02 BOOK OF ABSTRACTS .indd

Increasement of tumor oxygenation with topical
application of benzyl nicotinate
Zrinka Abramovi} 1 , Marjeta [entjurc 1 , Julijana Kristl 2 , Nadeem Khan 3 ,
Huagang Hou 3 , Harold M. Swartz 3
1
»Jo`ef Stefan« Institute, Jamova 39, 1000 Ljubljana, Slovenija; 2 University of Ljubljana,
Faculty of Pharmacy, A{ker~eva 7, 1000 Ljubljana, Slovenija; 3 EPR Center for the study of
Viable Systems, Department of Diagnostic Radiology, Dartmouth Medical School, Hanover,
03755, NH, USA
Tumor oxygenation is essential parameter that can influence the outcome of radioand
chemotherapy in cancer treatment. The ability to follow the time-course of
tumor pO 2
(partial pressure of oxygen) levels over the longer period of therapy
and finding new approaches to improve tumor oxygenation could therefore help to
optimize cancer therapy. In this study we tested a hypothesis that topical application
of vasodilators, which increase blood flow and consequently partial pressure of
oxygen (pO 2
) in skin and immediately underlying tissues, could be efficient way
to increase oxygenation of superficial tumor in skin with the ultimate goal to use
this approach in combination with radiotherapy. We have investigated the effect of
vasodilator benzyl nicotinate (BN), applied to the surface of the tumor in two drug
delivery systems: hydrogel and microemulsion on the oxygenation of subcutaneously
grown RIF-1 tumors by EPR oximetry in vivo.
RIF-1 tumors were grown subcutaneously in mice. When tumors reached appropriate
volume (100 mm 3 ) an oxygen sensitive paramagnetic probe lithium phthalocyanine
was implanted superficially into peripheral region of the tumors. For the next 5
days a preparation of 2.5% BN in hydrogel or microemlsion was applied on the skin
surface over the tumor and pO
72p1
2
was measured for 60 minutes.
It was found that BN applied topically on the tumor surface in microemulsion and
hydrogel increased tumor pO 2
above the baseline values. As a control microemulsion
or hydrogel without BN was applied on the tumor skin but no change in pO 2
was
observed. The efficacies of the two delivery systems on the action of BN were
compared in order to find optimal formulation, which would enable the best
penetration of vasodilator drug into the skin and consequently maximal increase in
tumor oxygenation. Two different parameters were used to evaluate the effect of
BN: t max
– the time required for the maximal pO 2
increase, and ΔpO 2max
– the maximal
relative increase of pO 2
with respect to the baseline oxygen concentration.
Our results show an increase in tumor oxygenation after topical application of BN in
both delivery systems. Microemulsions were found to be more convenient delivery
system than hydrogel. The observed increase in tumor oxygenation could potentially
lead to an increase in the effectiveness of radiotherapy of hypoxic tumors. This will
be tested in our future work where the efficacy of radiation therapy when irradiation
is done at times of maximal increase in tumor oxygenation after topical application
of BN will be determined.