Chapter 9
Prodrugs
Zeynep Ates-Alagoz1,2 and Adeboye Adejare2
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey, 2Department of Pharmaceutical Sciences,
Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, United States
9.1 Introduction
The term “prodrug” was first used by Albert (1958) to indicate pharmacologically inactive compound that is broken
down in vivo to give the active drug. It could be used instead
of the drug to achieve desired physicochemical properties
that can increase usefulness and/or decrease associated toxicity (Sriram and Yogeeswari, 2010). Medicinal chemists have
used this concept as a tool to solve issues with problematic
drugs. In order to exert desired pharmacological actions, prodrugs must undergo chemical or enzymatic biotransformation to the active forms and promoieties within the body
(Rautio et al., 2008b) (Fig. 9.1). The promoiety is carefully
selected to pass on a desirable property to the drug resulting
in prodrug with desired physicochemical properties. The prodrug should be safe and rapidly excreted from the body. It is
not necessary for pharmacologic activity (Andurkar, 2007).
Prodrugs can exist naturally or they can result from synthetic
or semisynthetic processes produced intentionally as part of
a rational drug design or unintentionally during drug development (Wu, 2009). Release of the active drug can be controlled depending upon the purpose for which prodrug is
designed (Sinkula and Yalkowsky, 1975; Stella et al., 1985).
The major goal in prodrug design is to overcome the
various physicochemical, pharmaceutical, biopharmaceutical, and pharmacokinetic limitations of parent drug,
which otherwise could hinder its clinical use (Stella et al.,
2007; Sherwood, 1996; Stella, 2004, 2006; Stella and
Nti-Addae, 2007; Oliyai, 1996). For example, prodrugs
provide possibilities for overcoming drug-delivery challenges, such as poor aqueous solubility, formulation,
insufficient oral absorption, chemical instability, inadequate brain penetration, toxicity, and local irritation.
Prodrugs can also improve drug targeting, and the development of a prodrug of an existing drug with improved
properties may represent a life-cycle management opportunity (Rautio et al., 2008a).
The prodrug concept has found a number of useful
applications in drug discovery and development. There are
a number of subcategories of prodrugs. The most common
category is one in which additional chemical substituents
have been attached covalently to the drug molecule.
Release of the free drug is then accomplished either enzymatically or chemically (Rautio et al., 2008a). Earlier
examples of prodrugs include methanamide (hexamine),
aspirin, and prontosil (Fig. 9.2; Stella, 2007). Methanamide
was used in 1899 as a urinary tract prodrug that delivers
the antibacterial formaldehyde. It is a stable inactive compound at pH greater than 5. However, in acidic environment, the compound disintegrates to form formaldehyde.
Aspirin (acetyl salicylic acid) is a common nonsteroidal
antiinflammatory drug used for the treatment of pain and
arthritis; a less irritating form of sodium salicylate (Stella
et al., 2007; Supernaw, 2007). In the body, aspirin is rapidly deacetylated to form salicylic and acetic acids. Aspirin
and salicylic acid have been proposed as antiinflammatory
agents (Kuehl et al., 2006). Acetic acid can be acted on
rapidly by metabolic enzymes, thus, is basically a nontoxic
byproduct (Fuchs, 2007). Prontosil is an example of accidental prodrugs. It is the first commercially available antibacterial antibiotic and a prodrug of sulfanilamide.
Prontosil is inactive as an antibacterial, but it is turned
FIGURE
concept.
Remington. DOI: https://doi.org/10.1016/B978-0-12-820007-0.00009-X
Copyright © 2021 University of the Sciences in Philadelphia. Published by Elsevier Inc. All rights reserved.
9.1 Illustration
of
prodrug
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SECTION | 3 Pharmaceutical Chemistry
FIGURE 9.2 Methanamide (A), prontosil (B), and acetyl salicylic acid (C).
in vivo to pharmacologically active sulfanilamide by the
enzyme azoreductase. These studies led to discovery of the
sulfonamides as antibacterial agents (Andurkar, 2007).
There are a number of ways that drugs can be modified. What is necessary is that the parent drug has a functionality that is amenable to modification. Functional
groups that are amenable to prodrug design include carboxylic, hydroxyl, amine, phosphate, and carbonyl
groups. Modifications of these groups can lead to esters,
carbonates, carbamates, amides, phosphates, and oximes.
These functional groups lead to prodrugs which can provide drug release triggered by esterases, phosphatases,
proteases, hypoxia, pH changes, reducing, oxidizing, and
light conditions (Rautio et al., 2008a). There are currently
a number of prodrugs in clinical trials. Classification of
them can be based on the therapeutic categories, for
example, anticancer, antiviral, antibacterial, nonsteroidal
antiinflammatory, and cardiovascular; or based on the categories of moiety that attach to the active drug, for example, esters, carbonates and carbamates, amides, and
oximes prodrugs (Han and Amidon, 2000; Hu, 2004;
Liederer and Borchardt, 2006); or based on the delivery
method, for example, oral, topical, or parenteral delivery.
This review will start with an overview of the delivery
systems, functional groups, and then more into prodrug
approaches for anticancer drugs.
9.2 Prodrug approaches based on drug
delivery
Oral delivery, the most desirable route of administration,
is the most difficult to attain as bioavailability by this
route is usually least efficient compared to other routes
(Lee, 1995). It is very important to be aware of the physicochemical and biological factors that are restraining the
oral bioavailability of a drug before starting a prodrug
strategy. Aqueous solubility, low permeability, tendency
to be an efflux substrate, rapid hepatic metabolism, and
biliary excretion are important physicochemical and biological factors that may limit oral delivery (Rautio et al.,
2008a). The rationale behind the prodrug strategy for
hydrophilic and/or charged compounds is to introduce
lipophilicity and mask hydrogen-bonding groups by the
addition of another moiety (Beaumont et al., 2003). These
prodrugs are often carboxylic acid esters, or phosphonic
acid esters, of poorly permeable but aqueous soluble parent drugs (Rautio et al., 2008a).
Use of carrier-mediated absorption is one of the prodrug approaches for improving oral drug delivery. This
prodrug approach uses transporters that facilitate membrane transport of polar and charged nutrients such as
amino acids and peptides. Therefore targeting specific
membrane transporters is particularly important when prodrugs are polar or charged. There have been many
attempts to improve drug absorption by targeting specific
membrane transporters, including amino acid, peptide,
and glucose transporters. Among the various membrane
transporters, peptide transporters are attractive targets in
prodrug design to improve oral drug absorption because
of several advantages such as broad substrate specificity
and high capacity. They have been extensively studied
(Incecayir et al., 2016).
When a drug cannot be taken orally due to oral absorption limitations or when immediate action of drug is
required, such as in anaphylactic reaction, parenteral drug
dosing is the desired route of administration. Most phosphate esters used in parenteral formulations are watersoluble prodrugs of poorly water-soluble parent drugs.
Phosphate esters are ionizable and have considerably higher
aqueous solubility than the parent compounds, and they are
rapidly hydrolyzed by phosphatases yielding the parent
drugs (Hemenway and Stella, 2007; Heimbach et al., 2003).
The ocular absorption of topically applied drugs is limited by the corneal epithelium barrier, the rapid precorneal
drug elimination and systemic absorption from the conjunctival. Prodrugs were introduced to ophthalmology about 35
years ago when ocular absorption of epinephrine was substantially improved by its prodrug (Jarvinen and Jarvinen,
1996). Dipivefrine (Fig. 9.3) is a dipivalic acid ester prodrug
of epinephrine which is able to release the parent drug within
the eye at a rate that meets therapeutic need. Dipivefrine
penetrates cornea 17 times better than epinephrine due to its
higher lipophilicity at pH 7.2 (Jarho et al., 1997).
Dermal drug delivery has some advantages over more
conventional treatments such as delivery of therapeutic
level of drug to the application site in a more effective
and safer way (Rautio et al., 2000). Thus it has been getting
Prodrugs Chapter | 9
171
FIGURE 9.3 In vivo conversion of dipivefrine to epinephrine.
increasing popularity. But, most drugs present inappropriate
physicochemical properties to efficiently penetrate the skin.
Therefore many attempts have been carried out to increase
drug permeation through the skin (Bonina et al., 2001).
Drugs containing polar functional groups have problems of
membrane permeability and biphasic solubility which limit
their dermal delivery. The prodrug approach can mask these
polar functional groups as esters which then hydrolyze to
the parent drug either enzymatically or chemically
(Majumdar and Sloan, 2006). Recent studies have shown
that prodrug needs to have adequate lipid as well as water
solubility to permeate the skin effectively because the skin
represents a lipid-aqueous biphasic barrier to permeation
due to nature of the stratum corneum. Thus prodrugs should
increase not only lipid but also aqueous solubility as need
be (Sloan and Wasdo, 2003, 2007).
9.3 Prodrug approaches based on
functional groups
Amines are highly ionized functional groups under physiological conditions (pH 5 18). However, this functional
group is found in many drug molecules (Sloan and
Wasdo, 2007; Simplı́cio et al., 2008). Drug molecules that
contain basic amine functional groups may actually permeate skin better than expected, and basic amine groups
incorporated into a prodrug may enhance its skin permeation (Sloan et al., 1984). Derivatizations of amines can
result in reduction in basicity. That could be favorable for
improving the rate of diffusion across biological membranes. Physicochemical and structural properties of the
promoiety that is incorporated into a drug molecule are
important. Hydrophilic promoieties are designed to
improve water solubility and lipophilic ones are designed
to improve membrane permeability of the parent drugs
(Krise and Oliyai, 2007).
