Targeting Toxins toward Tumors

Abstract

Many cancer diseases, e.g., prostate cancer and lung cancer, develop very slowly. Common chemotherapeutics like vincristine, vinblastine and taxol target cancer cells in their proliferating states. In slowly developing cancer diseases only a minor part of the malignant cells will be in a proliferative state, and consequently these drugs will exert a concomitant damage on rapidly proliferating benign tissue as well. A number of toxins possess an ability to kill cells in all states independently of whether they are benign or malignant. Such toxins can only be used as chemotherapeutics if they can be targeted selectively against the tumors. Examples of such toxins are mertansine, calicheamicins and thapsigargins, which all kill cells at low micromolar or nanomolar concentrations. Advanced prodrug concepts enabling targeting of these toxins to cancer tissue comprise antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), lectin-directed enzyme-activated prodrug therapy (LEAPT), and antibody-drug conjugated therapy (ADC), which will be discussed in the present review. The review also includes recent examples of protease-targeting chimera (PROTAC) for knockdown of receptors essential for development of tumors. In addition, targeting of toxins relying on tumor-overexpressed enzymes with unique substrate specificity will be mentioned.

Keywords: ADC; ADEPT; GDEPT; LEAPT; PROTAC; chemotherapy; drug targeting; overexpressed enzymes; prodrug.

Scheme 1

Dithiocarbamates and methylmaleic amides cleaved at low pH [20].

Scheme 2

Linkage of doxorubicin to serum albumin to prevent its penetration into benign cells; only in the acidic microenvironment of cancer cells is doxorubicin released [14,21,22].

Scheme 3

Conjugation of paclitaxel (7) to polymers that increase solubility [26].

Scheme 4

Oxidation of camptothecin-10-boronic acid (9) to give 10-hydroxycamptothecin (10) [15].

Scheme 5

Prodrug of doxorubicin (6) cleaved by ROS [15].

Scheme 6

Polyethylene glycol (PEG)-containing prodrug (13) of paclitaxel (7) that is cleaved by reactive oxygen species (ROS) [13].

Scheme 7

Prodrug (i.e., 15) of camptothecin (14) that is cleaved by glutathione [16].

Scheme 8

A doxorubicin (6) prodrug (i.e., 16) cleaved by matrix metalloproteinase (MMP) and other proteases (Cit = citrulline; hPhe = homophenylalanine) [34].

Scheme 9

Prodrug of doxorubicin (i.e., 17) that is cleaved by cathepsin B [35].

Scheme 10

Glucuronides (18 and 20) of doxorubicin (6) and 4′-epi-doxorubicin (19) [17].

Scheme 11

Water-soluble glucuronide-based prodrug (21) of paclitaxel (7) [38].

Scheme 12

Glucuronide of 7-aminocamptothecin (23) cleaved by β-glucuronidase [39].

Scheme 13

Prodrug (i.e., 25) of desacetylvinblastine (24) cleaved by prostate-specific antigen (PSA) [19].

Scheme 14

Doxorubicin prodrug (26) cleaved by PSA [41].

Scheme 15

Prodrug of ω-aminododecanolydesbutanoylthapsigargin (28) cleaved by PSA [43].

Scheme 16

The PSMA-sensitive prodrug mipsagargin (31) [56,60].

Figure 1

Cartoon illustrating the structure of an antibody–drug conjugate (ADC) drug.

Figure 2

Examples of payloads in ADCs.

Scheme 17

Diradical formation from calicheamicin γ₁^I after nucleophilic attack on the α,β-unsaturated ketone [66].

Scheme 18

Coupling of a calicheamicin to antibodies via lysine residues (the O-Sugar moiety is defined in Scheme 17) [63].

Scheme 19

Internalization of an antibody–mertansine conjugate occurs while the payload remains attached to the antibody via a lysine residue [63].

Figure 3

Antibody–enzyme conjugate bound to antigens on the surface of malignant cells.

Scheme 20

Doxorubicin prodrug (35) cleaved by 38C2 [70,71].

Figure 4

Cartoon illustrating the principle of gene-directed enzyme prodrug therapy (GEPDT) [69,70].

Figure 5

Galacturonamide of doxorubicin (36) for lectin-directed enzyme-activated prodrug therapy (LEAPT) [76].

Figure 6

Glucose and glucuronic acid derivatives (i.e., 37 and 38) of paclitaxel (7) displaying improved selectivity via LEAPT [77].

Scheme 21

Two-phase LEAPT. First a glycosylated enzyme binds to the cell surface and becomes internalized. Secondly, a glycosylated prodrug binds to the surface, and is then internalized whereafter it is cleaved by the internalized enzyme [78].

Figure 7

Cartoon illustrating the principle of protease-targeting chimera (PROTAC) [9,10,80]. A compound with affinity for the Hippel–Lincau-cullin-Ring (VHL) complex and the target protein (e.g., estrogen-related receptor α (ERRα)) is used to attach the protein to the E3 ligase in the VHL complex. After complexation the E3 conjugates ubiquitin to the protein making it a target for proteasomal degradation.