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Issue dated - 18th August 2005

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Chemical Drug Delivery Systems: Strategies And Applications

Dr. Amrita Bajaj, Mansi Desai, Shalini Sharma

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 drug efficacy.

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 hypotension.

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 Therapy (PTAPT)

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-Drug Conjugates

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:
ADEPT Carboxypeptidase A Methotrexate alanine Methotrexate
ADEPT B - Glucuronidase Epirubicin glucoronide Epirubicin
GDEPT Thymidine kinase Ganciclovir Ganciclovir triphosphate
GDEPT Cytosine deaminase 5-Fluorocytosine 5-Fluorouracil
GDEPT Nitroreductase 4-nitrobenzyloxy carbonyl derivative Actinomycin D


Schematic represe-ntation of Retrometabolic drug delivery approach.

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.

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