Ester formation is the most common prodrug design
strategy to increase lipophilicity by masking carboxylic
acids, phosphates, and other charged groups (Taylor,
1996). Such prodrug is activated by enzymatic (esterase)
or chemical hydrolysis (Ettmayer et al., 2004). Ester prodrugs are most often used to enhance oral absorption and
thus passive membrane permeability of poorly permeable
compounds (Beaumont et al., 2003).
Acylation or alkylation of alcohols or phenols could
lead to a less polar prodrug, while phosphorylation can
lead to a more water-soluble prodrug. Drugs containing
hydroxyl groups, including alcohols and phenols, can
have a variety of physical/chemical properties that have
advantages and disadvantages. Esterification of the
hydroxyl group has been one of the preferred prodrug
strategies to mask polar groups within a drug molecule
and thereby promote membrane permeability. Acyl
groups that have been incorporated to form promoieties
for the hydroxyl group range from lower alkyl groups to
long-chain fatty acids (Dhareshwar and Stella, 2007).
Phosphate ester prodrugs present several advantages
for the formulation and development of poorly watersoluble compounds. They are chemically stable, need
only a hydroxyl moiety, and enhance aqueous solubility
to allow oral or parenteral administration. Phosphate ester
prodrugs (Fig. 9.4) are readily hydrolyzed by endogenous
phosphatases to release the pharmacologically active parent compounds and phosphates (Kearney and Stella,
1993; McComb et al., 1979; Heimbach et al., 2007).
Phosphorus is an essential mineral for normal body function and is found as phosphate in the body (Food and
Nutrition Board, Institute of Medicine, 1997). Phosphates
are extremely important in living cells. Phosphates are
FIGURE 9.4 Illustrative in vivo conversion of
phosphate ester prodrugs to their active parent
compound.
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FIGURE 9.5 General structure of phosphates,
phosphonates, and phosphinates.
FIGURE 9.6 Illustration of how phosphorous ester prodrug moiety is cleaved by an enzymatic and/or chemical
process to active parent compound.
extensively circulated in the body and excreted in the
urine and feces and must be replaced in the diet (Food
and Nutrition Board, Institute of Medicine, 1997).
Phosphates, phosphonates, and phosphinates (Fig. 9.5)
are prominently represented pharmacophores in various
classes of biological agents. It is generally well recognized that the therapeutic potential of drugs containing a
phosphate, phosphonate, or phosphinate group is limited
by their inadequate membrane permeation and oral
absorption. These groups carry one or two negative
charges making them ionic. They do not readily undergo
passive diffusion across cell membranes. These compounds exhibit a low volume of distribution and efficient
renal clearance because of the ionization (Krise and
Stella, 1996; He et al., 2007).
To overcome these problems, a variety of promoieties
to mask ionizable phosphate, phosphonate, or phosphinate
groups have been designed by medicinal chemists. They
usually use phosphorus-coupled oxygen to form neutral
ester, which will decrease the polarity by increasing the
lipophilicity of the compound. Once the ester prodrug
gets into the target issues, moiety can be cleaved by an
enzymatic and/or chemical process to release free drug to
achieve the desired biological effect (He et al., 2007)
(Fig. 9.6). This process will be illustrated with several
examples, including nucleotides.
The monoalkyl/aryl ester analogs of phosphates failed to
act as efficient prodrugs for the delivery of nucleosidemonophosphate analogs intracellularly due to high degree of
polarity and lack of conversion of the monoalkyl esters
in vivo back to the parent nucleoside (Krise and Stella, 1996).
Serafinowska et al. have synthesized a series of dialkyl prodrugs of 9-[2-(phosphonomethoxy)ethoxy]adenine
(Fig. 9.7) to improve the poor bioavailability. Short-chain
FIGURE 9.7 General structure of dialkyl prodrugs of 9-[2-(phosphonomethoxy) ethoxy] adenine.
FIGURE 9.8 General structure
1-naphthalenemethylphosphonate.
of
3-phthalidyl
esters
of
diesters, being chemically stable, were predominantly
detected unchanged in the serum after oral administration
(Serafinowska et al., 1995).
In order to completely mask the negative charge on
phosphorous, a wide variety of tri-ester prodrugs have
been synthesized (Jones et al., 1989; McGuigan et al.,
1989, 1990, 1991). Generally, simple alkyl tri-esters are
too stable to be useful as prodrugs and the resulting phosphorous esters are inactive. However, aryl esters and activated alkyl esters are capable of functioning as nucleotide
prodrugs (Jones and Bischofberger, 1995).
Dang et al. synthesized a series of 3-phthalidyl esters of
1-naphthalenemethylphosphonate (Fig. 9.8) as a potential
Prodrugs Chapter | 9
prodrug approach to improve intracellular delivery of phosphonates. These 3-phthalidyl esters successfully delivered
1-naphthalenemethylphosphonate intracellularly in rat hepatocytes and were further optimized to give higher plasma
stability. Advantages possessed by this prodrug approach
over the traditional acyloxymethyl prodrug approach include
that these prodrugs do not generate formaldehyde and have
improved plasma stability (Dang et al., 1999).
Nucleoside and nucleotide analogs have great therapeutic
potential for the treatment of viral diseases and cancer
(Robins, 1984). Nucleosidic drugs depend on kinasemediated activation to create the phosphorylated nucleotide
and exhibit biological activity. Monophosphate formation is
the first step in phosphorylation and known to be highly specific and often causes the development of resistance
(Johnson et al., 1988). In contrast to nucleosides, nucleotides
are phosphorylated species and do not require that first step
in their metabolic activation (Jones and Bischofberger,
1995). Nucleotides, however, have some disadvantages over
nucleosides. They go into cells very poorly (Posternak,
1974) and show usually low or no activity in vitro, because
of their charge. Another disadvantage especially for nucleoside phosphate analogs is their low stability in biological
media, due to rapid dephosphorylation (Krise and Stella,
1996; LePage et al., 1975; Cohen and Plunkett, 1975).
Nucleotide prodrugs can potentially overcome these difficulties, and they were successfully used to increase oral absorption of nucleotides in vivo by masking the negative charge
(s) on the phosphorous with suitable functionalities. These
prodrugs can be converted chemically or biologically to the
parent nucleotide. They have been utilized to increase intracellular delivery and alter pharmacokinetic properties. They
have also been used for tissue-specific delivery of the
nucleotides in vivo resulting in altered selectivity and
reduced toxicity (Jones and Bischofberger, 1995).
9.4 Prodrug approaches for anticancer
drugs
Cancer is still a major cause of death in the world; thus
the urge to discover novel and effective therapeutic
FIGURE 9.9 In vivo conversion of miproxifene phosphate to miproxifene.
173
agents continues. Only 20% of the cancer patients can
benefit from surgical- or radiation-based therapies, and
that is why chemotherapy is the primary choice for cancer treatment (DeSantis et al., 2014). However, current
therapeutics may suffer from low bioavailability, high
toxicity, and drug resistance (Perkins et al., 2003).
Prodrugs provide possibilities for overcoming drugdelivery challenges, such as poor aqueous solubility,
formulation, insufficient oral absorption, chemical
instability, inadequate brain penetration, toxicity, and
local irritation (Rautio et al., 2008a).
Miproxifene phosphate (TAT-59, Fig. 9.9) is a triphenylethylene analog of tamoxifen. After oral administration, TAT-59 is immediately metabolized in the
digestive tract to its active form DP-TAT-59 which has
a high affinity for estrogen receptors. DP-TAT-59 suppresses the proliferation of human breast carcinoma
cells even at concentrations lower than 1/30th of the
level required for tamoxifen exhibiting this action
(Toko et al., 1995; Shibata et al., 2000). Unlike other
phosphate esters, TAT-59 exhibits unusually low water
solubility. The prodrug was successful because its solubility and dissolution rate were significantly higher
than those of the parent drug (Heimbach et al., 2007).
Estramustine phosphate (Fig. 9.10) is a phosphate
ester prodrug of the practically insoluble, nonionizable
parent drug estramustine. It is a cytotoxic drug that has
been used in the treatment of advanced prostatic carcinoma (Heimbach et al., 2007). A phosphate group was
added at the 17-β position of the steroid D ring to increase
the water solubility of the compound. Estramustine
phosphate sodium is immediately dephosphorylated in
the gastrointestinal tract, producing the main cytostatic
metabolite estramustine (Nicholson et al., 2002).
Etoposide (Fig. 9.11), a semisynthetic derivative of
podophyllotoxin, is an important chemotherapeutic agent
(CA) in the treatment of select patients with germ cell
tumors, lymphomas, and small cell lung cancer (Greco
et al., 1991; Greco and Hainsworth, 1995). The clinical use
of etoposide is adversely affected by its very poor water solubility and is formulated in polysorbate-80, polyethylene
glycol, and alcohol. Because of its poor solubility, even
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SECTION | 3 Pharmaceutical Chemistry
FIGURE 9.10 In vivo conversion of estramustine phosphate to estramustine.
FIGURE 9.11 In vivo conversion
of etoposide phosphate to etoposide.
with this formulation, etoposide must be diluted to avoid
precipitation. This dilution may cause fluid overload problems in patients receiving high doses of this agent and
requires prolonged nursing supervision, higher expenses,
and patient inconvenience and discomfort (Saulnier et al.,
1994). In addition, hypersensitivity and hypotensive reactions
have been reported. Etoposide phosphate, a water-soluble
prodrug of etoposide, has several potential advantages,
including easier and more rapid administration, avoidance of
large fluid loads, and elimination of hypersensitivity reactions
and other problems related to the solubilizer (Saulnier et al.,
1994).
