Chemotherapy for the treatment of tumor and cancer

Chemotherapy
has been one of the widely used therapeutic methods for treating cancer cells for
the last three to four decades. However, it is quite an expensive and painful
method with many associated side effects such as infertility and hair loss to
mention a few, after prolong periods of treatment.1 Due to these
effects, the development of alternative therapeutic approaches for the
treatment of tumor and cancer cells have become very attractive and of much
interest to the scientific community as a whole.

Photodynamic
therapy (PDT) is one of the promising alternative method for cancer treatment.
This method employs the use of a photosensitizing agent (drug) that can absorb
radiation (red light) at a specific wavelength of 656nm.2 Although,
a few drugs with the ability to absorb this radiation are currently in use;
there are still a number of limitations associated with them for PDT
applications. Some of the limitations include low photo-stability of the drug,
high toxicity, poor absorptivity, low lipophilicity (ability of the drug to be
localized in neoplastic tissues) and contamination by other compounds in the
human body.3

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The
main purpose of this proposal is to synthesize new potential photosensitizer,
by derivatizing phenothiazine (a promising aromatic ring) with either pyrrole
or pyridine rings which may satisfy most of the conditions mentioned above. A
potential advantage for adding pyrrole or pyridine to phenothiazine in one
compound is to increase the absorption wavelength of the drug which in-turn may
increase the quantum yield when exposed to radiation (red light used in PDT).
Increasing the quantum yield will improve the lipophilicity of the compounds
and hopefully increase the uptake of the drugs by damaged and cancer cells.
This will help to cure certain types of cancers.

Background
and Significance:

            Photodynamic therapy (PDT) also known as blue light
therapy is a method for treating cancer cells by the use of light sensitive
drugs which are usually known as photosensitizers or photosensitizing agent.4
PDT is generally used for the treatment of acne as well as very thin
superficial skin cancers. The treatment of the cancer cells involves the use of
light rays of specific wavelength.4 This is due to the fact that
wavelength of light used for the treatment solely depends on the type of
photosensitizer since each drug can only absorb photons produced by a specific
wavelength of light. Generally, the treatment of cancerous cells using PDT
involves three steps. The first step is the application of the drug on the area
or injection of the photosensitizing agent in to the bloodstream. The drug is
then absorbed by all body cells including the tumor or cancer cells but stays
longer in the cancer/tumor cells because of their strong selective binding to
cancer cells than the good cells in the body.5 Some of the reasons
behind the selective binding to cancer/tumor cells are that cancer cells have
larger volumes, lower extracellular pH, larger amount of newly formed
collagens, numerous receptors for lipoprotein, poor lymphatic drainage, and
larger fraction of microphage.6 After about 24 to 72 hours of
injection, the drug leave the healthy cells and remain mostly in the tumor
cells. Finally, the tumor cells are then exposed to light of specific
wavelength. The light then activates the photosensitizing drug to produce
oxygen radicals that kills the tumor cells.3 Although PDT has more
advantage over chemotherapy, there are only a few photosensitizing drugs
available in the market.1

            Photosensitizing agents are drugs
that are pharmacologically inactive but when exposed to light of specific
wavelength can produce active singlet oxygen which can be used to kill tumor
cells. The wavelength of operation for PDT is 600-900 nm. This is
because light of wavelength below 600 nm can be absorbed by some molecules in
the body such as hemoglobin and that above 900 nm usually does not produce
enough active singlet oxygen.6 For a photosensitizing drug to be
used in PDT it must meet some criteria. Some of the requirements are that the
drug should be nontoxic, produce a high amount of singlet oxygen (i.e. high
quantum yield), highly soluble in lipids, selective towards hyper-proliferating
tissues and photostable.7, 8, 9 A list of photosensitizers used for
PDT applications include porphyrin derivatives, purpurins, phenothiazine,
porphycenes and phophorbids. The widely used dihematoporphyrin derivatives have
poor absorption in the visible region and therefore there is the need to synthesize
new photosensitizing drugs.10 Over the years, phenothiazine
derivatives have become attractive for PDT and photodynamic antimicrobial
therapy (PACT) because they are known to inhibit viral growth under the
influence of light.11 Examples of phenothiazine derivatives include
methylene blue, thionine, toluidine blue and the demethylated analogues azure
C.

Methylene
blue (MB) contains two dimethyl amino groups and has been used in several drug
research for the treatment of various viral and bacterial infections.12
MB has a ?max values of 608 and 668 nm that make it suitable for
PDT.11 However, this phenothiazine derivative has poor lipophilicity
which in turn decreases it uptake by damaged and cancer cells.13
Therefore it is very important to work toward improving the lipophilicity of MB
and increase its potential for PDT application.

Mechanism
of photosensitization: Mechanism of photosensitization: The term
photosensitization is a reaction which involves the initiation of a photo
active molecule (photosensitizer) followed by transfer of energy to desired
species.14 These type of reactions can either be  in chemical systems or living tissues or
cells. PDT is related to photosensitization in living tissues. The ground state
photosensitizer (P) absorbs photons and are excited to energy rich states. The
excited photosensitizer (P*) with a half-life of about 10-6-10-9
seconds will then relax to the ground state via fluorescence or undergo
intersystem crossing to the triplet excited state of half-life 10-3
seconds.14 The excited photosensitizer in the triplet state then
interacts with tissue oxygen via two paths to produce the active singlet oxygen
species which is needed to kill tumor/cancer cells.15 In the first
path, excited photosensitizer (P*) reacts with a substrate (S) to
produce radical ions of both the photosensitizer (P.-) and substrate
(S.+). The substrate radical (S.+) then reacts with
triplet oxygen (3O2) atom to produce oxidized substrates
which ultimately leads to cell death. However, in the second path, the excited
photosensitizer (P*) reacts directly with triplet oxygen atom (3O2)
to produce the singlet oxygen (1O2) atom which then
reacts with the substrate (S) to produce oxidized substrates leading to cell
death while the original photosensitizer (P) is restored to the ground state.15
Singlet oxygen species produced
from these processes are short lived with a lifespan
between 0.01- 0.04 ?s; and diffuse a distance between 0.01-0.02 ?m per second
to targeted tissues.6, 11 Photosensitizers with high lipophilicity
have higher quantum yield compared to contemporary hydrophilic photosensitizers
due to the high diffusion rates of singlet oxygen in the lipophilic environment. Lipophilic
photosensitizers show high selectivity in
localization around lipid concentrated parts of cells and tissues due to their
high diffusion rates.11 Nuclear membranes, mitochondria, and
reticulum lysosomes are distinctive parts of
living cells with higher lipid contents where photosensitizers selectively accumulate
to boost apoptosis (cell death) when exposed to red light. Photo-oxidation also
aid cell death by the activation of phospholipase enzymes in cell membranes.11
The ultimate consequence of this activation process is the changes in the
permeability of cell membrane and inhibition of enzymes such as mitochondrial
enzymes. The inhibition of enzyme action in cells is understood to be the
predominant cause of cell death in photodynamic therapy.11