Tumor Specific Novel Taxoid-Monoclonal Antibody Conjugates

Abstract

The basic principle of the targeted delivery approach is that the conjugation of a drug to a tumor-specific molecule renders the drug inactive until it reaches the target site. Monoclonal antibodies (mAbs), which have shown high binding specificity for tumor-specific antigens, could be used as targeting agents. Paclitaxel has brought significant impact on the current cancer chemotherapy, but seriously suffers from the lack of tumor specificity. A series of paclitaxel-monoclonal antibody conjugates via C-2' ester linkage were reported. Taking into account the fact that the cytotoxicity of paclitaxel is not good enough and thus not applicable to this target delivery prodrug approach, new taxoids bearing methyldisulfanyl(alkanoyl) groups were designed, synthesized, and their activities evaluated. A highly cytotoxic C-10 methyldisulfanyl-propanoyl taxoid, was conjugated to monoclonal antibodies recognizing the epidermal growth factor receptor (EGFR). These conjugates were shown to possess remarkable target-specific antitumor activity in vivo against EGFR-expressing A431 tumor xenografts in SCID mice, resulting in complete inhibition of tumor growth in all the treated mice without any noticeable toxicity to the animals.

Preclinical development of drug delivery systems for paclitaxel-based cancer chemotherapy

“…In their design, a highly cytotoxic C-10 methyldisulfanylpropanoyl PTX was conjugated to an MAb recognizing the epidermal growth factor receptor (EGFR) expressed in human squamous cancers. [164] These conjugates were shown to possess remarkable target-specific antitumor activity in vivo against EGFR-expressing A431 tumor xenografts in SCID mice, resulting in complete inhibition of tumor growth in the treated mice without showing noticeable toxicities to the animals.…”

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

“…Antibodies (their size is about 12 nm) endowed with fluorescent dyes (e.g., Alexa Fluor 488 λEm=525 nm and Texas Red λEm=609 nm) [15][16][17] were used in the development of a wide range of effective targeted therapies [18][19][20][21][22] but they create clustering artifacts due to limited antibody penetration, which have an impact on insufficient labeling density. Thus, ligands that have been exploited for chemotherapeutic agent targeting systems can include monoclonal antibodies [23][24][25][26][27][28] but also low molecular weight receptor-binding conjugates such as dyelabeled peptides (arginine-glycine-aspartic acid-Cyt5,5) [29], peptide hormones [30,31], receptor antagonist and agonists [32], aptamers [33][34][35], transferrin [36][37], oligosaccharides [38], glycoconiugates [39], polyunsaturated fatty acids [40], oligopeptides [41,42], vitamin B12 [43], folic acid [44][45][46][47][48][49][50][51][52][53][54] and hyaluronic acid [55,56]. These ligands can be regarded as a tumor-specific receptor to construct a "guided molecular ...…”

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

“…Receptors can be also targeted by monoclonal antibodies. For example, targeting a tumor by conjugation of paclitaxel derivatives to monoclonal antibodies has been studied by Ojima et al [297]. Particular enzymes overexpressed by tumor tissue have also been used for targeted delivery of paclitaxel.…”