The anticancer drug CPT-11 (irinotecan, 7-ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin,
Fig. 9.12), is a prodrug that is activated by esterases to
yield SN-38 (7-ethyl-10-hydroxycamptothecin), a potent
topoisomerase I poison (Hatfield et al., 2011; Hyatt et al.,
2005). Irinotecan is a semisynthetic water-soluble camptothecin produced in an attempt to reduce the toxicity and
improve the therapeutic efficacy of the drug (Escoriaza
et al., 2000). Irinotecan shows encouraging activity in the
treatment of several types of tumors such as nonsmall cell
lung cancer, colorectal adenocarcinoma, and cancer of the
cervix. SN-38 has been shown to be 1001000 times
more potent than CPT-11 in in vitro and in vivo tests of
cytotoxicity (Rivory et al., 1996).
Irinotecan’s clinical utility is limited due to the
drawbacks such as poor bioconversion to the active drug
SN-38, severe toxicities, and the function of SN-38 as a
substrate of the breast cancer resistance protein efflux
pump (Ohwada et al., 2009). Ohwada et al. reported the
syntheses and biological activities of water-soluble prodrugs of hexacyclic camptothecin analog, CH0793076
(Fig. 9.13). It exhibits pH-dependent conversion to parent compound and showed better anticancer activity than
irinotecan. Among the prodrugs synthesized, TP300 is
highly water-soluble and rapidly generates CH0793076
at physiological pH in vitro. TP300 showed a broader
antitumor spectrum and more potent antitumor activity
than irinotecan in various human cancer xenograft models (Ohwada et al., 2009).
5-Fluorouracil (5-FU, Fig. 9.14) is an antimetabolite
with a broad spectrum of activity against solid tumors
(Calabresi and Parks, 1985). However, its administration
is accompanied by severe toxic side effects and delivery
problems. In order to solve these problems, low- and
Prodrugs Chapter | 9
175
FIGURE 9.12 In vivo conversion of irinotecan to SN-38.
FIGURE 9.13 In vivo conversion of TP300 to
CH0793076.
FIGURE 9.14 In vivo conversion of capecitabine to 5-fluorouracil.
macromolecular prodrugs of 5-FU have been developed. In
most instances the antitumoral activity of the polymeric
prodrugs is due to the free 5-FU released by a nonspecific
chemical hydrolysis of the ester (Akashi and Takemoto,
1990; Ouchi et al., 1990b), carbamate (Ouchi et al., 1992),
carbamoyl (Ouchi et al., 1990a,b, 1992), or amide (Ouchi
et al., 1990b, 1992) bonds between the Nl-pyrimidine atom
of the drug and the polymer backbone or an alkylene type
spacer (Nichifor et al., 1996). Capecitabine is a commercially available prodrug of 5-FU and it was first approved
in the United States in 1998 for the treatment of metastatic
breast cancer. This prodrug was designed to improve oral
bioavailability and selectivity of 5-FU to tumor cells.
Capecitabine passes intact through the intestinal mucosa
and selectively delivers 5-FU to tumor tissue by enzymatic
conversion (Shimma, 2007).
To enhance therapeutic index, and reduce the toxicity
issues of cytotoxic chemotherapy, targeted prodrug
approaches are new directions in the treatment of cancer
(Gonzalez-Mendez et al., 2019). These directions are
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SECTION | 3 Pharmaceutical Chemistry
FIGURE 9.15 Enzymatic activation of IQ-FdUrd under hypoxic conditions. IQ-FdUrd, 5-Fluorodeoxyuridine prodrug
bearing an indolequinone unit.
FIGURE 9.16 Mechanism of releasing Dox
from prodrug induced by pH. Dox, Doxorubicin.
receiving big attention for adjustment of physical properties of drugs such as the charges, lipophilicity, or reactivity by alteration of leads to selective delivery of the drugs
to cancer cells and tissues. Therefore prodrugs concentrate at their target cells and show their activities there in
a selective way (Jiho et al., 2019). Significant strategies
to accomplish the local activation of prodrugs include
enzymatic activation of prodrugs in hypoxic cells (Sriram
and Yogeeswari, 2010, Han and Amidon, 2000), the use of
pH-sensitive conjugates (Hong et al., 2019), antibodydrug conjugates (Cho et al., 2019), hydrophobic drug
self-delivery systems (Xue et al., 2019), and integration
of prodrugs with nanotechnology-based drug delivery.
Jiho et al. recognized an enzymatic one-electron
reduction as a useful reaction that can be applied in the
design of tumor hypoxia-targeting drugs. The enzymatic
reaction of 5-fluorodeoxyuridine (FdUrd) (Fig. 9.15)
prodrug bearing an indolequinone unit (IQ-FdUrd) is a
substrate of reductases that were characterized by them.
Release of FdUrd under hypoxic conditions after treatment with cytochrome NADPH P450 reductase and IQFdUrd was achieved. They also confirmed that IQ-FdUrd
showed selective cytotoxicity in hypoxic tumor cells (Jiho
et al., 2019).
Doxorubicin (Dox) is a potent anticancer drug, but it
causes dose-dependent cardiotoxicity. To overcome this
problem, Gonzalez-Mendez et al. designed pH-sensitive
prodrugs (Fig. 9.16) for improving its selectivity and
reducing the toxic effects of the free drug. They examined
Dox attached to adamantane (Ad) using three different
pH-sensitive linkers; ester, amide, and hydrazone to
reduce the toxicity of free drug. Kinetics of the in vitro
hydrolysis of the three proposed linkers was evaluated at
different pH values, considering the acid microenvironment that characterizes tumors. The cytotoxic activity of
the prodrug with the best release profile displayed a similar behavior to the free drug, illustrating use of appropriate linker in the design of pH-sensitive Dox prodrugs
(Gonzalez-Mendez et al., 2019).
A novel strategy named radiation-induced apoptosistargeted chemotherapy (RIATC) that could specifically
deliver cytotoxic agents to the tumor guided by radiotherapy
was proposed by Chung et al. They synthesized a novel
albumin-binding prodrug MPD02 (Fig. 9.17) by conjugating
cytotoxin monomethyl auristatin E (MMAE) to the
C-terminus of the KGDEVD peptide via self-eliminating
linker and introduced a maleimide group to the Lys side
chain of the peptide. They found that MPD02 metabolized
Prodrugs Chapter | 9
177
FIGURE 9.17 Mechanism of releasing MMAE from prodrug induced by caspase-3. MMAE, Monomethyl auristatin E.
FIGURE 9.18 Mechanism of releasing Dox and CA4 induced by light. CA4, Combretastatin A4; Dox, doxorubicin.
into a highly potent MMAE on caspase-3-mediated activation, showing a highly potent anticancer effect with good
safety profile in two different triple negative breast cancer
(TNBC) xenograft models (Chung et al., 2019).
Same researchers improved an RIATC prodrug by
introducing an apoptotic cell-binding moiety, ApoPep-1,
which binds to histone H1 translocated on the surface of
apoptotic cells. The prodrug named AP1-DEVD-S-Dox
was prepared by conjugating ApoPep-1 and Dox via a
caspase-3-cleavable linker, allowing cytotoxic Dox to be
released in the presence of caspase-3. Results showed
that prodrug AP1-DEVD-S-Dox was able to selectively
deliver Dox to the tumor with less systemic cytotoxicity
(Cho et al., 2019).
Since light is noninvasive external stimulus that can
be manipulated, photoremovable protection groups
(PPGs) have received much attention in recent years for
clinical applications (Döbber et al., 2017; Ieda et al.,
2016). Inactive prodrugs were prepared by conjugation of
active drug to PPGs with covalent bonds to achieve maximum activity and minimum toxic effects by controlled
release of active drug in the target region by light irradiation. Recently, various PPGs have been explored, but
most of them were investigated to deliver a solo drug
molecule (Ahmed and Fruk, 2013; Klan et al., 2013). Liu
et al. synthesized a photoresponsive hybrid prodrug that
has both Dox and combretastatin A4 (CA4) (Fig. 9.18) to
explore the application of PPGs in the field of combination chemotherapy. They found that Dox release was
achieved with 405 nm light and CA4 release with mostly
365 nm light. Cell viability assessment confirmed that the
prodrug had greater toxicity to MDA-MB-231 TNBC
cells compared to individual drugs, and a synergistic
effect was achieved (Liu et al., 2019a).
Gemcitabine (Gem), an anticancer agent, has a low
therapeutic effect due to its short circulation time and
rapid metabolism. To increase antitumor activity, a new
Z-GP-Gem prodrug was developed by modifying the
4-amino group of Gem by Sun et al. This prodrug can
effectively release Gem in the tumor through cleavage by
FAPα enzyme activation. Compared to Gem, the Z-GPGem prodrug showed significant inhibition on both tumor
growth and pulmonary metastasis in BALB/c mice bearing orthotopic breast 4T1 tumors. As Z-GP-Gem prodrug
had a long circulation time and a high tumor uptake, it
led to a remarkable improvement in systemic toxicity and
inhibition of tumor growth in 4T1 cells. Also, in the animal model, depletion of tumor-associated fibroblast was
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SECTION | 3 Pharmaceutical Chemistry
observed during the treatment of Z-GP-Gem prodrug.
Thus these findings showed that FAPα-activated prodrug
would be a desirable approach for tumor treatment (Sun
et al., 2019).
High toxicity of colchicine limited its medical application in cancer therapy (Lin et al., 2013). Colchicine
prodrugs and codrugs have been prepared to decrease
toxicity and increase therapeutic properties (Huczynski
et al., 2015; Nishiyama et al., 2014; Kurek et al., 2014;
Singh et al., 2015). Recently, many efforts focused on
colchicine nanoformulation, as well as chemical synthesis of colchicine prodrugs and codrugs with different linkers. Classification of colchicine prodrugs based on type
of conjugates is noted as biopolymers prodrugs, fluorescent prodrug, metal complexes prodrug, metal-labile prodrug, and bioconjugate prodrug by Ghawanmeh et al.
