Advances in Anticancer Protein Delivery Using Micro-/ Nanoparticles

Abstract

Proteins exhibiting anticancer activities, especially those capable of discriminately killing cancer cells, have attracted increasing interest in developing protein-based anticancer therapeutics. This progress report surveys recent advances in delivering anticancer proteins directly to tumor tissue for inducing apoptosis/necrosis or indirectly to antigen presenting cells for provoking immune responses. Protein delivery carriers such as inorganic particles, lipid particles, polymeric particles, DNA/protein based biomacromolecular particles as well as cell based carriers are reviewed with comments on their advantages and limitations. Future challenges and opportunities are also discussed.

Figure 1

Schematic of different carriers for anticancer protein delivery.

Figure 2

Multiwall carbon nanotube (MWCNT) mediated intracellular delivery of ricin A-chain (RTA) through clathrin-mediated endocytosis by Kong and coworkers. (A) Confocal fluorescent image of endoplasmatic reticulum. (B) Confocal fluorescent image of EGFP-RTA. (C) Co-localization of EGFP-RTA with endoplasmatic reticulum. (D) TEM image of MWCNT localized in endosome and (E) Magnification of the white rectangular in D shows individual MWCNTs. (F) Confocal image of cells incubated with MWCNT-RTA conjugate and (G) Control confocal image of cells incubated with soluble RTA. Reprinted with permission from ref.^[55]. Copyright 2010 American Chemical Society.

Figure 3

Intracellular delivery of caspase 3 using nanoparticle stabilized capsules (NPSC) by Rotello and coworkers. (A) Schematic of the preparation of protein-NPSC complex and mechanism for protein delivery. (B) Delivery of caspase 3 into the cytosol of HeLa cells by caspase 3-NPSC complex. Copyright 2013 American Chemical Society.

Figure 4

Sequential delivery of TRAIL and Doxorubicin (DOX) to specific cellular locus using a polymeric gel coated liposome (Gelipo) by Gu and coworkers.^[10] (A) Schematic of sequential deliveries of TRAIL to cell membrane and DOX to nucleus. I, TRAIL/DOX-Gelipo accumulated at tumor site by passive and active targeting. II, Degradation of the polymeric shell (HA) by overexpressed HAase at tumor site. IIIa, TRAIL was released and binds to the death receptors on cell surface. IIIb and IIIc, TRAIL induced apoptosis signaling and cell death. IVa and IVb, Liposome uptake mediated by surface modified R8H3 ligand. IVc and IVd, Endosome escape and release Dox into nucleus. IVe, Dox induced cell death. (B) Hydrodynamic size and TEM image of TRAIL/DOX-Gelipo. Scale bar 200 nm. (C) Mice bearing MDA-MB-231 xenograft treated with (a) Saline, (b) DOX solution, (c) DOX-Gelipo and (d) TRAIL/Dox-Gelipo. Reprinted with permission from ref.^[10]. Copyright 2014 Wiley-VCH.

Figure 5

Self-degradable single protein nano-capsule for delivering caspase 3 by Tang and coworkers. (A) Schematic diagram of the in situ polymerization process. (B) TEM characterization of freshly prepared caspase-3 capsule and (C) TEM image of self degradable caspase-3 capsule after incubation at 37 °C for 12h . (D) Bright field image of HeLa cells treated with saline, self-degradable caspase-3 capsule, non-degradable caspase-3 capsule and naked caspase-3 for 24 h. Reproduced with permission from ref.^[88]. Copyright 2009 American Chemical Society.

Figure 6

Coating pH responsive dendritic shell on protein surface for intracellular delivery by Weil and coworkers. (A) Schematic diagram of the pH responsive dendritic coating and de-coating on protein surface. (B) Colocalization of dendronized papain and A549 cell lysosome. (C) Structure of the dendron. Reprinted with permission from ref.^[97]. Copyright 2013 Wiley-VCH.

Figure 7

Charge-conversional PIC micelles for delivering cytochrome c by Kataoka and Coworkers. Schematic of the preparation of the PIC micelle. Copyright 2009 Wiley-VCH.

Figure 8

Deliver antibodies with logic aptamer-gated nanorobot by Douglas and coworkers. (A) Schematic view the nanorobot in closed and open status. (B) Mechanism of the aptamer guided lock and open. Aptamer strand (blue), complementary strand to the aptamer (orange) and antigen (red). (C) TEM characterization of the open and close of nanorobot (left lane), nanorobot loaded with 5 nm gold nanoparticle (middle lane) and nanorobot loaded with antigen (right lane). Reprinted with permission from ref.^[110]. Copyright 2012 Science.

Figure 9

Coating TRAIL on leukocyte surface to target circulating tumor cells in bloodstream by King and coworkers. (A) Schematic diagram of liposome assisted coating of leukocytes with TRAIL and tumor targeting. (B) Schematic diagram of synthesizing liposomes containing TRAIL and E-selectin. (C) Confocal image of TRAIL coated leukocytes. Reproduced with permission from ref.^[32]. Copyright 2014 PNAS.