Bioengineering strategies for designing targeted cancer therapies

Abstract

The goals of bioengineering strategies for targeted cancer therapies are (1) to deliver a high dose of an anticancer drug directly to a cancer tumor, (2) to enhance drug uptake by malignant cells, and (3) to minimize drug uptake by nonmalignant cells. Effective cancer-targeting therapies will require both passive- and active-targeting strategies and a thorough understanding of physiologic barriers to targeted drug delivery. Designing a targeted therapy includes the selection and optimization of a nanoparticle delivery vehicle for passive accumulation in tumors, a targeting moiety for active receptor-mediated uptake, and stimuli-responsive polymers for control of drug release. The future direction of cancer targeting is a combinatorial approach, in which targeting therapies are designed to use multiple-targeting strategies. The combinatorial approach will enable combination therapy for delivery of multiple drugs and dual ligand targeting to improve targeting specificity. Targeted cancer treatments in development and the new combinatorial approaches show promise for improving targeted anticancer drug delivery and improving treatment outcomes.

Figure 1

Passive targeting. (A) Nanoparticles accumulate in tumor tissue due to the enhanced permeability and retention (EPR) effect. Enhanced permeability is due to large endothelial gaps that result in leaky vasculature. Enhanced retention is due to poor lymphatic drainage. (B) Smaller particles are able to quickly enter and exit tumor tissue through large endothelial gaps, while larger particles diffuse more slowly, resulting in the accumulation of a greater number of particles and drug. Figure modified and used with permission from (Danhier et al., 2010).

Figure 2

Active targeting. Active targeting of particles is achieved by conjugation of ligands that target overexpressed receptors on the surface of cancer cells. Ligands bind to overexpressed receptors on malignant cells and are endocytosed. Anticancer drugs must then escape the endosome to avoid degradation and to perform their function within the cell.

Figure 3

Structure of liposomes. (A) Unilamellar liposomes contain a large aqueous core for storage of water-soluble drugs. (B) Multilamellar liposomes are composed of multiple layers of phospholipid groups for storage of lipid-soluble drugs between the hydrophobic tail groups in each layer.

Figure 4

Micelle structure. Micelles are composed of phospholipids, with hydrophilic head groups forming the outer shell. Micelles encapsulate water-insoluble drugs in their hydrophobic cores. Figure modified and used with permission from (Husseini and Pitt, 2008).

Figure 5

Dendrimer branch structure. Dendrimers are created by polymerization of a core monomer to create a branched polymer structure. Each polymerized layer radiates from the core and correlates to the generation of the dendrimer. Various surface functional groups may be used to modify the surface charge of the dendrimer. Figure used with permission from (Kaczorowska and Cooper, 2008).

Figure 6

Structure of polymeric nanoparticles. (A) Polymer nanospheres are solid structures composed of a polymer matrix. Drugs can be loaded into the matrix by absorption or chemically conjugated to the surface. (B) Polymer nanocapsules are hollow structures containing an outer polymer shell. Drug can be encapsulated in the core of nanocapsules during formation or absorbed into the polymer shell. Figure modified and used with permission from (Griffiths et al., 2010).

Figure 7

Carbon nanotube structure. Carbon nanotubes (CNTs) are hollow tubes composed of graphene sheets. CNTs can be either (A) single-walled or (B) multi-walled.