Size matters: gold nanoparticles in targeted cancer drug delivery

Abstract

Cancer is the current leading cause of death worldwide, responsible for approximately one quarter of all deaths in the USA and UK. Nanotechnologies provide tremendous opportunities for multimodal, site-specific drug delivery to these disease sites and Au nanoparticles further offer a particularly unique set of physical, chemical and photonic properties with which to do so. This review will highlight some recent advances, by our laboratory and others, in the use of Au nanoparticles for systemic drug delivery to these malignancies and will also provide insights into their rational design, synthesis, physiological properties and clinical/preclinical applications, as well as strategies and challenges toward the clinical implementation of these constructs moving forward.

Figure 1. Applications of colloidal Au nanoparticles in drug delivery and laser photothermal therapy

(A) Au nanospheres; (B) Au nanorods, (C) Au nanoshell; and (D) Au nanocages. HIFU: High-intensity focused ultrasound; PEG: Poly(ethylene glycol); PPTT: Plasmonic photothermal therapy; R6G: Rhodamine 6G. (A2–A4) Reprinted with permission from [38,166,138]. © American Chemical Society (2009, 2003 and 2006), respectively. (B2–B4) Reprinted with permission from [45]. © Elsevier (2008); [167] © American Chemical Society (2004); [140] © National Academy of Sciences (2010), respectively. (C2;C4) Reprinted with permission from [48]. © National Academy of Sciences (2003); [168] © Elsevier (1998), respectively. (D2–D4) Reprinted with permission from [46] © Wiley-VCH Verlag GmbH & Co. KGaA (2010); [169] © American Chemical Society (2006); [170] © Royal Society of Chemistry (2011), respectively.

Figure 2. Turkevich/Frens synthesis of Au nanoparticles and seed-mediated growth of gold nanorods

(A) Au(III) is reduced to Au(I) when citrate is oxidized to dicarboxyacetone in the presence of chloroauric acid and/or heating. Au(I) chloride is believed to form a bidentate complex with dicarboxyacetone, which undergoes a disproportination reaction to form (2) zero-valent Au atoms and (1) Au(III) chloride. (B) (i) Au(III) chloride quantitatively displaces Br^– counterions in micelles of CTAB and subsequent borohydride reduction produces small (~1.5 nm diameter) seed nanoparticles surface stabilized by a CTAB-bilayer.(ii) Au(III) bound to CTAB micelles is reduced to Au(I) by ascorbic acid. Directional growth of Au nanorods occurs via crystallographically preferential reduction of Au(I) onto the seed nanoparticles. For simplicity, note that (B) omits shape-directing contributions from adsorbed halide ions and Ag(I) ions. CTAB: Cetyltrimethylammonium bromide. (A) Data from [98,99]. (B) Data from [108,109,171].

Figure 3. Reaction of ethyl(dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide coupling commonly used to conjugate various molecules to surface-functionalized Au nanoparticles.

Figure 4. Pharmacokinetics of PEGylated Au nanoparticles

(A) Relationship between circulatory half-lives, hydrodynamic diameter and tumor accumulation for spherical Au nanoparticles of varying size and thiolated PEG surface stabilizer molecular weight. (B) The circulatory half-lives of PEGylated Au nanospheres are inversely proportional to particle size and PEG molecular weight (for particles >16-nm core diameter). (C) The similar pharmacokinetics of PEGylated Au nanoparticles in tumor-bearing and nontumor-bearing mouse models. PEG: Poly(ethylene glycol). Reprinted with permission from [124]. © American Chemical Society (2009).

Figure 5. Selective biodiagnostic labeling of cell cultures using antibody–Au nanoparticle conjugates

(A) Nonmalignant HaCaT keratinocyte cells show only nonspecific labeling by Au nanospheres conjugated with antibodies for anti-EGFR. Malignant (B) HSC-3 and (C) HOC-313 squamous cell carcinoma cells show high binding with anti-EGFR Au nanoparticles due to their characteristically high cell-surface EGFR expression levels. Reprinted with permission from [136]. © American Chemical Society (2005).

Figure 6. Conjugation and in vivo tumor accumulation of a photodynamic therapy photosensitizer–Au nanoparticle conjugate

(A) AuNPs were functionalized with Pc4 photosensitizer through Au–N bond formation at the terminal amine group on the Pc4’s axial ligand. Fluorescence images of a tumor-bearing mouse at (B) 1 min, (C) 30 min and (D) 2 h after intravenous injection with Pc4–AuNPs. Fluorescence from Pc4 molecules indicated efficient delivery and accumulation of the drug in the rear flank tumor site (white circle). (E) Mice injected only with Pc4 exhibited no appreciable drug circulation or tumor-specific accumulation. AuNP: Au nanoparticle; NP: Nanoparticle; PDT: Photodynamic therapy; PEG: Poly(ethylene glycol). Reprinted with permission from [153]. © American Chemical Society (2008).

Figure 7. Selective targeting and in vitro near-IR plasmonic photothermal therapy of cancerous and noncancerous cell lines

(A) Au nanorods conjugated with antibodies to anti-EGFR showed increased labeling of HSC-3 and HOC malignant cell lines which overexpress EGFR, whereas nonmalignant cells remained unlabeled. (B) Near-IR laser exposure at various laser powers revealed that malignant cell lines were killed at and above 19 W/cm² while nonmalignant cell lines required 57 W/cm². Reprinted with permission from [157]. © Elsevier (2006).

Figure 8. In vitro near-IR photothermal therapy using nanobody-conjugated branched Au nanoparticles

Specific labeling of SKOV3 cells was achieved using (A) HER2 antibody (anti-HER2) and (C) PSA antibody (anti-PSA) Au–NP conjugates. Non-conjugated (B) anti-HER2 and (D) anti-PSA exhibited no image contrast. (E–H) Near-IR laser (continuous wave, 690 nm, 38 W/cm²) treatment for 5 min showed increased cell death with increasing incubation concentration of anti-HER2-Au NPs. NP: Nanoparticle; OD: Optical density (concentration); PSA: Prostate-specific antigen. Reprinted with permission from [158]. © American Chemical Society (2011).

Figure 9. Internalization and delivery of the chemotherapeutic drug doxorubicin in multidrug-resistant breast cancer cells through conjugation with Au nanoparticles

(A) Au nanoparticles were functionalized with DOX through an acid-liable poly(ethylene glycol) linker. (B) DOX-Au nanoparticles enter the cell through endocytosis and subsequently released the conjugated drug once in the acidic endo/lysosomal environment. Drug release, here, can be monitored using DOX fluorescence, which becomes de-quenched upon released from the Au nanoparticle. DOX: Doxorubicin; MDR: Multidrug resistance. Reprinted with permission from [162]. © American Chemical Society (2011).