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The porphyrin handbook - Kadish K.M.

Kadish K.M. The porphyrin handbook - Academic press, 2000. - 368 p.
Download (direct link): kadishsmishgulilard2000.djvu
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160
Pandey and Zheng
hydrophobicity, pH, lymphatic drainage and lipoprotein binding
influence the biodistribution and localization of sensitizers in tissue
and tumors. Porphyrin localizing in tumors may depend on one or more of
these factors. Descriptions of some of these factors follows.
1. Hydrophobicity
Among porphyrin-based photosensitizers, the hydrophobic porphyrins are
preferentially accumulated and partitioned into corresponding hydrophobic
loci in vivo. This seems to be apparent in the case of the HpD
components.51-53 Moan et al. have shown that among diether derivatives of
hematoporphyrins, the retention in cells increases with decreasing
polarity.54 Pandey et al.55 and Henderson et al.56 have studied the
uptake of a series of alkyl ether derivatives of pyropheophorbide a (a
chlorophyll-a derivative) and found that a strong correlation exists
between uptake and hydrophobicity, with the most hydrophobic dodecyl
ether derivative accumulated mainly in tumor, although such correlation
can not be extended to the in vivo PDT efficacy. On the other hand,
photosensitizers with high partition coefficient values (increased
hydrophobicity) induces sensitizer insolubility, thus preventing drugs
from entering the circulation. A proper balance between hydrophobicity
and hydrophilicity is probably the most important factor which influences
the tumor localization of sensitizers.
2. pH
It is known that the pH of interstitial fluid in malignant tumors tends
to be somewhat lower than that of normal tissue.57'58 This phenomenon
reflects the elevated production of lactic acid by tumor cells which
maintain high rates of aerobic glycolysis to meet their energy needs.
Thus, Moan et al. suggested that the lower pH of tumors may cause high
retention of porphyrins.54 However, it was Thomas and Girotti59 who
provided the first evidence that a decrease of tumor pH by glucose
administration prior to PDT results in a greater accumulation of HpD and
more ^ extensive photodamage of tumor cells.60 Later, Moan and Ma61
reported similar observations, in which tumor uptake of meso-
tetrahydroxyphenylchlorin -) was enhanced by administration of
glucose.
3. Lymphatic Clearance
Tumors generally have poor lymphatic drainage either due to
underdevelopment of the lymphatic system or to lymphatic obstruction.62
The poor lymphatic drainage of tumors along with normally enhanced tumor
vasculature permeability and hypervascularity63 64 are considered to be
the main reasons for the accumulation of proteins and macromolecules in
tumors. Such mechanisms could also profoundly affect the preferential
localization of photosensitizers because they bind to serum proteins.
4. Serum Protein Binding
It has been well recognized that porphyrins bind to serum proteins,
especially albumin, which serve as carriers of
endogenous porphyrin in the blood.65-67 Several studies have shown that
porphyrins, including HpD and H2(TPPS), tend to bind to lipoproteins,
particularly the low-density lipoproteins (LDL).68-70 Since the LDL can
enter the cells through specific receptors, it was suggested that LDL can
serve as an effective carrier for porphyrins. Kessel showed that the
distribution pattern of HpD in tissues correlated with the relative
number of LDL receptors, and also suggested that the affinity of
porphyrins to lipoproteins may dictate the distribution pattern of the
tumor-localization fraction of HpD in vivo.53 Later, Jori and Reddi also
showed the possible significance of lipoproteins in the transport and
uptake of porphyrins.71 Therefore, LDL receptor-mediated endocytosis
might contribute to tumor localization of porphyrins.
Other possible mechanisms that may contribute to tumor localization
include aggregation,72 molecular charge73 and membrane potential74 of
tumor cells.
C. BASIC REQUIREMENTS FOR AN IDEAL PHOTOSENSITIZER FOR PDT
The properties for an ideal photosensitizer are:
1. It should be chemically pure.
2. It should have a high quantum yield of singlet oxygen production.
3. It should have a significant absorption at the long wavelength region
(700-800 nm).
4. It should have preferential tumor localization.
5. It should have minimal dark toxicity and delayed phototoxicity.
6. It should be stable and easy to dissolve in the injectable solvents
(formulation).
As mentioned, the first property of an effective sensitizer is
chemical purity. This simplifies the interpretation of dose- response
relationships in a situation made complex by extra variables including
drug-light interval, total energy, fluence rate and especially
pharmacokinetics. With a multicomponent sensitizer (such as Photofrin)
the rational interpretation of the causes for the overall effect becomes
very difficult.
To achieve an effective destruction of tumor cells, a high quantum
yield of singlet oxygen is required. Even in the absence of heavy atom
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