Chemical Drug Delivery Systems: Strategies And Applications
Despite the considerable progress of the last century, rational drug design
that allows the development of effective pharmaceutical agents with minimal
side effects remains an elusive goal. Many therapeutic drugs have undesirable
properties that may become pharmacological, pharmaceutical or pharmacokinetic
barriers in clinical drug applications. Among the various approaches to minimize
the undesirable drug properties, the chemical modulation using drug derivatization
offers high flexibility and has been demonstrated as an important means of improving
The prodrug concept was revived for improving drug therapy in early nineteen
seventies and numerous prodrugs have been designed and developed to overcome
various barriers like poor oral drug absorption, non-specificity, toxicity,
chemical instability and poor patient compliance.
Targeted Prodrug Design to Optimize Drug Delivery
Prodrugs are pharmacologically inert chemical derivatives that can be converted
in- vivo to the active drug molecules, enzymatically or nonenzymatically, to
exert a therapeutic effect Chemical Delivery Systems (CDS) are more advanced
version of prodrugs in which the drug is transformed into an inactive derivative,
which then undergoes sequential enzymatic transformations to deliver the drug
at the site of action. Prodrugs are usually activated in single step enzymatic
attack, however chemical delivery systems involve a cascade of enzymatic reactions
for activation. Chemical delivery systems are utilized for sustained drug delivery
as well as site-specific targeted drug delivery.
Chemical drug delivery systems and prodrugs are designed to target specific
enzymes or carriers by considering enzyme-substrate specificity or carrier-substrate
specificity in order to overcome various undesirable drug properties.
- Targeted prodrug design is based on the following:
- Targeting specific enzymes.
- Targeting specific membrane transporters.
- Prodrug Design Based on Targeting Enzymes:
In prodrug design, enzymes are recognized as prodrug-drug in vivo reconversion
sites. The enzyme-targeted prodrug approach has been used to improve oral drug
absorption, as well as site-specific drug delivery. Colon specific drug delivery
has been designed by producing a polar promoiety with retarded intestinal absorption.
Sulphasalazine is a typical example of colon specific chemical drug delivery.
It is synthesized by coupling diazotized 2-sulphanilamide pyridine and 5-amino
salicylic acid. After reaching colon the prodrug is cleaved into active 5-amino
salicylic acid by azoreductase associated with colonic microflora. This enables
the selective delivery of 5-amino salicylic acid to colon.
Glycosidase activity of the colonic microflora offers an opportunity to design
a colon-specific drug delivery system. Glycoside derivatives are hydrophilic
and poorly absorbed from the small intestine, but once they reach the colon,
they can be effectively cleaved by bacterial glycosidases to release the free
drug. Glycosidic prodrug of Dexamethasone utilizing the activity of bacterial
glycosidases has been reported.
Kidney possesses high concentration of L-glutamyl transpeptidase and L-amino
acid decarboxylase enzymes. These enzymes are used to provide selective delivery
of Dopamine to kidney in the form of its prodrug L-g-glutamyl dopa. The prodrug
is first cleaved by L-glutamyl transpeptidase producing L-dopa, which is converted
to dopamine by L-amino acid decarboxylase. This leads to selective delivery
of drug to kidney resulting in desired renal vasodilatation while avoiding systemic
Chemical delivery systems are also designed for b-blocking agents used in the
treatment of glaucoma. Propranolol is converted into its prodrug Propranolol
oxime. On application to eye, Propranolol oxime undergoes hydrolysis to give
propranolone followed by reduction to yield propranolol. This reaction mediated
by intraoccular enzymes liberates the drug at the site of action and results
in no change in the heart rate or any other cardiovascular effects.
Recently, new therapies have been proposed which attempt the localization of
prodrug activation enzymes into specific cancer cells prior to prodrug administration.
These new approaches are referred to as
Anti-body directed enzyme prodrug therapy (ADEPT)
Gene directed enzyme prodrug therapy (GDEPT)
Anti-body Directed Enzyme Prodrug Therapy
Enzymes that activate prodrugs can be directed to human xenografts by conjugating
them to tumor selective monoclonal antibodies. An antitumor antibody is conjugated
to an enzyme not normally present in extracellular fluid or on cell membranes
and then these conjugates are localized in the tumor via IV infusion. In ADEPT
procedure after allowing for the conjugate to clear from the blood, a prodrug
is administered that is normally inert but is activated by the enzyme delivered
to the tumor.
Gene Directed Enzyme Prodrug Therapy
Tumors have also been targeted with genes encoding prodrug-activating enzymes.
This approach uses a viral vector eg. retroviral or adenoviral to carry a prodrug-activating
enzyme gene into both tumor and normal cells. By linking the foreign gene downstream
of tumor-specific transcription units, tumor-specific expression of the foreign
enzyme gene can be achieved. This approach has been called as GDEPT.
In addition to viral vectors, several methods for delivery of the genes to the
target tumor, under the control of tumor-selective promoters, have been proposed
using liposomes and cationic lipids. ADEPT type liposomes bearing antibodies
and enzymes on their surface are used to localize enzymes at the tumor site
before administration of a prodrug.
