Best practices in cancer nanotechnology: perspective from NCI nanotechnology alliance

Abstract

Historically, treatment of patients with cancer using chemotherapeutic agents has been associated with debilitating and systemic toxicities, poor bioavailability, and unfavorable pharmacokinetics. Nanotechnology-based drug delivery systems, on the other hand, can specifically target cancer cells while avoiding their healthy neighbors, avoid rapid clearance from the body, and be administered without toxic solvents. They hold immense potential in addressing all of these issues, which has hampered further development of chemotherapeutics. Furthermore, such drug delivery systems will lead to cancer therapeutic modalities that are not only less toxic to the patient but also significantly more efficacious. In addition to established therapeutic modes of action, nanomaterials are opening up entirely new modalities of cancer therapy, such as photodynamic and hyperthermia treatments. Furthermore, nanoparticle carriers are also capable of addressing several drug delivery problems that could not be effectively solved in the past and include overcoming formulation issues, multidrug-resistance phenomenon, and penetrating cellular barriers that may limit device accessibility to intended targets, such as the blood-brain barrier. The challenges in optimizing design of nanoparticles tailored to specific tumor indications still remain; however, it is clear that nanoscale devices carry a significant promise toward new ways of diagnosing and treating cancer. This review focuses on future prospects of using nanotechnology in cancer applications and discusses practices and methodologies used in the development and translation of nanotechnology-based therapeutics.

Figure 1

Definition of nanotechnology and examples of nanotechnology platforms used in drug development. This figure was obtained with permission from McNeil et al, Nanotechnology for the Biologist. Journal of Leukocyte Biology, Volume 78, pages 585-594, 2005 (Figure 3 of this paper).

Figure 2

Collage of nanomedical particles and devices developed by members of the NCI Alliance for Nanotechnology in Cancer. This figure was obtained with permission from Hinkal et al, Cancer Therapy Through Nanomedicine. IEEE Nanotechnology Magazine, Volume 5(2), pages 6-12, June 2011 (Figure 1 of this paper).(Photo courtesy of the NCI Alliance for Nanotechnology in Cancer, Nanotechnology Image Library).

Figure 3

Nanoparticle biocompatibility trends. The zeta potential, size, and solubility affect the cytotoxicity (surface reactivity), clearance process (renal or biliary), MPS/RES recognition and EPR effect. This figure was obtained with permission from McNeil. Nanomedicine and Nanobiotechnology, Volume 1(3), pages 264–271, May/June 2009 (Figure 3 of this paper).

Figure 4

Efficacy of BIND-014 PSMA-targeted docetaxel nanoparticles in PSMA-expressing human LNCaP prostate cancer xenograft mouse model. Passively targeted docetaxel nanoparticles (PTNP, green) decrease tumor growth rate compared to conventional docetaxel (DTXL, red). BIND-014 (blue) is identical to PTNP in every way except for PSMA-targeting ligand on the surface. The additional active PSMA binding by BIND-014 results in tumor shrinkage of nearly 50%, a vast improvement over DTXL. Mice were treated four times with five mg/kg of DTXL, PTNP or BIND-014 at four day intervals (i.e., Q4D x 4). This figure was obtained with permission from Gu F, Zhang L, Teply BA, Mann N, Wang A, Radovic-Moreno AF, et al. Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proc Natl Acad Sci U S A. 2008;105(7):2586-91.

Figure 5

Summary of the clearance of nanoparticle agents via the mononuclear phagocyte system (MPS). Most of the studies evaluating factors affecting nanoparticle agents have been performed in patients receiving PEGylated and non-PEGylated liposomal agents and thus these carrier systems are depicted in the figure. However, in theory these factors may also affect other nanocarrier systems but need to be evaluated in future studies. Nanoparticle agents are primarily cleared via the monocytes, macrophages and dendritic cells of the MPS that are located in the liver, spleen, and blood. In addition, the MPS cells in the lung and bone marrow also appear to be involved. The tumor delivery of nanoparticle agents is determined by the EPR effect and potentially MPS in tumors. The factors affecting the PK and PD of nanoparticle agents in patients and animal models included age, gender, body composition, tumors in the liver, the dose and regimen, other drugs, type of cancer and prior therapy.