Russian Chemical Bulletin, International Edition, Vol. 66, No. 11, pp. 1982—2008, November, 2017
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1982—2008, November, 2017.
10665285/17/66111982 © 2017 Springer Science+Business Media, Inc.
Folic acid and its derivatives for targeted photodynamic therapy of cancer
N. V. Suvorov, A. F. Mironov, and M. A. Grin
Moscow Technological University, Institute of Fine Chemical Technologies,
86 prosp. Vernadskogo, 119571 Moscow, Russian Federation.
Fax: +7 (499) 215 6565. Email: email@example.com
The fundamentals of folic acid and folate receptors functioning in the body, changes in the
expression level of folate receptors in carcinogenesis, as well as use of folic acid and its deriva
tives for targeted delivery of photosensitizers to tumors have been reviewed. The ways of
increasing the efficacy of photodynamic therapy by creating multifunctional nanoplatforms
that ensure both passive targeting and receptormediated internalization of photosensitizers in
tumor cells have been discussed.
Key words: folic acid, targeted therapy, photodynamic therapy, photosensitizer.
Folic acid (FA, 1) is a vitamin that participates in
numerous metabolic reactions, including transfer of single
carbon fragments from one molecule of an organic com
pound to another. Since FA is essential for the synthesis of
purine and pyrimidine bases, it is required in large quanti
ties for rapidly proliferating tumor cells. Various types of
cancer cells are characterized by overexpression of folate
receptors (FR), whose amount is several orders of magni
tude higher than in normal epithelial cells. This makes FA
an attractive vector molecule in the development of inno
vative drugs for targeted cancer therapy. For the time being,
the FA conjugates with various chemotherapeutic agents
have been prepared, most of which have demonstrated
elevated uptake in tumors with FR overexpression (ova
rian, and uterine cancer, etc.). This review describes FA
conjugates with different photosensitizers (PS), which
could be prospective for photodynamic therapy (PDT) of
cancer. This method of treatment is noninvasive, and
consists in the PS uptake by tumor, whose local irradia
tion with light of a certain wavelength causes a chain of
photochemical reactions. This results in generation of
active oxygen forms, including singlet oxygen, and death
of both individual tumor cells and tumor tissue as a whole.
However, the insufficient selectivity of the PS uptake in
tumor tissues imposes restrictions on the possibilities of
this method. The use of FA conjugates with PS can sig
nificantly improve the PDT efficiency, and this review
considers the studies of recent years in this field. More
over, the review includes a chapter devoted to nano
structures, which are not only "containers" of a folate vector
and PS as an agent for PDT, but also have a number of
unique properties that enhance the treatment efficacy.
Folic acid and its properties
Folic acid, more known as vitamin B
, is a vital com
pound that participates in many important biochemical
processes, such as regulation of gene activity, biosynthesis
of red and white blood cells, skin and intestinal mucosa
regeneration, as well as in synthesis of substances, regulat
ing brain function.
Nowadays, FA can be produced both
from natural sources and synthetically.
of physiological pH, FA exists in an anionic form called
folate. Folic acid became first known in the 30s of the last
century due to studies of L. Wills. The new compound was
found in yeast and appeared to be able to prevent megalo
blastic anemia, later on called the Wills factor.
the compound was called folic acid (from the Latin "Fo
lium" (leaf)), as it is contained in the leaves of most green
plants, including herbs.
Further studies helped to under
stand the mutual metabolism of FA, vitamin B
methionine, as well as to determine the FA role in the
synthesis of purine and pyrimidine bases, in homocysteine
metabolism, DNA replication and methylation. Folic acid
was revealed essential for normal development of tissues,
especially for rapidly dividing cells of the body, for ex
ample in embryos. The FA deficiency causes complica
tions related to female infertility, neural tube defects dur
ing embryonic development, and other pregnancy com
The chemical structure of FA is represented by the
three components: pterin (2), paminobenzoic (3), and
glutamic (4) acids. Pterin is connected to paminobenzoic
acid by a methylene group, whereas paminobenzoic acid
is bound to glutamine through an amide bond. Folic acid has
an extremely low solubility both in water (0.01 mg mL
and in most organic solvents, with the exception of DMF