They summarized the biological importance of colchicine nanoformulation, colchicine prodrugs, and codrugs
(Ghawanmeh et al., 2018).
Methotrexate (MTX) is a CA used clinically for the
treatment of different types of cancer, rheumatoid arthritis, psoriasis, and other autoimmune diseases (Chen et al.,
2014; Khan et al., 2012; Tondwal and Singh, 2015; Yang
et al., 2012). The therapeutic effect of MTX is reduced by
its low tumor cell uptake, and it can cause severe side
effects at therapeutic doses (Chatterjee et al., 1997). MTX
also has low permeability, poor aqueous solubility, and
poor bioavailability. To address all these limitations, an
ionic liquid (IL) formulation of MTX has been prepared
by Moshikur et al. (2019). An IL formulation of active
pharmaceutical ingredients (APIs) was used to address the
issue of polymorphisms (Furukawa et al., 2016; Ferraz
et al., 2011; Shamshina and Rogers, 2014), which is often
responsible for reducing therapeutic efficiency, bioavailability and thermal stability (Ferraz et al., 2011;
Shamshina and Rogers, 2014; Yan et al., 2018). They
synthesized a series of IL-APIs using MTX, and biocompatible IL-forming cations (choline and amino acid esters)
as potential anticancer prodrugs. A mammalian cell line
(HeLa cells) was used to evaluate their cytotoxicity.
MTX-ILs showed 5000 times more water solubility than
free MTX, and more solubility in both water and imitated
body fluids, compared to a sodium salt of MTX. Proline
ethyl ester MTX prodrug showed similar solubility to
MTX sodium salt, but better in vitro antitumor activity.
These results show that newly synthesized API-ILs are
promising (Moshikur et al., 2019).
Another advanced drug-delivery opportunity for prodrugs design is called enzyme prodrug therapy (EPT). A
prodrug designed for it undergoes bioconversion by a
specifically identified enzyme placed in a specific place
in the body. Unlike general prodrugs, quantitative drug
recovery is less important, and the main objective is to
provide site-specific recovery. The localization of the
enzyme at the desired site can be accomplished in
various ways, with various degrees of success, and
laboratory-to-clinic progression. Historically, antibodydirected EPT (ADEPT) is the earliest known success of
EPT (Bagshawe et al., 1994). An antibody developed
against a tumor antigen binds to an enzyme and is
injected into the blood, thereby, causing selective binding of the enzyme within the tumor. The second step is
to administer the prodrug after cleansing the free antibodyenzyme conjugate from the blood stream. In such a
case the enzyme-mediated prodrug activation is carried
out only by the antigen-bound enzyme thus providing
localized drug delivery. Alkaline phosphatase is a member of phosphoesterases and was the first enzyme used in
ADEPT (Senter, 1990; Springer et al., 1990). The first
drugs used in ADEPT were clinically approved anticancer drugs, etoposide, mitomycin, and Dox (Senter,
1990). Such EPTs in medicinal chemistry are discussed
in detail by Walther et al. (2017).
Gene-directed EPT (GDEPT) has also received big
attention because it limits toxicity at healthy cells and
increases tumor cell uptake for cancer therapies (Bhaumik
et al., 2012). GDEPT has two steps. First is transfer of the
enzyme gene to the tumor cell by loading the carrier vector and expression of this gene in the tumor cell (Denny,
2002; Dachs et al., 2005). Second step is conversion of
nontoxic prodrug to cytotoxic drug by enzyme catalysis.
After all, the active drug is transported to other cancer
cells (Zhang et al., 2017a). Nitroreductases (NTR) catalyze the reduction of nitro compounds by using NAD(P)
H. The use of NTR in GDEPT studies is extraordinary.
For discovery of new prodrug/NTR combinations, nitrocontaining aromatic amides (A1-A23) (Denny, 2002)
were designed and synthesized in silico ADMET and
molecular docking experiments were then performed by
Güngör et al. (2019). Reduction potentials of prodrug candidates were studied using Ssap-NtrB by HPLC system.
Cyototoxic properties of prodrugs were investigated using
different cancer cell lines such as Hep3B and PC3. As a
result of biological studies, it was determined that combinations of A5, A6, and A20 (Fig. 9.19) with Ssap-NtrB
can be suggested as potential prodrugs/enzyme combinations in NTR-based cancer therapy (Güngör et al., 2019).
Paclitaxel (PTX) is an anticancer drug mostly used for
breast cancer, and ovarian cancer (Schiff et al., 1979). It
has a unique microtubule mechanism during mitosis, but
the long-term use can lead to the development of resistance that further limits its applications (Dowdy et al.,
2006). To address this limitation, it is important to
increase drug accumulation in tumor tissues and reduce
their resistance. Histone deacetylase inhibitors (HDACIs)
have shown good activity in multiple cancers, either alone
or by combination with conventional anticancer drugs
(Huang and Geng, 2017; Fallkenberg and Johnstone, 2014).
Prodrugs Chapter | 9
179
FIGURE 9.19 Structures of nitro-containing aromatic amides A5, A6, and A20.
FIGURE 9.20 PTXSAHA coprodrugs with Gly (1a) and succinic acid (1b) linkers. Gly, Glycine; PTX, paclitaxel; SAHA, suberoylanilide hydroxamic acid.
Suberoylanilide hydroxamic acid (SAHA) is an HDACI
that has strong anticancer effects in hematological tumors
(Duvic and Vu, 2007). It has been shown that SAHA could
potentiate PTX-induced antitumor effects against some cancers (Cooper et al., 2007; Modesitt and Parsons, 2010; Shi
et al., 2010).
Liu et al. (2019b) improved the stability of SAHA and
decreased drug resistance after cellular uptake of the
PTXSAHA coprodrugs by conjugating them in a cleavable
way. They attached the hydroxamic acid group of SAHA
and the 20 -OH of PTX to create a coprodrug and further
formed the coprodrug nanomicelles with mPEG2000PLA1750 as the carrier (Sankar and Ravikumar, 2014).
They used glycine (Gly) and succinic acid as the linker of
PTXSAHA coprodrugs (Fig. 9.20). The releasing mechanism of coprodrugs is hydrolysis of the carbonic ester bound
to SAHA by hydrolysis or enzymolysis first. Subsequently,
the rate of release of PTX depends essentially on the stability of the remaining complex. It has been found that PTX20 -Gly is unstable when exposed to water and the other is
more stable under the same conditions (Greenwald et al.,
2003; Wong and Choi, 2015). They examined the stability
of coprodrugs and in vitro cytotoxicity in human colorectal
cell line HCT-116, breast cancer cell lines MCF-7 and
MCF-7/ADR. It was found that 1a effectively releases PTX
and SAHA and had better cytotoxicity than 1b. Comparing
free PTX and 1a coprodrug, 1a coprodrug increased the
anticancer efficacy and effectively reversed PTX resistance
in cancer treatment (Liu et al., 2019).
Phosphoinositide 3-kinase (PI3K) inhibitors have
been considered as adjuvant therapy for advanced prostate cancer. But, expected results have not been achieved
in the clinic. Increasing the effectiveness of PI3K inhibitors against prostate cancer by the conversion of the
inhibitor to an inactive prodrug through adding a separable specific prostate-specific antigen (PSA) peptide
(Abet et al., 2017) has been explored. In systemic circulation, PSA is inactive and protease activity is limited to
prostate or prostate-derived cancer cells. The cleavable
peptide has the sequence Mu-LEHSSKLQL (N-(4morpholinylcarbonyl)-Leu-Glu-His-Ser-Ser-Lys-Leu-GlnLeu), and HSSKLQ is the substrate for PSA. Therefore
activation of the water-soluble prodrug yields the active
drug, a PI3K inhibitor LY294002-analog, which minimizes systemic toxicity and increases delivery to the
tumor site (Fig. 9.21; Abet et al., 2017; Morales et al.,
2013; Baiz et al., 2012).
The primary cause of melanoma, the most dangerous
type of skin cancer and which develops from melanocytes, is ultraviolet (UV) light exposure. Melanintargeting probes (MTPs) are a group of arylcarboxamide
families with high affinity for melanins which contain
molecular targets detected in more than 90% of primary
melanoma cases and 30%50% of metastatic lesions.
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SECTION | 3 Pharmaceutical Chemistry
FIGURE 9.21 Conversion of water-soluble prodrug to
active drug.
FIGURE 9.22 Conversion of the prodrug to the active drug by cleavation of the disulfide bond.
The use of such MTPs to transport an anticancer drug
into the melanoma tumor site was explored by El Aissi
et al. (2015). They reported synthesis and evaluation of a
prodrug (Fig. 9.22) for pigmented melanoma therapy. It
contains an MTP conjugated to the antimetabolite 5-iodo20-deoxyuridine. The fragments were linked by a binder
comprising a disulfide bond that is stable in plasma but is
cleaved effectively by intracellular reduction systems
found in hypoxic tumor cells. The resulting thiol undergoes cyclization to provide free anticancer agent (Abet
et al., 2017; El Aissi et al., 2015; Vivier et al., 2008).
Nitrogen mustards are anticancer drugs that act by
alkylating DNA in purine rings. However, they have
very important side effects in noncancerous tissues and
cells resulting from nondiscriminatory alkylation of
biomolecules. Also, aziridinium ion formation is suppressed in the presence of electron withdrawing groups
in N-aryl nitrogen mustard and, by contrast, increases
with donating groups on the aryl ring. Johnson et al.
