{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/321428"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/321428","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Amorphous calcium phosphate nanoparticles for biomedical cargo delivery","abstract":"Oral delivery of intact biomolecules is desirable but challenging. This thesis presents a potential approach, using amorphous calcium phosphate (ACP) nanoparticles as carriers of organic cargo. ACP is widely used as an in vitro delivery vehicle but similar in vivo use has not been realised. This PhD encompasses development of a practical synthetic route to stable ACP colloids of suitable size alongside their characterisation, formulation, and proof-of-principle in vivo testing. After reviewing the relevant literature, experimental and theoretical methods were employed to consider the solubility and stability of bulk ACP and its magnesium substituted counterpart. These findings subsequently informed the synthesis of functionalised ACP nanoparticles via an impinging jet reactor that I developed for this purpose. Particle size was tuneable, varying with reactor parameters, particularly flow rate and impingement angle. Surface chemistry could also be tailored, via coating selection. Process optimisation led to disperse ACP colloids of 50–300 nm at concentrations of up to 1% (w/v). The lead material proved to be size stable in complex media and was amenable to loading with diverse cargo – from soluble dyes and quantum dots to protein conjugates. Efficient in vitro delivery of a FRET pair (calcein & TRITC-BSA) was demonstrated with murine RAW cells. Finally, the particles were formulated in novel gastro-protective gels and tested, orally, in a murine model. This demonstrated proof-of-principle cargo delivery to intestinal lymphoid tissue. The materials and methods developed in this thesis make a significant contribution to the promising application of colloidal minerals to oral delivery of bio-active molecules.","abstract_html":"Oral delivery of intact biomolecules is desirable but challenging. This thesis presents a potential approach, using amorphous calcium phosphate (ACP) nanoparticles as carriers of organic cargo. ACP is widely used as an in vitro delivery vehicle but similar in vivo use has not been realised. This PhD encompasses development of a practical synthetic route to stable ACP colloids of suitable size alongside their characterisation, formulation, and proof-of-principle in vivo testing. After reviewing the relevant literature, experimental and theoretical methods were employed to consider the solubility and stability of bulk ACP and its magnesium substituted counterpart. These findings subsequently informed the synthesis of functionalised ACP nanoparticles via an impinging jet reactor that I developed for this purpose. Particle size was tuneable, varying with reactor parameters, particularly flow rate and impingement angle. Surface chemistry could also be tailored, via coating selection. Process optimisation led to disperse ACP colloids of 50–300 nm at concentrations of up to 1% (w/v). The lead material proved to be size stable in complex media and was amenable to loading with diverse cargo – from soluble dyes and quantum dots to protein conjugates. Efficient in vitro delivery of a FRET pair (calcein & TRITC-BSA) was demonstrated with murine RAW cells. Finally, the particles were formulated in novel gastro-protective gels and tested, orally, in a murine model. This demonstrated proof-of-principle cargo delivery to intestinal lymphoid tissue. 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Process optimisation led to disperse ACP colloids of 50–300 nm at concentrations of up to 1% (w/v). The lead material proved to be size stable in complex media and was amenable to loading with diverse cargo – from soluble dyes and quantum dots to protein conjugates. Efficient in vitro delivery of a FRET pair (calcein & TRITC-BSA) was demonstrated with murine RAW cells. Finally, the particles were formulated in novel gastro-protective gels and tested, orally, in a murine model. This demonstrated proof-of-principle cargo delivery to intestinal lymphoid tissue. 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