For example, the conjugation of interleukin-2 to the surface of non-stealth
liposomes allows the targeting of toxic immunosuppressants to areas of immune
system participating in graft rejection, such as T-cells expressing the IL-2
receptor without affecting other parts of immune system.
Prodrug Design Targeting Membrane Transporters
This targeted prodrug approach uses transporters designed
for facilitating membrane transport of polar nutrients such as amino acids and
peptides. Targeting specific membrane transporters is particularly important
when prodrugs are polar or charged. Intestinal epithelial transporters to facilitate
the absorption of appropriately modified drugs have been proved to improve the
bioavailability of poorly absorbed drug molecules. Prodrugs are designed to
resemble the intestinal nutrients structurally and to be absorbed by specific
carrier proteins. Many attempts have been made to improve drug absorption by
targeting specific membrane transporters, including amino acids, peptides, and
glucose transporters. For example: p-nitrophenyl-?-D-glucopyranoside was found
to be actively absorbed by glucose transporters resulting in its enhanced membrane
permeability. The brain uptake of the potent glycine-NMDA receptor antagonists,
7-chlorokynurenic acid and 5,7-dichlorokynurenic acid, was significantly improved
by their prodrugs, L-4-chlorokynurenine and L-4, 6-dichlorokynurenine, which
are amino acids.
Schematic representation of ADEPT and GDEPT: Approaches
for tumor targeting.
Peptide Transporter Associated Prodrug
Peptide transporters have broad substrate specificity and high capacity and
are a good target for prodrug development to improve oral drug absorption. A
polar drug with low membrane permeability through passive diffusion is converted
into a prodrug that is absorbed via the peptide transporter into the mucosal
cell. Following membrane transport, enzymes in the mucosal cell, blood, or liver
hydrolyze the prodrug to release the active drug. This prodrug strategy has
been effective for improving the membrane permeability and systemic availability
of the polar µ-methyldopa through peptidyl derivative (µ-methyldopa-proline).
Recently the application of PTAPT is broadened to nonpeptidyl type prodrugs,
such as amino acid ester prodrugs. For example: Several amino acid ester prodrugs
of the nucleoside antiviral drugs Acyclovir and Azathioprine have been synthesized
and examined for their intestinal absorption.
These prodrugs have shown significant increase (3-10 fold)
in intestinal absorption of their parent drugs via a peptide transporter mediated
mechanism, even though they do not have a peptide bond in their structure. Following
the membrane transport, these prodrugs were rapidly converted to the active
drugs by intracellular hydrolysis.
Polymer anticancer drug conjugates are designed to enhance the physico-chemical
properties of the drug and to administer the drug specifically to the tumor
site. They are prepared by conjugating anticancer drug to a polymeric backbone
via covalent linkage. Biodegradable spacer is inserted in the conjugate to insure
stability during systemic circulation and to facilitate specific enzymatic or
hydrolytic release of the drug.
Eg: Doxorubicin-HPMA conjugate. The polymer used is N (2-hydroxyp-ropyl)
methacrylamide copolymer. The anticancer drug is bound to the polymer backbone
using peptidyl spacer (Gly-Phe-Leu-Gly linker) designed to be cleaved by Lysosomal
thiol dependant proteases. The conjugate has a molecular weight of approx. 30,000
Da and a Doxorubicin content of approx. 8.5 wt %. Examples of polymer drug conjugates
that have entered clinical trials include: HPMA-doxorubicin, HPMA-dox-galactosamine,
HPMA-Paclitaxel and HPMA-Camptothecin.
|Appropriate combinations of enzymes and prodrugs proposed
for ADEPT and GDEPT approaches are:
||B - Glucuronidase
||4-nitrobenzyloxy carbonyl derivative
Schematic represe-ntation of Retrometabolic drug delivery
Retrometabolic Drug Design
Retrometabolic appr-oach represents systematic drug design methodologies that
thoroughly integrate structure-activity and structure-metabolism relationships
into the drug design process and aim to design safe compounds with an improved
therapeutic index. It includes both Chemical Drug Delivery and Soft
Drug (SD) approach.
Soft drugs are designed to have highly improved therapeutic efficacy by controlling
their metabolism, after they achieve their therapeutic role. Soft analogs are
close structural analogs of known active drugs that have a specific metabolically
sensitive moiety built into their structure to allow facile, one-step controllable
deactivation and detoxication after the desired therapeutic activity is achieved.
The desired activity of soft drugs is generally local and they are administered
at or near the site of action. The design of soft drugs is based primarily on
their directed inactivation by hydrolytic enzymes to avoid oxidative pathways
and the slow, easily saturable oxygenases.
Soft drug design has proved to be effective for b-blockers
such as Metoprolol and Atenolol used in the treatment of glaucoma. The ester
derivatives of these drugs have provided prolong reduction in intraocular pressure
and reduced side effects. Other successfully designed soft drugs already marketed
include Esmolol, Landiolol and Ioteprednol etabonate (soft corticosteroids).
Prodrug design can no longer be considered as just a chemical modification to
solve problems associated with drugs. Prodrug design is becoming more elaborate
in the development of efficient and selective drug delivery systems. The targeted
prodrug approach, which when combined with gene delivery and controlled expression
of enzymes and carrier proteins, is a promising strategy for precise and efficient
drug delivery and the enhancement of therapeutic efficacy.