Abstract
A large proportion of cancer morbidities and mortalities is due to treatment
related side effects and other complications. Besides that, most patients
succumb to cancer due to failure of treatment and/or cancer recurrence after
a seemingly successful treatment. Moreover, some patients, especially in
low-income countries (LICs) and lower middle-income countries (LMICs),
do not survive cancer due to inability to pay for expensive therapies. Hence,
the task of making newer therapies for cancer, comes with the responsibility
to ensure that the therapy being made is not only effective on cancer, but
also should avoid or limit side effects, while it remains inexpensive for
peoples’ affordability. To achieve all these characteristics, a therapeutic
option needs to be determinedly designed to actively target cancer cells
while preventing toxicity on normal cells, and should be given keen attention
in ensuring accessibility and affordability of the procedures used.
This study therefore sought to explore Photodynamic Therapy (PDT), a
targeted therapy for cancer that uses an inexpensive, but highly photoactive
compound referred to as photosensitizer (PS), which is inert in its ground
state but only upon activation using a specific activation probe, technically
light of specific wavelength in the appropriate excitation wavelength range,
gets activated to become toxic to cells within a small distance of its
localization. The PS selectively accumulates in cancer cells due to certain
characteristics of cancer cells and the light is directed only at the tumour
site, guaranteeing a twofold selectivity that limits effects on normal cells
and/or organs. PDT is also cost effective, because the PSs are available
either as natural phytochemicals or as simple synthetic dyes, the light is
easily generated using lasers or other light source, and the whole procedure
is tolerable to repeated doses without causing serious side effects.
However, because cancer cells are inherently adaptable to most changes
in their microenvironment including changes caused by therapies, the
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traditional usage of PDT has shown some limitations and in certain
instances, resistance to PDT has been reported. Regardless, PDT still has
many advantages of over most conventional therapies, hence addressing
these shortfalls by way of enhancing the efficacy of PDT to curb resistance
is worthwhile. Fortuitously, the current surge in the use of nanoparticles
(NPs) for drug delivery has provided some solution to this problem.
Moreover, immunogenic proteins in cancer are relevant targets for
therapeutics, hence ligand-specific monoclonal antibodies (mAbs) can be
useful in directing delivery of the PS to tumour cells. Gold (Au) NPs have
been used previously as vehicles for delivery of drugs and mAbs have been
used singularly as therapeutic entities or coupled to drugs for active
targeting of specific antigens on target cells. Both these can potentially add
value to the delivery of PS resulting in enhancement of PDT efficacy and
attenuation of resistance.
To achieve this, a phthalocyanine PS, Aluminium (III) Phthalocyanine
Chloride Tetrasulfonic Acid (AlPcS4Cl) and mAbs directed to E6
oncoproteins in Human Papillomavirus (HPV)-transformed cervical cancer
cells, were chemically conjugated to 10 nm AuNP that were surface
functionalized with Polyethylene glycol (PEG) containing a carboxylic acid
terminal. This chemical conjugation formed a photoactive nanoparticleantibody-
phthalocyanine scaffold for use in directed PDT of HPVtransformed
cervical cancer cells. The newly developed molecular scaffold
was confirmed by the assessment of its physicochemical and biological
characteristics that showed binding of the three compounds by both
chemical bonds and physical interactions. Bond characterization showed
formation of amide linkages between the anti E6 mAbs and the PEG moiety
of the AuNPs through its carboxylic acid terminal. The PS was bound by
both hydrogen bonds and ionic interactions. The particles’ stability under
physiological conditions was confirmed by Zeta Potential (ZP) to be a stable
compound, and optical properties using spectrophotometry showed the PS
retained its excitation characteristics when bound onto the scaffold.