(2014) reported that a new nitrogen mustard prodrug
was prepared in which mustard binds to Tirapazamine,
a heterocyclic di-N-dioxide that undergoes enzymatic
deoxygenation in hypoxic solid tumor cells to produce
mono-N-oxide metabolite (Fig. 9.23). This method
resulted in significant increase in the reactivity of the
mustard unit and unmasked the bioactive material in
the hypoxic cells (Abet et al., 2017).
Unsaturated fatty acids (UFAs) have been extensively
investigated in the rational design of CA-UFA prodrugs
in cancer therapy, with good advantages of biocompatibility and innate tumor targeting effect. In the last few decades, numerous chemotherapeutic CA-UFA prodrugs
have been developed (Sun et al., 2017). Among these,
Gemelaidic acid conjugate (CP-4126), cytarabinelaidic
acid conjugate (CP-4055), and PTXDHA conjugate
have successfully entered clinical trials. However, clinical
results of the prodrugs lagged behind expectations.
Several factors may be responsible for the inadequate
clinical outcomes, such as tumor types and heterogeneity,
therapeutic program, and drug resistance. To address
these problems, prodrug-based nanodrug-delivery system
(DDS) combining the advantages of prodrug strategy and
nanotechnology has shown great potential in cancer therapy, particularly for promising CA-UFA prodrug-based
spontaneous nano-assemblies. The advanced drugdelivery strategies based on UFA conjugates and focusing
on recent advances in CA-UFA prodrugs and the emerging CA-UFA prodrug-based nano-DDS were reviewed by
Sun et al. (2017). They focused on the rational design of
CA-UFA prodrugs in response to multiple barriers to chemotherapy, emphasizing the latest developments in both
preclinical and clinical trials. The resulting CA-UFA prodrug-based nano-DDS was also discussed. It emphasized
the prospects and potential challenges of CA-UFA prodrug-based drug-delivery strategies in chemotherapy. The
emerging multifaceted nano-platform based on CA-UFA
conjugates shows significant advantages in drug bioavailability, delivery efficiency and has great potential for clinical applications (Sun et al., 2017).
Prodrug-based nanosystems are of great interest as
they provide significant benefits such as increased chemical stabilities in vivo, longer drug-release profiles, and
low toxicities before degradation takes place (Yu et al.,
2018). Researchers are working extensively to find new
prodrugs and improve pharmacokinetics and pharmacodynamics in vivo (Zhang et al., 2017b). Prodrugs enhance
the therapeutic effects and reduce side effects by placing
stimuli-responsive properties such as redox, pH, and temperature into the nanoparticles (NPs) (Ma et al., 2018).
Such a system was synthesized by Hong et al. They
encapsulated a curcumin (CUR) and peptide-Dox (U11Dox) to an NP system (U11-Dox/CUR NPs) to treat lung
cancer. Prodrug-based nanosystems showed a remarkable
antitumor effect with less toxicity in vivo (Hong et al.,
2019).
Furthermore, Zhu et al. prepared a novel pH-sensitive
and charge-convertible prodrug nanogel to achieve targeted delivery of Dox to enhance the efficacy and reduce
side effects. They synthesized an NP system containing a
folic acidmodified gelatin (Gel-FA)/pluronic F127chitosan-CAD (F127-CS-CAD)/cis-aconitic anhydrideDox prodrug successfully. It was found that the system
had better therapeutic effects on tumors, and the toxic
side effects were decreased significantly when compared
to free Dox (Zhu et al., 2019).
A prodrug of 5-FU (Fig. 9.24) covalently conjugated
to low molecular weight chitosan (LMWC) via a photocleavable linker has been synthesized by Horo et al. to
improve hydrophilicity as well as increase the biological
retention time of the drug. Then, they used ionic gelation
technique to the LMWC-5-FU conjugate into NPs
for effective penetration into cells. The conjugate was
FIGURE 9.23 Conversion of nitro mustard prodrug to
a mono-N-oxide metabolite.
182
SECTION | 3 Pharmaceutical Chemistry
FIGURE 9.24 Mechanism of releasing 5-FU induced by 365 nm light. 5FU, 5-Fluorouracil.
designed to be cleaved under 365 nm UV-A radiation.
The conjugate was been found to exhibit greater water
solubility compared to LMWC and formed hydrogel
(Horo et al., 2019).
9.5 Summary
Prodrugs are usually used with the aim of increasing drug
permeation by enhancing lipophilicity or water solubility.
The prodrug must exhibit enough aqueous solubility and
stability, adequate lipophilicity, sufficient safety, and reasonable conversion to the parent drug in vivo. To enhance
therapeutic index, and reduce toxicity issues of cytotoxic
chemotherapy, targeted prodrug approaches are new
directions in the treatment of cancer. Prodrugs can concentrate at desired cells and show activities there in a
selective way. Prodrug-based nanosystems also are of
great interest as they can provide significant benefits such
as increased chemical stability in vivo, longer drugrelease period, and low toxicity before degradation takes
place. Wide-ranging research in this field and growing
knowledge of drug delivery should generate more new
marketable prodrugs in the future.
References
Abet, V., Filace, F., Recio, J., Alvarez-Builla, J., Burgos, C., 2017.
Prodrug approach: an overview of recent cases. Eur. J. Med. Chem.
127, 810827.
Ahmed, I., Fruk, L., 2013. The power of light: photosensitive tools for
chemical biology. Mol. Biosyst. 9 (4), 565570.
Akashi, M., Takemoto, K., 1990. New aspects of polymer drugs. Adv.
Polym. Sci. 97, 107.
Albert, A., 1958. Chemical aspects of selective toxicity. Nature 182,
421423.
Andurkar, S.V., 2007. Chemical modifications and drug delivery. In: Gibaldi,
M. (Ed.), Gibaldi’s Drug Delivery Systems in Pharmaceutical Care.
American Society of Health-System Pharmacists, Bethesda, MD.
Bagshawe, K.D., Sharma, S.K., Springer, C.J., Rogers, G.T., 1994.
Antibody directed enzyme prodrug therapy (ADEPT): a review of
some theoretical, experimental and clinical aspects. Ann. Oncol. 5,
879891.
Baiz, D., Pinder, T.A., Hassan, S., Karpova, Y., Salsbury, F., Welker, M.
E., et al., 2012. Synthesis and characterization of a novel prostate
cancer-targeted phosphatidylinositol-3-kinase inhibitor prodrug. J.
Med. Chem. 55, 80388046.
Beaumont, K., Webster, R., Gardner, I., Dack, K., 2003. Design of ester
prodrugs to enhance oral absorption of poorly permeable compounds: challenges to the discovery scientist. Curr. Drug Metab. 4,
461485.
Bhaumik, S., Sekar, T.V., Depuy, J., Klimash, J., Paulmurugan, R., 2012.
Noninvasive optical imaging of nitroreductase gene-directed enzyme
prodrug therapy system in living animals. Gene Ther. 19, 295302.
Bonina, F.P., Puglia, C., Barbuzzi, T., de Caprariis, P., Palagiano, F.,
Rimoli, M.G., et al., 2001. In vitro and in vivo evaluation of polyoxyethylene esters as dermal prodrugs of ketoprofen, naproxen and
diclofenac. Eur. J. Pharm. Sci. 14 (2), 123134.
Calabresi, P., Parks, R.E., 1985. Antimetabolites. In: Goodman, L.S.,
Raal, T.W., Murad, F. (Eds.), Pharmacological Basis of
Therapeutics. Macmillan, New York, pp. 12681276.
Chatterjee, D.J., Li, W.Y., Koda, R.T., 1997. Effect of vehicles and penetration enhancers on the in vitro and in vivo percutaneous absorption of methotrexate and edatrexate through hairless mouse skin.
Pharm. Res. 14, 10581065.
Chen, J., Huang, L., Lai, H., Lu, C., Fang, M., Zhang, Q., et al., 2014.
Methotrexate-loaded PEGylated chitosan nanoparticles: synthesis,
characterization, and in vitro and in vivo antitumoral activity. Mol.
Pharm. 11, 22132223.
Cho, Y.S., Chung, S.W., Kim, H.R., Won, T.H., Choi, J.U., Kim, I.S.,
et al., 2019. The novel strategy for concurrent chemoradiotherapy by
conjugating the apoptotic cell-binding moiety to caspase-3 activated
doxorubicin prodrug. J. Control. Release 296, 241249.
Chung, S.W., Cho, Y.S., Choi, J.U., Kim, H.R., Won, T.H., Kim, S.Y.,
et al., 2019. Highly potent monomethyl auristatin E prodrug activated by caspase-3 for the chemoradiotherapy of triple-negative
breast cancer. Biomaterials 192, 109117.
Cohen, S.S., Plunkett, W., 1975. The utilization of nucleotides by animal
cells. Ann. N. Y. Acad. Sci. 255, 269286.
Cooper, A.L., Greenberg, V.L., Lancaster, P.S., van Nagell, J.R.,
Zimmer, S.G., Modesitt, S.C., 2007. In vitro and in vivo histone deacetylase inhibitor therapy with suberoylanilide hydroxamic acid
(SAHA) and paclitaxel in ovarian cancer. Gynecol. Oncol. 104 (3),
596601.
Dachs, G.U., Tupper, J., Tozer, G.M., 2005. From bench to bedside for
gene-directed enzyme prodrug therapy of cancer. Anticancer Drugs
16, 349359.
