Biodegradable Thermogelling Poly(Organophosphazenes) and Their Potential Biomedical Applications - In-Situ Gelling Polymers: For Biomedical Applications - page 52

in the endosomes and lysosomes. From the in vivo antitumor activity studies, the
conjugate hydrogels were shown to inhibit tumor growth over 20 days, which was
more effectively and longer than paclitaxel and saline alone.
3.2 Human Growth Hormone Delivery
Human growth hormone (hGH) used for growth stimulation and cell repro-
duction is one of the major protein drugs for treatment of short stature caused
by growth hormone deficiency and growth failure due to Turner syndrome or
chronic renal failure [ 129 ]. However, due to its poor absorbability in the gastro-
intestinal tract and short half-life in vivo, a daily administration by injection is
necessary, leading to poor patient compliance and renal toxicity [ 130 ]. In order
to solve the problems associated with the current hGH release systems, such
as low loading efficiency, high initial burst release, protein aggregation, dena-
turation and inflammation [ 131 ], an injectable and biodegradable thermogel
based on poly(organophosphazenes) loaded with polyelectrolyte drug complex
has been developed and investigated for its controlled and sustained delivery of
hGH to improve patient compliance [ 69 ]. The aqueous solution of polymer 18
containing polyelectrolyte complex formed between poly-L-arginine (PLA) and
hGH showed a sol-gel transition at 37 ºC. In the in vitro release study, all poly-
electrolyte complex loaded hydrogels exhibited a slower release rate than the
hydrogels with hGH alone. Zinc increased the released amount of hGH from
hydrogels for both in vitro and in vivo studies. The single administration of the
hydrogel loaded with polyelectrolyte complex in male Sprague-Dawley rats
with a dose of 1.1 mg/kg, resulted in sustained release of hGH for 5 days. For
the purpose of more prolonged hGH release profile in human body, a dual ionic
interaction system was developed by introducing carboxylic acid groups in
poly(oganophosphazene) side groups (structure 19 ) [ 85 ]. A positively charged
polyelectrolyte complex was formed between hGH and protamine sulfate, the
size of which can be adjusted by using varying ratio of each component. Later,
an additional ionic interaction between the positively charge polyelectrolyte
complex and anionic poly(organophosphazenes) was induced in the thermosen-
sitive hydrogels. The resultant hydrogels suppressed the initial burst release of
hGH and extended the release period in vitro and in vivo. In the in vivo effi-
cacy study, a significantly increased growth rate for 7 days was observed by
single injection of polyelectrolyte complex loaded anionic hydrogel, compared
to daily injection of hGH solution. The results showed that the introduction
of additional ionic interaction between polyelectrolyte complex and polymer
matrix highly improved the bioavailability of hGH and an increased released
manner.
As an alternative method, the release period of hGH can be efficiently increased
by forming polyelectrolyte complex with cationic poly(organophosphazene)
hydrogels. The positive charge can be introduced by modification of carboxylic