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Title: Enhancing the bioavailability of BCS Class IV drugs using polymeric nanoparticles
Author: Soundararajan, R.
ISNI:       0000 0004 7230 1734
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Hydrophobic drugs that are P-gp substrates (BCS Class IV) such as paclitaxel, CUDC-101 etc. pose a serious challenge for oral drug delivery. Polymeric amphiphiles such as N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ) are capable of enhancing the bioavailability of hydrophobic drugs by forming nanoparticles. The general hypothesis is that the physicochemical properties of the polymer will affect the colloidal stability, encapsulation efficiency and absorption of hydrophobic drugs. The main aims of the project are as follows: a) to examine the feasibility of using GCPQ with different characteristics, for the oral and subcutaneous delivery of CUDC-101 and b) to examine the effect of N-(2-phenoxyacetamide)-6-O-glycolchitosan (GCPh) on the P-gp efflux of paclitaxel. GCPh, a new polymeric amphiphile was synthesized by conjugating glycol chitosan to phenoxy acetic acid. Paclitaxel and CUDC-101 were encapsulated with GCPh and GCPQ of different molecular weights and hydrophobicity. The in vivo oral drug absorption profile for paclitaxel-GCPh nanoparticles and paclitaxel-Taxol® nanoparticles were determined in mice with and without verapamil, a P-gp inhibitor. In another study, the oral and subcutaneous drug absorption profile for CUDC-101 – GCPQ nanoparticles were conducted in mice and rat models respectively. Results indicated that GCPh improved the oral absorption of paclitaxel by improving the dissolution and promoting particle uptake through enterocytes. Experiments with Taxol® suggested that it is possible to saturate the P-gp pumps by improving the drug’s dissolution. Oral absorption of CUDC-101 was poor due to the drug’s extremely poor water solubility. The subcutaneous absorption of CUDC-101 – GCPQ nanoparticles were excellent. The colloidal stability and absorption of these nanoparticles can be improved by increasing polymer concentration and its hydrophobicity. These nanoparticles also prolonged the life span of human A431 tumour bearing mice by 28 days (p < 0.001). To conclude, the new polymeric amphiphile (GCPh), capable of improving the oral absorption of BCS Class IV P-gp substrates was developed. A new strategy to nullify the P-gp efflux was developed. A clinically relevant subcutaneous dosage form for CUDC-101 was also successfully developed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available