Recent trends in targeted anticancer prodrug and conjugate design

Abstract

Anticancer drugs are often nonselective antiproliferative agents (cytotoxins) that preferentially kill dividing cells by attacking their DNA at some level. The lack of selectivity results in significant toxicity to noncancerous proliferating cells. These toxicities along with drug resistance exhibited by the solid tumors are major therapy limiting factors that result into poor prognosis for patients. Prodrug and conjugate design involves the synthesis of inactive drug derivatives that are converted to an active form inside the body and preferably at the site of action. Classical prodrug and conjugate design have focused on the development of prodrugs that can overcome physicochemical (e.g., solubility, chemical instability) or biopharmaceutical problems (e.g., bioavailability, toxicity) associated with common anticancer drugs. The recent targeted prodrug and conjugate design, on the other hand, hinge on the selective delivery of anticancer agents to tumor tissues thereby avoiding their cytotoxic effects on noncancerous cells. Targeting strategies have attempted to take advantage of low extracellular pH, elevated enzymes in tumor tissues, the hypoxic environment inside the tumor core, and tumor-specific antigens expressed on tumor cell surfaces. The present review highlights recent trends in prodrug and conjugate rationale and design for cancer treatment. The various approaches that are currently being explored are critically analyzed and a comparative account of the advantages and disadvantages associated with each approach is presented.

Fig. (1)

Major prodrugs available in market.

Fig. (2)

Enzyme activated anticancer prodrugs.

Fig. (3)

General design of carrier-linked anticancer prodrugs.

Fig. (4)

Antibody conjugates of maytansinoid (huC242-DM1) and auristatins (cAC10-vcMMAE).

Fig. (5)

Structure of Mylotarg. Mylotarg is only approved immunoconjugate for cancer therapy.

Fig. (6)

Folate-targeted prodrugs.

Fig. (7)

Folate and LHRH-targeted prodrugs.

Fig. (8)

ASGPR-targeted prodrug.

Fig. (9)

Schematic presentation of antibody-directed enzyme prodrug therapy (ADEPT). mAb-enzyme conjugate is given first, which binds to antigens expressed on tumor surfaces. Prodrug is given next, which is converted to active drug by the pre-targeted enzyme. Redrawn from ChemMedChem 2008, 2, 20.

Fig. (10)

Representative examples of prodrugs in ADEPT system.

Fig. (11)

Schematic presentation of gene-directed enzyme prodrug therapy (GDEPT). Gene for foreign enzyme is transfected to tumor cells, which express the enzyme to activate the systemically administered prodrug. Redrawn from Nature Rev. Cancer 2007, 7, 870.

Fig. (12)

Herpes simplex virus-thymidine kinase / ganciclovir (HSV TK/GCV) based GDEPT system.

Fig. (13)

Common nitrogen mustard prodrugs. The structure of self-immolative prodrug is also shown. Prodrug ZD2767P is shown in Fig. (10).

Fig. (14)

Schematic presentation of membrane transporter targeted prodrug uptake. Redrawn from AAPS Pharmsci 2000, 2, 1.

Fig. (15)

HPMA-copolymer conjugates of doxorubicin (DOX), paclitaxel (CT), and camptothecin (CPT) for passive targeting of prodrugs.

Fig. (16)

Passively targeted anticancer prodrugs: Xyotax and Prothecan.

Fig. (17)

Schematic presentation of PDEPT strategy. Polymeric prodrug is administered first to promote the tumor targeting followed by polymer-enzyme conjugate for prodrug activation. Redrawn from Nature Rev. Drug Disc. 2003, 2, 347.

Fig. (18)

PDEPT system consisting HPMA copolymer-C-Dox and HPMA copolymer-β-lactamase. The mechanism of drug release is also shown.

Fig. (19)

Bond cleavage by tumor-associated enzymes. The cleavage sites are marked.

Fig. (20)

Acid sensitive linkages used in prodrug design. The cleavage sites are enclosed in box.

Fig. (21)

Prodrug activation in hypoxic environment. Prodrug is reduced to free radicals, which is converted back to prodrug by oxygen present in the oxic cells. The process is irreversible in hypoxic cells and prodrug free radical is converted to active drug. Also shown is activation mechanism of Tirapazamine (TPZ) and Anthraquinone (AQ4N). Redrawn from Nature Rev. Cancer 2004, 4, 437.

Fig. (22)

Self-immolative spacers in prodrug design.