Optimising Polymeric Nanocarrier Environments to Encapsulate and Deliver Highly Potent Anti-Cancer Drug SN-38

• Main Author: Armstrong, Claire Iris May
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2021
• Subjects: Alzheimers disease; Cancer therapies; Cell division; Cellular biology; Chemistry; Chemotherapy; Chromatography; Colorectal cancer; Cytotoxicity; Drug delivery systems; Drug dosages; Expenditures; Health services; Hemodialysis; HIV; Human immunodeficiency virus; Immune system; Lifestyles; Lipids; Medical research; Medicine; Metastasis; Mutation; Oncology; Patients; Pharmacology; Polymer chemistry; Polymers; R&D; Research & development; Research methodology; Solvents; Surgery; Toxicity
• ISBN: 9798522949303

Chemotherapy is undeniably a highly effective cancer treatment, which has saved or prolonged many patients’ lives. However, its indiscriminate nature, acute toxicities and low aqueous solubility has limited the ability to achieve maximum therapeutic effectiveness and usage clinically. Irinotecan, a water-soluble prodrug of highly potent SN-38, is used clinically to treat multiple cancers. The active metabolite, SN-38, exhibits 100- to 1000- fold more cytotoxicity compared to irinotecan, but the metabolism of irinotecan to SN-38 is highly inefficient with significant interpatient variability. Direct administration of SN-38 is highly desirable; however, the extreme hydrophobicity exhibited by SN-38 has prevented its clinical use. Herein, branched vinyl copolymer nanoparticles have been utilised to encapsulate SN38, offering sustained release profiles and superior in vitro cytotoxic behaviour compared to irinotecan. Co-nanoprecipitation has proven to be a fast, reproducible and efficient nanoformulation technique for the preparation of sterically stabilised SN-38 loaded branched vinyl copolymer aqueous nanoparticle dispersions. The preparation of which involved the simultaneous nanoprecipitation of highly branched hydrophobic vinyl copolymers with amphiphilic PEG-based AB block copolymers and SN-38. Methanolic atom transfer radical polymerisation, a versatile polymerisation technique, was used for the production of novel hydrophobic branched vinyl polymers and AB block copolymers; this provided an easy synthetic strategy to impart different polymer characteristics through varying different monomer chemistries. Fundamental studies were carried out to gain an understanding of how these differing polymer chemistries affected the formation of the nanoparticles and their stability, and in-turn influenced the drug loading capabilities and subsequent in vitro and in vivo pharmacological behaviour. The SN-38 loaded nanoparticles were characterised with small sizes (< 180 nm), slight negative charges (< -20 mV) and respectable drug loadings (< 10 wt.%) with high drug encapsulation efficiencies (> 88%) and extremely low IC50 values following in vitro analyses in both human and murine cancer cell lines. Radiometric labelling of SN-38 allowed for the release profiles to be accurately determined and highlighted that the particles offer sustained, slow release at physiological relevant conditions (< 17% release). Overall, it has been demonstrated that SN-38 can be successfully encapsulated within aqueous branched vinyl copolymer nanoparticle dispersions, which display promising in vitro behaviour; thereby providing an opportunity to further explore the potential of these systems in vivo as an anti-cancer drug treatment.