Dang, Q., Brown, B.S., van Poelje, P.D.V., Colby, T.J., Erion, M.D.,
1999. Synthesis of phosphonate 3-phthalidyl esters as prodrugs for
potential intracellular delivery of phosphonates. Bioorg. Med. Chem.
Lett. 9 (11), 15051510.
Denny, W.A., 2002. Nitroreductase-based GDEPT. Curr. Pharm. Des. 8,
13491361.
DeSantis, C.E., Lin, C.C., Mariotto, A.B., et al., 2014. Cancer treatment
and survivorship statistics. CA Cancer J. Clin. 64 (4), 252271.
Prodrugs Chapter | 9
Dhareshwar, S.S., Stella, V.J., 2007. Prodrug of alcohols and phenols.
In: Stella, V., et al., (Eds.), Prodrugs: Challenges and Rewards. Part
2. AAPS Press/Springer, New York, pp. 3382.
Döbber, A., Phoa, A.F., Abbassi, R.H., Stringer, B.W., Day, B.W.,
Johns, T.G., et al., 2017. Development and biological evaluation of
a photoactivatable small molecule microtubule-targeting agent. ACS
Med. Chem. Lett. 8 (4), 395400.
Dowdy, S.C., Jiang, S.J., Zhou, X.C., Hou, X., Jin, F., Podratz, K.C.,
et al., 2006. Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells. Mol. Cancer Ther. 5 (11),
27672776.
Duvic, M., Vu, J., 2007. Vorinostat: a new oral histone deacetylase
inhibitor approved for cutaneous T-cell lymphoma. Expert Opin.
Investig. Drugs 16 (7), 11111120.
El Aissi, R., Chezal, J.-M., Tarrit, S., Chavignon, O., Moreau, E., 2015.
Melanoma targeted delivery system (part 1): design, synthesis and
evaluation of releasable disulfide drug by glutathione. Eur. J. Med.
Chem. 101, 668680.
Escoriaza, J., Aldaz, A., Castellanos, C., Calvo, E., Giráldez, J., 2000.
Simple and rapid determination of irinotecan and its metabolite SN38 in plasma by high-performance liquid-chromatography: application to clinical pharmacokinetic studies. J. Chromatogr. B: Biomed.
Sci. Appl. 740 (2), 159168.
Ettmayer, P., Amidon, G.L., Clement, B., Testa, B., 2004. Lessons
learned from marketed and investigational prodrugs. J. Med. Chem.
47, 23932404.
Fallkenberg, K.J., Johnstone, R.W., 2014. Histone deacetylases and their
inhibitors in cancer, neurological diseases and immune disorders.
Nat. Rev. Drug Discov. 13 (9), 673691.
Ferraz, R., Branco, L.C., Prudêncio, C., Noronha, J.P., Petrovski, Ž.,
2011. Ionic liquids as active pharmaceutical ingredients.
ChemMedChem 6, 975985.
Food and Nutrition Board, Institute of Medicine, 1997. Phosphorus.
Dietary Reference Intakes: Calcium, Phosphorus, Magnesium,
Vitamin D, and Fluoride. National Academy Press, Washington,
DC, pp. 146189.
Fuchs, T., 2007. Case study: cefuroxime axetil: an oral prodrug of
cefuroxime. In: Stella, V., et al., (Eds.), Prodrugs: Challenges and
Rewards. Part 2. AAPS Press/Springer, New York, pp. 497503.
Furukawa, S., Hattori, G., Sakai, S., Kamiya, N., 2016. Highly efficient
and low toxic skin penetrants composed of amino acid ionic liquids.
RSC Adv. 6, 8775387755.
Ghawanmeh, A.A., Chong, K.F., Sarkar, S.M., Bakar, M.A., Othaman,
R., Khalid, R.M., 2018. Colchicine prodrugs and codrugs: chemistry
and bioactivities. Eur. J. Med. Chem. 144, 229242.
Gonzalez-Mendez, I., Solano, J.D., Porcu, P., Rui, A., Rojas-Aguirre, Y.,
Rivera, E., 2019. Optimized synthesis, characterization and in vitro
systematic evaluation of adamantane-doxorubicin prodrugs sensitive
to pH in breast cancer cells. J. Mol. Struct. 1177, 143151.
Greco, F.A., Hainsworth, J.D., 1995. Etoposide phosphate or etoposide
with cisplatin in the treatment of small cell lung cancer: randomized
phase II trial. Lung Cancer 12 (3), S85S95.
Greco, F.A., Johnson, D.H., Hainsworth, J.D., 1991. Chronic oral etoposide. Cancer 67 (S1), 303309.
Greenwald, R.B., Zhao, H., Reddy, P., 2003. Synthesis, isolation, and
characterization of 20 -paclitaxel glycinate: an application of the
Bsmoc protecting group. J. Org. Chem. 68 (12), 48944896.
183
Güngör, T., Önder, F.C., Tokay, E., Gülhan, Ü.G., Hacıoğlu, N., Tok, T.
T., et al., 2019. Prodrugs for nitroreductase based cancer therapy-2:
novel Amide/Ntr combinations targeting Pc3 cancer cells. Eur. J.
Med. Chem. 171, 383400.
Han, H.K., Amidon, G.L., 2000. Targeted prodrug design to optimize
drug delivery. AAPS Pharm. Sci. 2, 1.
Hatfield, M.J., Tsurkan, L., Garrett, M., Shaver, T.M., Hyatt, J.L., Edwards,
C.C., et al., 2011. Organ-specific carboxylesterase profiling identifies
the small intestine and kidney as major contributors of activation of the
anticancer prodrug CPT-11. Biochem. Pharmacol. 81 (1), 2431.
He, G.-X., Krise, J.P., Oliyai, R., 2007. Prodrugs of phosphates, phosphonates, and phosphinates. In: Stella, V., et al., (Eds.), Prodrugs:
Challenges and Rewards. Part 2. AAPS Press/Springer, New York,
pp. 625632.
Heimbach, T., Oh, D.-M., Li, L.Y., Rodrı́guez-Hornedo, N., Garcia, G.,
Fleisher, D., 2003. Enzyme-mediated precipitation of parent drugs
from their phosphate prodrugs. Int. J. Pharm. 261 (12), 8192.
Heimbach, T., Fleisher, D., Kaddoumi, A., 2007. Overcoming poor aqueous solubility of drugs for oral delivery. In: Stella, V., et al., (Eds.),
Prodrugs: Challenges and Rewards. Part 1. AAPS Press/Springer,
New York, pp. 159199.
Hemenway, J., Stella, V.J., 2007. Prodrugs and parenteral drug delivery.
In: Stella, V., et al., (Eds.), Prodrugs: Challenges and Rewards. Part
1. AAPS Press/Springer, New York, pp. 219264.
Hong, Y., Che, S., Hui, B., Yang, Y., Wang, X., Zhang, X., et al., 2019.
Lung cancer therapy using doxorubicin and curcumin combination:
targeted prodrug based, pH sensitive nanomedicine. Biomed.
Pharmacother. 112, 108614.
Horo, H., Das, S., Mandal, B., Kundu, L.M., 2019. Development of a
photoresponsive chitosan conjugated prodrug nano-carrier for controlled delivery of antitumor drug 5-fluorouracil. Int. J. Biol.
Macromol. 121, 10701076.
Hu, L., 2004. The prodrug approach to better targeting. In: Meeting
Report of Prodrugs: Effective Solutions for Solubility, Permeability,
and Targeting Challenges. June 2829, 2004, Philadelphia, PA.
Available from: ,http://www.currentdrugdiscovery.com. (accessed
08.08.09.).
Huang, M., Geng, M., 2017. Exploiting histone deacetylases for cancer
therapy: from hematological malignancies to solid tumors. Sci.
China Life Sci. 60 (1), 9497.
Huczynski, A., Rutkowski, J., Popiel, K., Maj, E., Wietrzyk, J.,
Stefanska, J., et al., 2015. Synthesis, antiproliferative and antibacterial evaluation of C-ring modified colchicine analogues. Eur. J.
Med. Chem. 90, 296301.
Hyatt, J.L., Tsurkan, L., Morton, C.L., Yoon, K.J.P., Harel, M.,
Brumshtein, B., et al., 2005. Inhibition of acetylcholinesterase by
the anticancer prodrug CPT-11. Chem. Biol. Interact. 157-158, 247.
Ieda, N., Yamada, S., Kawaguchi, M., Miyata, N., Nakagawa, H., 2016.
(7-Diethylaminocoumarin-4-yl)methyl ester of suberoylanilide
hydroxamic acid as a caged inhibitor for photocontrol of histone
deacetylase activity. Bioorg. Med. Chem. 24, 2789.
Incecayir, T., Sun, J., Tsume, Y., Xu, H., Gose, T., Nakanishi, T., et al.,
2016. Carrier-mediated prodrug uptake to ımprove the oral bioavailability of polar drugs: an application to an oseltamivir analogue. J.
Pharm. Sci. 105 (2), 925934.
Jarho, P., Jarvinen, K., Urtti, A., Stella, V.J., Jarvinen, T., 1997. The use
of cyclodextrins in ophthalmic formulations of dipivefrin. Int. J.
Pharm. 153, 225.
184
SECTION | 3 Pharmaceutical Chemistry
Jarvinen, T., Jarvinen, K., 1996. Prodrugs for improved ocular drug
delivery. Adv. Drug Deliv. Rev. 19, 203224.
Jiho, Y., Kurihara, R., Kawai, K., Yamada, H., Uto, Y., Tanabe, K., 2019.
Enzymatic activation of indolequinone-substituted 5-fluorodeoxyuridine
prodrugs in hypoxic cells. Bioorg. Med. Chem. Lett. 29, 13041307.
