aggregation. Overall, this study has shed light on the structure of HMP, established its usefulness as a potential therapy for HO and kidney stones, developed a vehicle for its targeted delivery, and investigated its safety and efficacy in vivo.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):