Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology

Abstract

Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000's. The path to the commercialization of oncology drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnology can meaningfully contribute to create differentiated products and improve clinical outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL® and Abraxane®. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncology, where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential "retention" in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor associated macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers.

Keywords: Active targeting; Drug delivery; Enhanced permeation and retention effect; Imaging; Nanomedicine; Nanoparticles; Patient enrichment; Personalized medicine; Tumor microenvironment; Vessel normalization.

Figure 1

The EPR effect results from 2 distinct phenomena: the extravasation of the colloid from the blood vessels and their subsequent movement in the tumor extracellular matrix (ECM) by diffusion and convection.

Figure 2

After intratumoral injection in melanoma xenografts (Mu89), the diffusion coefficient of macromolecules and nanomaterial in the ECM is inversely proportional to the hydrodynamic radius. Diffusion of bovine serum albumin (BSA, circles), 70-kDa dextran (squares), immunoglobulins (IgG, triangles), 2-MDa dextran (diamonds) and liposomes (inverted triangles) follows 2 phases with fast (closed symbols) and slow colloid populations (open symbols). Adapted with permission from [61].

Figure 3

In murine S-180 sarcoma, the tumor accumulation levels of macromolecules (○) are in direct relation with the total body exposure (AUC, ▲) and inversely proportional to their renal clearance (●). This holds true for other types of tumors and nanomaterials. Used with permission from [76]

Figure 4

In human, the accumulation of liposomes in tumors is different in each type of cancer. Sarcomas seem to be the sole cancers for which the accumulation of liposomes in tumor is superior to that in plasma or surrounding tissue. (●) from [116], DOX concentration in malignant infusion vs. plasma concentration, using Doxil®. (□) from [119], ¹¹¹In-DTPA-labelled liposomes in tumor ROI vs. plasma concentration. (◇) from [121], ^99mTc-DTPA-labelled Doxil® tumor ROI vs. skull bone marrow. (▲) from [117] DOX concentration in tumor biopsies vs. plasma concentration, using DOX-containing PEGylated liposomes. (○) from [120], ^99mTc-DTPA-labelled liposomes tumor ROI vs. surrounding tissue (■) from [118], DOX concentration in bone metastases vs. plasma concentration, using Doxil®. All ratios are given for concentrations measured at the same time-point and individual patients are presented when possible; the doses of DOX used are labeled on the figure (closed symbols); open symbols represent the use of empty liposomes.

Figure 5

The physicochemical properties of the ligand and the NP affect their blood circulation profiles, their biodistribution and their ability to be internalized by cancer cells.

Figure 6

Actively-targeted NPs have shown promises in early clinical trials. A. BIND-014, a PSMA targeted, docetaxel-containing polymeric NP has shown impressive anticancer response in heavily-pretreated patients; the regression of lung metastases experienced by one patient suffering from cholangiocarcinoma after two cycles of BIND-014 is evidenced here by CT scans. B. SGT53, a TfR-targeted liposomes containing plasmid DNA for the p53 gene were shown to allow expression of the exogenous p53 gene by DNA PCR; tumor biopsies were taken 100 (T1) and 26 hours (T2) after administration of different doses in 2 different patients. C. CALAA-01, a TfR-targeted polymeric NPs encapsulating siRNA was shown to reduce mRNA (77 %) and protein expression (32 %) compared to baseline (C2_pre) in one patient receiving 30 mg/m2 of siRNA (C2_post); mRNA expression was assessed by qRT-PCR while protein expression was evidenced by western blotting. Figures are used with permissions from [4], [310] and [2], respectively.