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Page 2 of 14 Anand et al. J Cancer Metastasis Treat 2019;5:6 I http://dx.doi.org/10.20517/2394-4722.2018.98

Results: CPBN pretreatment of 4T1 tumors increased cellular differentiation, reduced proliferation, raised PpIX
levels, enhanced tumor cell death, and reduced metastatic spread of 4T1 cells post-PDT, relative to vehicle-only
controls.

Conclusion: The use of CPBN as a non-toxic PDT neoadjuvant for treatment of BCA represents a novel approach
with significant potential for translation into the clinic.

Keywords: Photodynamic therapy, protoporphyrin IX, aminolevulinic acid, breast cancer, metastasis, cell death,
4T1, in vivo imaging system

INTRODUCTION
Breast cancer (BCA) is the most common type of malignancy in women, with 1.7 million new cases
[1]
diagnosed worldwide each year and it is also a leading cause of mortality among women, accounting
[1-3]
for over half a million deaths annually . The main cause of death is not the primary tumor, but distant
metastases that create significant morbidity. Although 80% of BCA patients receive adjuvant chemotherapy,
[4]
~40% of those patients relapse and ultimately die due to metastatic disease . While 5-year survival rates
of BCA patients are increasing overall due to advanced therapeutic techniques, relatively low survival rates
[4]
and poor prognoses are still observed in patients with metastatic BCA . BCA cells metastasize mainly to
[4]
the lung, liver, brain and bone; metastases to the skin (cutaneous metastasis) occur in ~20% of cases . Local
[4]
relapse and chest wall metastases occur at a rate of 5% . The chest wall tumors are notable because they can
[5,6]
be very painful, and are hard to treat due to their resistance to chemotherapy . Ionizing radiation therapy
(RT) has been successfully used for the treatment of cutaneous chest wall metastases; however, multiple
rounds of therapy are required and are typically associated with side effects such as radiation dermatitis,
blistering and chronic ulcers. An alternative to RT, constituting a safer treatment that might be given either
alone or together with chemotherapy, is urgently needed.

Photodynamic therapy (PDT) is a non-mutagenic, non-scarring treatment modality for cancer. PDT
[7-9]
employs a photosensitizer (PS) and visible light in the presence of oxygen to kill tumor cells . During
PDT, two steps provide dual selectivity. First, the cancer cells accumulate and retain PS to a greater extent
than normal cells. Second, focusing the light source onto the tumor further enhances tumor specificity.
[8]
The PS is activated, triggering cell death by releasing free radicals . In the early history of PDT, the PS was
given systemically and carried a high risk of increased skin phototoxicity (sunburn). To reduce toxicity and
improve tumor selectivity, a newer mechanism of PDT that uses a prodrug, aminolevulinic acid (ALA)
instead of the pre-formed PS, was developed [10,11] . ALA, given systemically, orally or topically, is taken up
and enzymatically converted into protoporphyrin IX (PpIX) within mitochondria. PpIX is then activated by
strong visible light to generate reactive oxygen species that kill the cancer cells [9,12,13] . Skin cancers are easily
illuminated from the surface using red light that penetrates up to 1 cm into tissue. PDT is now successfully
[14]
used in Europe to treat superficial basal cell carcinoma and squamous cell carcinoma (SCC) . PDT has
several advantages over other modalities: (1) unlike surgical excision, PDT is non-scarring (and may actually
inhibit fibrosis [15,16] ); and (2) unlike RT, PDT can be repeated multiple times and because PDT targets
mitochondria rather than DNA, there is minimal risk of genetic mutations.

Although PDT is currently employed mostly for skin cancers, it carries tremendous potential to shrink or
eliminate BCA and its associated metastases; this research area has only been explored in a preliminary
fashion [17,18] . Up until now, the need for specialized equipment and better-standardized protocols has delayed
the acceptance of PDT as a main line of treatment for BCA and its metastases. In a recent clinical trial in
China, ALA-PDT used in combination with RT to treat cutaneous BCA metastases, showed a better complete
[19]
response (50% vs. 20%) and a reduced time to clearance (110 days vs. 175 days) vs. RT alone . It was also
shown that lowering the photosensitizing drug dose and the light fluence rate can improve the clearance