Odyssey of a cancer nanoparticle: from injection site to site of action

Abstract

No chemotherapeutic drug can be effective until it is delivered to its target site. Nano-sized drug carriers are designed to transport therapeutic or diagnostic materials from the point of administration to the drug's site of action. This task requires the nanoparticle carrying the drug to complete a journey from the injection site to the site of action. The journey begins with the injection of the drug carrier into the bloodstream and continues through stages of circulation, extravasation, accumulation, distribution, endocytosis, endosomal escape, intracellular localization and-finally-action. Effective nanoparticle design should consider all of these stages to maximize drug delivery to the entire tumor and effectiveness of the treatment.

Figure 1. Recent progress in cancer survival rates

In the past several decades steady progress has been made in treating tumors and some sites have shown impressive cure rates. While this progress is encouraging, no revolutionary “cure” has been discovered in spite of several promising new technologies, including nanomedicine [4].

Figure 2. Chemotherapy side effects

Within minutes of intravascular administration, drugs and nanoparticles are thoroughly mixed in the circulatory system and distribute throughout the body. Wherever the drug comes in contact with healthy tissues non-specific toxicity will result causing unpleasant side effects. These side effects can be severe enough to limit the drug dosage and treatment effectiveness.

Figure 3. Classes of nanoparticles in cancer therapy

Nanoparticles come in a large variety of forms and a broad range of sizes. One of the chief advantages of nanoparticles is the ease with which it can be modified to carry drugs, targeting vectors and imaging agents.

Figure 4. Protein adsorption onto nanoparticle

(a) PEGylation of nanoparticles helps to slow the adsorption of proteins to the nanoparticle surface. The exposed surface of a non-PEGylated nanoparticle quickly develops a protein corona. The opsonized surface then promotes phagocytosis by MPS cells leading to rapid clearance of the nanoparticles. (b) The hydrophilic polymers grafted onto the nanoparticle form a brush-like barrier that repels most proteins before it can bind to the surface and thus significantly slows the clearance of the nanoparticles.

Figure 5. Barriers to extravasation

Extravasation from the tumor vasculature mostly occurs through the unusually large openings in the tumor vasculature, but is inhibited by several aspects of tumor physiology. High interstitial fluid pressure greatly reduces the driving force for bulk flow which can carry material out of the blood cell in healthy tissue. The dense collagen matrix and tumor cells can also trap nanoparticles as they diffuse out of the capillary preventing extravasation of subsequent particles.

Figure 6. Capillary distribution

Recruitment of capillaries from nearby blood vessels leaves the tumor periphery better vascularized than the core. The large distance from the capillary to the center of the tumor causes hypoxic conditions in the core and necessitates nanoparticles to diffuse large distances to reach all areas of a tumor.

Figure 7. Diffusion barriers

a) The architecture of a tumor can severely limit particle diffusion through the tissue. The densely packed cells increase the total path length the particle must travel to cover a linear distance, which can significantly impact the effective diffusion. b) The collagen matrix barrier becomes increasingly important as the particle size approaches or exceeds the matrix mesh size which ranges between 20–40 nanometers in solid tumors. Particles larger than the mesh size can be prevented from diffusing from the matrix entirely, those near the mesh size can be significantly hindered, and small particles can pass through relatively uninhibited.

Figure 8. Cell heterogeneity in tumors

Tumors contain many cell types including macrophages, stem cells, endothelial cells and tumor cells. Cells may also bear a variety of different receptors expressed in varying amounts and will have other genotypic differences which may affect drug sensitivity (represented as different shading in tumor cells).

Figure 9. Active cell uptake

The major methods of nanoparticle cell uptake are receptor mediated endocytosis and pinocytosis. Both draw the particles into interior vesicles which eventually fuse with lysosomes to undergo cellular digestions which can neutralize some or all of the drug. Releasing the drug from the endosome before the lysosomal phase can increase the availability of drug in the cytoplasm.