Nanoparticles in the clinic

Abstract

Nanoparticle/microparticle-based drug delivery systems for systemic (i.e., intravenous) applications have significant advantages over their nonformulated and free drug counterparts. For example, nanoparticle systems are capable of delivering therapeutics and treating areas of the body that other delivery systems cannot reach. As such, nanoparticle drug delivery and imaging systems are one of the most investigated systems in preclinical and clinical settings. Here, we will highlight the diversity of nanoparticle types, the key advantages these systems have over their free drug counterparts, and discuss their overall potential in influencing clinical care. In particular, we will focus on current clinical trials for nanoparticle formulations that have yet to be clinically approved. Additional emphasis will be on clinically approved nanoparticle systems, both for their currently approved indications and their use in active clinical trials. Finally, we will discuss many of the often overlooked biological, technological, and study design challenges that impact the clinical success of nanoparticle delivery systems.

Keywords: clinic; clinical translation; clinical trials; drug delivery; nanomedicine; nanoparticles; translational medicine.

Figure 1

Clinically relevant nanoparticles. Organic and inorganic nanoparticles have been approved for a variety of clinical indications (black text) and are being investigated in current clinical studies for additional indications (red text). Examples included (a) Doxil (200 nm scale bar), (b) Abraxane (200 nm scale bar), (c) CRLX101 (50 nm scale bar), (d) Feraheme (20 nm scale bar), (e) early iteration of Cornell Dots (50 nm scale bar), and (f) gold nanoshells (inset: 100 nm scale bar, main figure: 1,000 nm scale bar) from Nanospectra, makers of AuroLase. (a) Reprinted from ref. 16. Copyright (2016), with permission from Elsevier. (b) Adapted by permission from Macmillan Publishers Ltd: Nature Communications,17 copyright (2015). (c) Reprinted from ref. 18 (d) Reprinted from refs. 16 and 19. Copyright (2016), with permission from Elsevier. (e) Adapted with permissions from ref. 20. Copyright (2012) American Chemical Society. (f) Reprinted from ref. 21

Figure 2

Examples of successful nanoparticle targeting in humans. (a) (i) Transferrin‐receptor targeting of a cyclodextrin‐based nanoparticle for the successful delivery of siRNA and subsequent knockdown of the anticancer target RRM2. Data show knockdown percentages of RRM2 in three patients (before: grey bars, after: black bars) as analyzed by quantitative reverse‐transcriptase polymerase chain reaction (qRT‐PCR) and western blot analysis. (ii) Transferrin‐receptor targeting of a liposomal nanoparticle for delivery of p53 for restoring p53 function. Data show increased presence of p53 in patient's tumors (as compared to negative control skin biopsy in same patients) following the targeted therapy. (b) PSMA‐targeted polymeric particles show shrinkage of tumors after two treatment cycles at 42 days for patients with tonsillar cancer (top) and lung metastases (bottom). (c) cRGDY‐peptide functionalized silica particles with radioactive iodine and a fluorescent dye (Cornell Dots) increased contrast in a pituitary lesion. Interestingly, contrast increased over time where tumor‐to‐background (both tumor‐to‐brain and tumor‐to‐liver) ratios highlight the efficiency and success of cRGDY targeting. (ai) Adapted by permission from Macmillan Publishers Ltd: Nature,61 Copyright (2010). (aii) Adapted by permission from Macmillan Publishers Ltd: Molecular Therapy,62 Copyright (2013). (b) From ref. 91. Reprinted with permission from AAAS. (c) From ref. 92. Reprinted with permission from AAAS

Figure 3

Biological challenges that intravenous nanoparticle formulations face. (a–c) Time‐dependent biodistribution [(a) 2, (b) 24, and (c) 72 hr] of Cornell Dots in a human. (d) Tissue‐ and cell‐level nanoparticle (green) confocal images of CALAA‐01 in three human patients with melanoma (epi, epidermis; m, melanophage; s, skin side; t, tumor side). (a–c) From ref. 92. Reprinted with permission from AAAS. (d) Adapted by permission from Macmillan Publishers Ltd: Nature,61 Copyright (2010)

Figure 4

Technological challenges that intravenous nanoparticle formulations face. (a) Overview of a nanoparticle selection process based on (1) a given synthesis approach for (2) high‐throughput iterative in vitro and (3) in vivo selection of nanoparticles with favorable performance, and (4) the scale‐up of a final nanoparticle formulation. (b) A close‐up snapshot of the various particle parameters that can be iteratively optimized for a desired performance standard. (a, b) From ref. 91. Reprinted with permission from AAAS