German, Lisa; (2001) Body distribution of dextrin and D-2-S and evaluation of their potential as novel polymeric-drug carriers. Doctoral thesis (Ph.D.), University College London.

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Abstract

Water soluble polymers, including natural polymers (e.g. polyamino acids and polysaccharides) and synthetic polymers (e.g. polyethyleneglycol (PEG)) and N-(2- hydroxypropyl)methacrylamide (HPMA) copolymers) are finding increasing use as polymer therapeutics. Dextrin and dextrin-2-Sulphate (D-2-S) are poly(1-4 glucose) polymers that have entered into clinical use: dextrin as a peritoneal dialysis solution and D-2-S as an anti-HIV treatment. The aim of this study was (1) to quantitate the biodistribution of dextrin and D-2-S and (2) to evaluate the potential of these polymers for use as drug carriers. First, pendant groups were introduced by succinoylation (1-60 mol%). To study biodistribution (after s.c., i.v. or i.p. administration) probes were then synthesised containing either -TyrNH2 or -DTPA (~1 mol%) to allow labelling with 125I iodine or 111In indium respectively. After i.p. administration 125I-labelled D-2-S remained longer in the peritoneal cavity (~27 times) than 125I-labelled dextrin (t1/2 = 2.3 h and 5 min respectively). Maximum tissue accumulation was seen in the liver, for 125I-labelled dextrin approximately 20% administered dose (2 min) and for 125I-labelled D-2-S (15.3% administered dose (24 h). Gamma camera images obtained using 111In-labelled polymers were consistent with the data obtained using 125I-labelled compounds. Using the succinoylated intermediate, dextrin- and D-2-S-amphotericin B conjugates (AmpB) were prepared containing 0.01-3.50 wt% and 0.01-16.0 wt% AmpB respectively. Conjugation increased drug solubility approximately 10 fold. Preliminary in vitro testing showed IC50 values for AmpB, dextrin- and D-2-S-AmpB (IC50 of 11.0 >50, and >50 μg/ml respectively) and haemolytic activity at 24 h (Hb50 of 0.06 mg/ml, >50 μg/ml and 8.0 μg/ml respectively). Additionally, experiments were carried out with dextrin-doxorubicin (Dox) (9 wt%, Dox-equiv) to ascertain its tumour targeting potential and antitumour activity. Whereas free Dox was inactive (T/C= 105%) in a s.c. B16F10 tumour model dextrin- Dox had a T/C = 144%. Dextrin and D-2-S have shown that they have potential for further development as water soluble drug carriers.

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