Description:
Princeton University Invention #
10-2589
Researchers at
Princeton University, Department of Chemical Engineering together with
researchers at the National Institute of Cancer have developed protected
nanoparticle formulations of the diazeniumdiolate class of anti-cancer lead
compounds. Examples include PABA/NO
O2-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl}
1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate and
double-JS-K(1,5-bis{[1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolato]-O2)-2,4-dinitrobenzene),
through their incorporation into polymer-protected
nanoparticles.
The prodrugs
were formulated in block copolymer-stabilized nanoparticles with sizes from 220
to 450 nm by a novel rapid precipitation process. The block copolymers, with
polyethylene glycol (PEG) soluble blocks, provide a steric barrier against NO
prodrug activation by glutathione. Too rapid activation and NO release has been
a major barrier to effective administration of this class of compounds. The
nanoparticle extends the NO release half times from 15 min to 5 hours for
PABA/NO and from 4.5 min to 40 min for double JS-K. The more hydrophobic PABA/NO
produces more stable nanoparticles and correspondingly more extended release
times. The hydrophobic blocks of the polymer were either polystyrene or
polylactide. Both blocks produced nanoparticles of approximately the same size
and release kinetics. This combination of PEG protected nanoparticles with sizes
appropriate for cancer targeting by enhanced permeation and retention (EPR) and
delayed release of NO may afford enhanced therapeutic
benefit.
Nitric oxide (NO) is a mediator of diverse physiological processes and
has been shown to have anti-proliferative activity1-3. Due to the
poor bioavailability of NO, typically prodrugs of nitric oxide such as
diazeniumdiolates are used as surrogates of NO4.
O2-(2,4-dinitrophenyl) diazeniumdiolates are important members of the
diazeniumdiolate class of nitric oxide prodrugs that have shown promising
anti-cancer activity5.
Some important examples are JS-K6-15 and
PABA/NO16-22, as cited below, which have both shown potent
tumoristatic effects in animal models. For example, JS-K was found to inhibit
the in vivo growth of xenografts of cells derived from human leukemia,
multiple myeloma, and prostate carcinoma. PABA/NO showed tumoristatic
activity against A2780 human ovarian cancer xenografts in female SCID mice with
a potency comparable to that of cisplatin. Tests of formulated
preparations of selected NO prodrugs in mouse tumor xenograft models are planned
with development for translation to clinical use as
appropriate.
Princeton is
currently seeking commercial partners for the further development and
commercialization of this opportunity. Patent protection is
pending.
For more information on Princeton
University invention # 10-2489 please contact:
Laurie Tzodikov
Office of Technology Licensing and Intellectual Property
Princeton University
4 New South Building
Princeton, NJ 08544-0036
(609) 258-7256
(609) 258-1159 fax
tzodikov@princeton.edu