Johnson, M.A., Ahluwalia, G., Connelly, M.C., Conney, D.A., Brodor,
S., Johns, D.G., et al., 1988. Metabolic pathways for the activation
of the antiretroviral agent 2’,3’-dideoxyadenosine in human lymphoid cells. J. Biol. Chem. 263 (30), 1535415357.
Johnson, K.M., Parsons, Z.D., Barnes, C.L., Gates, K.S., 2014. Toward
hypoxia-selective DNA-alkylating agents built by grafting nitrogen
mustards onto the bioreductively activated, hypoxia-selective DNAoxidizing agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine). J. Org. Chem. 79, 75207531.
Jones, R.J., Bischofberger, N., 1995. Minireview: nucleotide prodrugs.
Antiviral Res. 27 (12), 117.
Jones, B.C., McGuigan, C., Riley, P.A., 1989. Synthesis and biological
evaluation of some phosphate triester derivatives of the anti-cancer
drug araC. Nucleic Acids Res. 17 (18), 71957201.
Kearney, A.S., Stella, V.J., 1993. Hydrolysis of pharmaceutically relevant phosphate monoester monoanions: correlation to an established
structure-reactivity relationship. J. Pharm. Sci. 82, 6972.
Khan, Z.A., Tripathi, R., Mishra, B., 2012. Methotrexate: a detailed
review on drug delivery and clinical aspects. Expert Opin. Drug
Deliv. 9, 151169.
Klan, P., Šolomek, T., Bochet, C.G., Blanc, A., Givens, R., Rubina, M.,
et al., 2013. Photoremovable protecting groups in chemistry and biology: reaction mechanisms and efficacy. Chem. Rev. 113 (1), 119191.
Krise, J.P., Stella, V.J., 1996. Prodrugs of phosphates, phosphonates, and
phosphinates. Adv. Drug Deliv. Rev. 19, 287310.
Krise, J.P., Oliyai, R., 2007. Prodrugs of amines. In: Stella, V., et al.,
(Eds.), Prodrugs: Challenges and Rewards. Part 2. AAPS Press/
Springer, New York, pp. 103124.
Kuehl, G.E., Bigler, J., Potter, J.D., Lampe, J.W., 2006. Glucuronidation
of the aspirin metabolite salicylic acid by expressed UDPglucuronosyltransferases and human liver microsomes. Drug Metab.
Dispos. 34 (2), 199202.
Kurek, J., Boczon, W., Myszkowski, K., Murias, M., Borowiak, T.,
Wolska, I., 2014. Synthesis of sulfur containing colchicine derivatives and their biological evaluation as cytotoxic agents. Lett. Drug
Des. Discov. 11, 279289.
Lee, H.J., 1995. Biopharmaceutical properties and pharmacokinetics of
peptide and protein drugs. In: Taylor, M.D., Amidon, G.L. (Eds.),
Peptide Based Drug Design. Controlling Transport and Metabolism.
ACS Books, Washington, DC, pp. 6997.
LePage, G.A., Naik, S.R., Katakkar, S.B., Khaliq, A., 1975. 9-beta-Darabinofuranosyladenine 5’-phosphate metabolism and excretion in
humans. Cancer Res. 35 (11), 30363040.
Liederer, B.M., Borchardt, R.T., 2006. Enzymes involved in the bioconversion of ester-based prodrugs. J. Pharm. Sci. 95, 11771195.
Lin, Z.-Y., Wu, C.-C., Chuang, Y.-H., Chuang, W.-L., 2013. Anti-cancer
mechanisms of clinically acceptable colchicine concentrations on
hepatocellular carcinoma. Life Sci. 93, 323328.
Liu, W., Liang, L., Zhao, L., Tan, H., Wu, J., Qin, Q., et al., 2019a.
Synthesis and characterization of a photoresponsive doxorubicin/combretastatin A4 hybrid prodrug. Bioorg. Med. Chem. Lett. 29, 487490.
Liu, S., Zhang, K., Zhu, Q., Shen, Q., Zhang, Q., Yu, J., et al., 2019b.
Synthesis and biological evaluation of paclitaxel and vorinostat
co-prodrugs for overcoming drug resistance in cancer therapy
in vitro. Bioorg. Med. Chem. 27, 14051413.
Ma, B., Zhuang, W., Wang, Y., Luo, R., Wang, Y., 2018. pH-sensitive
doxorubicin-conjugated prodrug micelles with charge-conversion for
cancer therapy. Acta Biomater. 70, 186196.
Majumdar, S., Sloan, K.B., 2006. Synthesis, hydrolyses and dermal delivery
of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) derivatives of phenol, imide and thiol containing drugs. Bioorg. Med. Chem.
Lett. 16 (13), 35903594.
McComb, R.B., Bowers, G.N.J., Posen, S., 1979. Alkaline Phosphatase.
Plenum Press, New York and London, p. 986.
McGuigan, C., Tollerfield, S.M., Riley, P.A., 1989. Synthesis and biological evaluation of some phosphate triester derivatives of the antiviral drug AraA. Nucleic Acids Res. 17 (15), 60656075.
McGuigan, C., O’Connor, T.J., Nicholls, S.R., Nickson, C., Kinchington,
D., 1990. Synthesis and anti-HIV activity of some novel substituted
dialkyl phosphate derivatives of AZT and ddCyd. Antivir. Chem.
Chemother. 1 (6), 355360.
McGuigan, C., Devine, K.G., O’Connor, T.J., Kinchington, D., 1991.
Synthesis and anti-HIV activity of some haloalkyl phosphoramidate
derivatives of 3’-azido-3’-deoxythymidine (AZT): potent activity of
the trichloroethyl methoxyalaninyl compound. Antiviral Res. 15 (3),
255263.
Modesitt, S.C., Parsons, S.J., 2010. In vitro and in vivo histone deacetylase inhibitor therapy with vorinostat and paclitaxel in ovarian
cancer models: does timing matter? Gynecol. Oncol. 119 (2),
351357.
Morales, G.A., Garlich, J.R., Su, J., Peng, X., Newblom, J., Weber, K.,
et al., 2013. Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next
generation PI3K inhibitors. J. Med. Chem. 56, 19221939.
Moshikur, R.M., Chowdhury, M.R., Wakabayashi, R., Tahara, Y.,
Moniruzzaman, M., Goto, M., 2019. J. Mol. Liq. 278, 226233.
Nichifor, M., Schacht, E.H., Seymour, L.W., 1996. Macromolecular prodrugs of 5-fluorouracil. 2: Enzymatic degradation. J. Control.
Release 39 (1), 7992.
Nicholson, K.M., Phillips, R.M., Shnyder, S.D., Bibby, M.C., 2002. In
vitro and in vivo activity of LS 4477 and LS 4559, novel analogues
of the tubulin binder estramustine. Eur. J. Cancer 38 (1), 194204.
Nishiyama, H., Ono, M., Sugimoto, T., Sasai, T., Asakawa, N., Ueno, S.,
et al., 2014. 4-Chlorocolchicine derivatives bearing a thiourea side chain
at the C-7 position as potent anticancer agents. MedChemComm
5, 452458.
Ohwada, J., Ozawa, S., Kohchi, M., Fukuda, H., Murasaki, C., Suda, H.,
et al., 2009. Synthesis and biological activities of a pH-dependently
activated water-soluble prodrug of a novel hexacyclic camptothecin
analog. Bioorg. Med. Chem. Lett. 19 (10), 27722776.
Oliyai, R., 1996. Prodrugs of peptides and peptidomimetics for
improved formulation and delivery. Adv. Drug Deliv. Rev. 19 (2),
275286.
Ouchi, T., Banba, T., Matsumoto, T., Suzuki, S., Suzuki, M., 1990a.
Synthesis and antitumor activity of conjugates of 5-fluorouracil and
chito-oligosaccharides involving a hexamethylene spacer group and
carbamoyl bonds. Drug Des. Deliv. 6 (4), 281287.
Ouchi, T., Fujino, A., Tanaka, K., Banba, Y., 1990b. Synthesis and antitumor activity of conjugates of poly(α-malic acid) and 5-fluorouracils
bound via ester, amide or carbamoyl bonds. J. Control. Rel. 12 (2),
143153.
Prodrugs Chapter | 9
Ouchi, T., Hagihara, Y., Takahashi, K., Takano, Y., Igarashi, I., 1992.
Synthesis and antitumor activity of poly(ethylene glycols)s linked to 5fluorouracil via a urethane or urea bond. Drug Des. Discov. 9, 93105.
Perkins, R., Fang, H., Tong, W., Welsh, W.J., 2003. Quantitative
structure-activity relationship methods: perspectives on drug discovery and toxicology. Environ. Toxicol. Chem. 22 (8), 16661679.
Posternak, T., 1974. Cyclic AMP and cyclic GMP. Annu. Rev.
Pharmacol. 14, 2333.
Rautio, J., Nevalainen, T., Taipale, H., Vepsäläinen, J., Gynther, J., Laine,
K., et al., 2000. Piperazinylalkyl prodrugs of naproxen improve in vitro
skin permeation. Eur. J. Pharm. Sci. 11 (2), 157163.
Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Järvinen,
T., et al., 2008a. Prodrugs: design and clinical applications. Nat.
Rev. Drug Discov. 7, 255270.
Rautio, J., Laine, K., Gynther, M., Savolainen, J., 2008b. Prodrug
approaches for CNS delivery. AAPS J. 10 (1), 92102.
Rivory, L.P., Bowles, M.R., Robert, J., Pond, S.M., 1996. Conversion of
irinotecan (CPT-11) to its active metabolite, 7-ethyl-10hydroxycamptothecin (SN-38), by human liver carboxylesterase.
