Cancer nanomedicine: progress, challenges and opportunities

Abstract

The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.

Figure 1. Historical timeline of major developments in the field of cancer nanomedicine

EPR, enhanced permeability and retention; FDA, US Food and Drug Administration; nab, nanoparticle albumin bound; NP, nanoparticle; PLGA-PEG, poly(D,L-lactic-co-glycolic acid)-b poly(ethylene glycol); PRINT, particle replication in non wetting template; siRNA, small interfering RNA.

Figure 2. The impact of nanoparticle properties on systemic delivery to tumours

Nanoparticles (NPs) can be made from different materials and have various physicochemical properties (for example, size, geometry, surface features, elasticity and stiffness, among others) and can be modified with a myriad of targeting ligands of different surface density (part a). NP properties affect the biological processes involved in the delivery to tumour tissues, including interactions with serum proteins (part b), blood circulation (part c), biodistribution (part d), extravasation to perivascular tumour microenvironment through the leaky tumour vessels and penetration within the tumour tissue (part e), and tumour cell targeting and intracellular trafficking (part f). NPs can also be designed to control the release profile of payloads (part g). ID, injected dose.

Figure 3. Potential markers for predicting EPR effect and nanotherapeutic efficacy

a | Companion imaging agents (for example, ferumoxytol nanoparticle (NP)) have been applied to predict the accumulation of poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-PEG) NP-encapsulated docetaxel and its anticancer activity in solid tumours, and ferumoxytol is currently in clinical trials to determine its feasibility as a predictive marker for the liposomal irinotecan MM-398. b | Therapeutic NPs labelled with imaging agents (for example, radioisotopes), also called theranostic NPs, have been used to monitor their biodistribution and tumour accumulation using various imaging techniques both preclinically and clinically. c | Serum and tissue biomarkers may also serve as surrogate markers for the enhanced permeability and retention (EPR) effect, as suggested by one recent example showing strong correlation of liposome accumulation in tumours with the relative ratio of matrix metalloproteinase 9 (MMP9) to tissue inhibitor of metalloproteinase 1 (TIMP1) in the circulation.

Figure 4. Nanoparticle targeting of the tumour microenvironment and the premetastatic niche

Targeting of the tumour vasculature or stromal cells in the tumour microenvironment (part a) and the premetastatic microenvironments such as the bone marrow niche, where induction of the osteogenic differentiation of mesenchymal stem cells enhances bone strength and volume (part b). Cell-specific targeting can be achieved via the modification of nanoparticles (NPs) with ligands that bind to specific receptors (for example, α_vβ₃ integrin and mannose receptor) on the surface of tumour endothelial cells, stromal cells or other target cells. It should be noted that even without targeting ligands, NPs can be engineered for preferential cellular uptake. The payloads released from NPs localized in tumours or premetastatic tissues can also be nonspecifically taken up by these cells.