Targeting of drugs and nanoparticles to tumors

Abstract

The various types of cells that comprise the tumor mass all carry molecular markers that are not expressed or are expressed at much lower levels in normal cells. These differentially expressed molecules can be used as docking sites to concentrate drug conjugates and nanoparticles at tumors. Specific markers in tumor vessels are particularly well suited for targeting because molecules at the surface of blood vessels are readily accessible to circulating compounds. The increased concentration of a drug in the site of disease made possible by targeted delivery can be used to increase efficacy, reduce side effects, or achieve some of both. We review the recent advances in this delivery approach with a focus on the use of molecular markers of tumor vasculature as the primary target and nanoparticles as the delivery vehicle.

Figure 1.

Synaphic targeting of tumors. The targeted receptors can be on tumor cells, tumor vessels, or shared by both. (A) Probes that recognize solely tumor cells provide little improvement of tumor accumulation over a nontargeted probe. (B) Probes that recognize tumor vessels accumulate in the tumor, but entry into tumor tissue relies on passive mechanisms. (C) Probes that recognize both the vessels and tumor cells combine the (limited) efficiency of the two targeting mechanisms. (D) Tumor-penetrating targeting probes (so far only peptides with such characteristics are known) provide a particularly potent targeting system.

Figure 2.

Saturation of receptors affects the specificity of synaphic targeting. Once the receptors of the homing peptide have been saturated, the specificity of the targeting declines (adapted from experimental data in Kranenborg et al., 1998). au, arbitrary units.

Figure 3.

Treating tumors with cooperative nanoparticles. This scheme illustrates a method to induce cooperative nanoparticle behavior that results in more effective delivery of treatments to tumors. This example uses a two-component system consisting of gold nanorods and targeted, thermally sensitive liposomes. (A) Passive accumulation of gold nanorods. The circulating nanorods passively accumulate in the tumor as a result of leakiness of the tumor vasculature (the EPR effect). (B) Laser irradiation of nanorods activates tumor cells. The gold nanorods absorb laser energy, heating the surrounding tissue. This localized rise in temperature increases tissue permeability and induces expression of receptor proteins on the surface of the tumor cells. (C) Targeted nanoparticles (liposomes) bind to tumor. Receptor-specific targeting peptides attached onto the secondary nanoparticles allow these particles to bind to the overexpressed receptor proteins on the heat-activated tumor cells. (D) Activation of targeted liposomes releases drug. In this example, thermally responsive liposomes containing a drug payload are heated with a second laser pulse, inducing rupture of the liposome shell and release of its contents.