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1.
Biomaterials ; 283: 121416, 2022 04.
Article in English | MEDLINE | ID: mdl-35217483

ABSTRACT

Personalised nanomedicine is an advancing field which has developed significant improvements for targeting therapeutics to aggressive cancer and with fewer side effects. The treatment of gliomas such as glioblastoma (or other brain tumours), with nanomedicine is complicated by a commonly poor accumulation of drugs in tumour tissue owing to the partially intact blood-brain barrier (BBB). Nonetheless, the BBB becomes compromised following surgical intervention, and gradually with disease progression. Increased vasculature permeability generated by a tumour, combined with decreased BBB integrity, offers a mechanism to enhance therapeutic outcomes. We monitored a spontaneous glioma tumour model in immunocompetent mice with ongoing T2-weighted and contrast-enhanced T1-weighted magnetic resonance imaging gradient echo and spin echo sequences to predict an optimal "leakiness" stage for nanomedicine injections. To ascertain the effectiveness of targeted nanomedicines in treating brain tumours, subsequent systemic administration of targeted hyperbranched polymers was then utislised, to deliver the therapeutic payload when both the tumour and brain vascularity had become sufficiently susceptible to allow drug accumulation. Treatment with either doxorubicin-loaded hyperbranched polymer, or the same nanomedicine targeted to an ephrin receptor (EphA2) using a bispecific antibody, resulted in uptake of chemotherapeutic doxorubicin in the tumour and in reduced tumour growth. Compared to vehicle and doxorubicin only, nanoparticle delivered doxorubicin resulted in increased tumour apoptosis, while averting cardiotoxicity. This suggests that polyethylene based (PEGylated)-nanoparticle delivered doxorubicin could provide a more efficient treatment in tumours with a disrupted BBB, and that treatment should commence immediately following detection of gadolinium permeability, with early detection and ongoing 'leakiness' monitoring in susceptible patients being a key factor.


Subject(s)
Brain Neoplasms , Nanomedicine , Animals , Blood-Brain Barrier , Brain , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/drug therapy , Doxorubicin , Drug Delivery Systems/methods , Humans , Mice , Nanomedicine/methods
2.
ACS Appl Bio Mater ; 4(3): 2675-2685, 2021 03 15.
Article in English | MEDLINE | ID: mdl-35014306

ABSTRACT

Improving our understanding of how design choices in materials synthesis impact biological outcomes is of critical importance in the development of nanomedicines. Here, we show that fluorophore labeling of polymer nanomedicine candidates significantly alters their transport and cell association in multi-cellular tumor spheroids and their penetration in breast cancer xenografts, dependent on the type of the fluorophore and their positioning within the macromolecular structure. These data show the critical importance of the biomaterials structure and architecture in their tissue distribution and intracellular trafficking, which in turn govern their potential therapeutic efficacy. The broader implication of these findings suggests that when developing materials for medical applications, great care should be taken early on in the design process as relatively simple choices may have downstream impacts that could potentially skew preclinical biology data.


Subject(s)
Biocompatible Materials/chemistry , Fluorescent Dyes/chemistry , Polymers/chemistry , Spheroids, Cellular/chemistry , Animals , Biocompatible Materials/chemical synthesis , Biocompatible Materials/pharmacokinetics , Cells, Cultured , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/pharmacokinetics , Humans , Mammary Neoplasms, Experimental/diagnostic imaging , Materials Testing , Mice , Molecular Structure , Nanomedicine , Particle Size , Polymers/chemical synthesis , Polymers/pharmacokinetics , Tissue Distribution
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