Toward a magic or imaginary bullet? Ligands for drug targeting to cancer cells: principles, hopes, and challenges

Abstract

There are many problems directly correlated with the systemic administration of drugs and how they reach their target site. Targeting promises to be a hopeful strategy as an improved means of drug delivery, with reduced toxicity and minimal adverse side effects. Targeting exploits the high affinity of cell-surface-targeted ligands, either directly or as carriers for a drug, for specific retention and uptake by the targeted diseased cells. One of the most important parameters which should be taken into consideration in the selection of an appropriate ligand for targeting is the binding affinity ( K D ). In this review we focus on the importance of binding affinities of monoclonal antibodies, antibody derivatives, peptides, aptamers, DARPins, and small targeting molecules in the process of selection of the most suitable ligand for targeting of nanoparticles. In order to provide a critical comparison between these various options, we have also assessed each technology format across a range of parameters such as molecular size, immunogenicity, costs of production, clinical profiles, and examples of the level of selectivity and toxicity of each. Wherever possible, we have also assessed how incorporating such a targeted approach compares with, or is superior to, original treatments.

Aminoflavone-loaded EGFR-targeted unimolecular micelle nanoparticles exhibit anti-cancer effects in triple negative breast cancer

“…Despite promising effects, AF is also associated with dose-limiting pulmonary toxicity. This and other drugs that display negative off-target effects can be re-evaluated using NP-based delivery systems that can deliver drug more specifically to targeted tumor tissues due to their passive (i.e., via the EPR effect) and active (i.e., receptor-mediated) tumor-targeting abilities [45, 46]. Drug nanocarriers can potentially increase the therapeutic index of the drug while reducing undesirable off-target effects and systemic toxicity [47].…”

Unintended effects of drug carriers: Big issues of small particles

“…These include monoclonal antibodies, single-chain variable fragments (scFvs), antigen-binding fragments (Fabs), single domain antibodies (sdAb), DARPins, peptides, aptamers, and small molecules (Fig. 9) [282–284]. Monoclonal antibodies consist of two immunoglobulin (Ig) heavy chains and two Ig light chains, each with constant and variable domain regions.…”

“…Fabs consist of a single constant and variable domain form each heavy and light chains. Compared to conventional IgG antibodies (~150kDa), single-chain variable fragment (scFv) antibodies (~27kDa) and antigen-binding (Fab) fragments (~57kDa) are smaller in molecular size and weight [282,285,286]. …”

“…DARPins are around one-tenth the size of conventional IgG molecules and have high thermal stability. Another type of single domain targeting molecules are affibodies [282,288]. Affibodies are very small (−6.5kDa) targeting moieties developed by combinatorial protein engineering of the staphylococcal protein A-derived Z-domain scaffold.…”

Current development of targeted oligonucleotide-based cancer therapies: Perspective on HER2-positive breast cancer treatment

“…Additional reviews on the EPR effect and nanomedicine can be found elsewhere. 39, 43 Once accumulated in tumors by the EPR effect, active targeting can be achieved by decorating outer surface of nanoparticles with targeting agents (homing targets), 44 such as monoclonal antibodies, single-chain variable fragments (scFv), targeting peptides, transferrin, folic acid, and aptamers. This strategy exploits the binding between targeting agents and receptors (or other membrane proteins) on the tumors, which is followed by cellular uptake of the particles termed receptor-mediated endocytosis.…”