Biochem. Pharmacol. 52 (7), 11031111.
Robins, R.K., 1984. The potential of nucleotide analogs as inhibitors of
retroviruses and tumors. Pharm. Res. 1 (1), 1118.
Sankar, R., Ravikumar, V., 2014. Biocompatibility and biodistribution of
suberoylanilide hydroxamic acid loaded poly (DL-lactide-co-glycolide) nanoparticles for targeted drug delivery in cancer. Biomed.
Pharmacother. 68 (7), 865871.
Saulnier, M.G., Langley, D.R., Kadow, J.F., Senter, P.D., Knipe, J.O.,
Tun, M.M., et al., 1994. Synthesis of etoposide phosphate, BMY40481: a water-soluble clinically active prodrug of etoposide.
Bioorg. Med. Chem. Lett. 4 (21), 25672572.
Schiff, P.B., Fant, J., Horwitz, S.B., 1979. Promotion of microtubule
assembly in vitro by taxol. Nature 277, 665667.
Senter, P.D., 1990. Activation of prodrugs by antibody-enzyme conjugates: a new approach to cancer therapy. FASEB J. 4, 188193.
Serafinowska, H.T., Ashton, R.J., Baily, S., Harnden, M.R., Sutton, D.,
1995. Synthesis and in vivo evaluation of prodrugs of 9-[2-(phosphonomethoxy)ethoxy]adenine. J. Med. Chem. 38, 13721379.
Shamshina, J.L., Rogers, R.D., 2014. Overcoming the problems of solid
state drug formulations with ionic liquids. Ther. Deliv. 5, 489491.
Sherwood, R.F., 1996. Advanced drug delivery reviews: enzyme prodrug
therapy. Adv. Drug Del. Rev. 22, 269288.
Shi, Y.K., Li, Z.H., Han, X.Q., Yi, J.H., Wang, Z.H., Hou, J.L., et al.,
2010. The histone deacetylase inhibitor suberoylanilide hydroxamic
acid induces growth inhibition and enhances taxol-induced cell death
in breast cancer. Cancer Chemother. Pharmacol. 66 (6), 11311140.
Shibata, J., Toko, T., Saito, H., Fujioka, A., Sato, K., Hashimoto, A., et al.,
2000. Estrogen agonistic/antagonistic effects of miproxifene phosphate
(TAT-59). Cancer Chemother. Pharmacol. 45 (2), 133141.
Shimma, N., 2007. Case study: capecitabine: a prodrug of 5-fluorouracil.
In: Stella, V., et al., (Eds.), Prodrugs: Challenges and Rewards. Part
2. AAPS Press/Springer, New York, pp. 475482.
Simplı́cio, A.L., Clancy, J.M., Gilmer, J.F., 2008. Prodrugs for amines.
Molecules 13 (3), 519547.
Singh, B., Kumar, A., Joshi, P., Guru, S.K., Kumar, S., Wani, Z.A., et al.,
2015. Colchicine derivatives with potent anticancer activity and reduced
P-glycoprotein induction liability. Org. Biomol. Chem. 13, 56745689.
Sinkula, A.A., Yalkowsky, S.H., 1975. Rationale for design of biologically
reversible drug derivatives: prodrugs. J. Pharm. Sci. 64 (2), 181.
185
Sloan, K.B., Wasdo, S., 2003. Designing for topical delivery: prodrugs
can make the difference. Med. Res. Rev. 23, 763.
Sloan, K.B., Wasdo, S., 2007. Topical delivery using prodrugs.
In: Stella, V., et al., (Eds.), Prodrugs: Challenges and Rewards. Part
1. AAPS Press/Springer, New York, pp. 84117.
Sloan, K.B., Koch, S.A.M., Siver, K.G., 1984. Mannich base derivatives
of theophylline and 5-fluorouracil: syntheses, properties and topical
delivery characteristics. Int. J. Pharm. 21 (3), 251264.
Springer, C.J., Antoniw, P., Bagshawe, K.D., Searle, F., Bisset, G.M.F.,
Jarman, M., 1990. Novel prodrugs which are activated to cytotoxic alkylating agents by carboxypeptidase G2. J. Med. Chem. 33, 677681.
Sriram, D., Yogeeswari, P., 2010. Chapter 3: Drug metabolism and prodrugs, Medicinal Chemistry, second ed. Pearson, pp. 5574.
Stella, V.J., 2004. Prodrugs as therapeutics. Expert Opin. Ther. Pat. 14
(3), 277280.
Stella, V., 2006. Prodrug strategies for improving drug-like properties.
In: Borchardt, R., Hageman, M., Stevens, J., Kerns, E., Thakker, D.
(Eds.), Optimizing the “Drug-Like” Properties of Leads in Drug
Discovery. Springer, New York, pp. 221242.
Stella, V.J., 2007. A case for prodrugs. In: Stella, V.J., Borchardt, R.T.,
Hageman, M.J., Oliyai, R., Maag, H., Tilley, J.W. (Eds.), Prodrugs:
Challenges and Rewards, vol. 1. Published by AAPS Press and
Springer, New York, pp. 333.
Stella, V.J., Nti-Addae, K.W., 2007. Prodrug strategies to overcome poor
water solubility. Adv. Drug Deliv. Rev. 59, 677694.
Stella, V.J., Charman, W.N., Naringrekar, V.H., 1985. Prodrugs. Do they
have advantages in clinical practice? Drugs 29 (5), 455473.
Stella, V.J., Borchardt, R.T., Hageman, M.J., Oliyai, R., Maag, H.,
Tilley, J.W., 2007. Prodrugs: challenges and rewards, vol. 12.
Published by AAPS Press and Springer, New York.
Sun, B., Luo, C., Cui, W., Sun, J., He, Z., 2017. Chemotherapy agentunsaturated fatty acid prodrugs and prodrug nanoplatforms for cancer chemotherapy. J. Control. Release 264, 145159.
Sun, J., Yang, D., Cui, S.-H., Zhang, H.-T., Fu, Y., Wang, J.-C., et al.,
2019. Enhanced anti-tumor efficiency of gemcitabine prodrug by
FAPα-mediated activation. Int. J. Pharm. 559, 4857.
Supernaw, R.B., 2007. In Part A: Pharmacologic management of pain.
Chapter 111: Simple Analgesics. Pain Manag. 2, 927933.
Taylor, M.D., 1996. Improved passive oral drug delivery via prodrugs.
Adv. Drug Deliv. Rev. 19 (2), 131148.
Toko, T., Shibata, J., Sugimoto, Y., Yamaya, H., Yoshida, M., Ogawa,
K., et al., 1995. Comparative pharmacodynamic analysis of TAT-59
and tamoxifen in rats bearing DMBA-induced mammary carcinoma.
Cancer Chemother. Pharmacol. 37 (12), 713.
Tondwal, R., Singh, M., 2015. Effect of increasing alkyl chain of 1st tier
dendrimers on binding and release activities of methotrexate drug:
an in vitro study. J. Mol. Liq. 211, 466475.
Vivier, M., Rapp, M., Papon, J., Labarre, P., Galmier, M.-J., Sauziere, J.,
et al., 2008. Synthesis, radiosynthesis, and biological evaluation of
new proteasome inhibitors in a tumor targeting approach. J. Med.
Chem. 51, 10431047.
Walther, R., Rautio, J., Zelikin, A.N., 2017. Prodrugs in medicinal chemistry and enzyme prodrug therapies. Adv. Drug Deliv. Rev. 118,
6577.
Wong, P.T., Choi, S.K., 2015. Mechanisms of drug release in nanotherapeutic delivery systems. Chem. Rev. 115 (9), 33883432.
Wu, K.-M., 2009. A new classification of prodrugs: regulatory perspectives. Pharmaceuticals 2, 7781.
186
SECTION | 3 Pharmaceutical Chemistry
Xue, P., Wang, J., Han, X., Wang, Y., 2019. Hydrophobic drug selfdelivery systems as a versatile nanoplatform for cancer therapy: a
review. Colloids Surf., B: Biointerfaces 180, 202211.
Yan, Z., Ma, L., Shen, S., Li, J., 2018. Studies on the interactions of some
small biomolecules with antibacterial drug benzethonium chloride and
its active pharmaceutical ingredient ionic liquid (API-IL) benzethonium
L-proline at varying temperatures. J. Mol. Liq. 255, 530540.
Yang, F., Kamiya, N., Goto, M., 2012. Transdermal delivery of the antirheumatic agent methotrexate using a solid-in-oil nanocarrier. Eur. J.
Pharm. Biopharm. 82, 158163.
Yu, J., Li, W., Yu, D., 2018. Atrial natriuretic peptide modified oleate
adenosine prodrug lipid nanocarriers for the treatment of myocardial
infarction: in vitro and in vivo evaluation. Drug Des. Devel. Ther.
12, 16971706.
Zhang, X., You, X.Q., Zhang, X., 2017a. Prodrug strategy for cancer cellspecific targeting: a recent overview. Eur. J. Med. Chem. 139, 542563.
Zhang, R., Ru, Y., Gao, Y., Li, J., Mao, S., 2017b. Layer-by-layer nanoparticles co-loading gemcitabine and platinum (IV) prodrugs for
synergistic combination therapy of lung cancer. Drug Des. Devel.
Ther. 11, 26312642.
Zhu, Y., Ma, Y., Zhao, Y., Yang, M., Li, L., 2019. Preparation and evaluation of highly biocompatible nanogels with pH sensitive chargeconvertible capability based on doxorubicin prodrug. Mater. Sci.
Eng. C. 98, 161176.