Multifunctional to multistage delivery systems: The evolution of nanoparticles for biomedical applications

Abstract

Nanomaterials are advancing in several directions with significant progress being achieved with respect to their synthesis, functionalization and biomedical application. In this review, we will describe several classes of prototypical nanocarriers, such as liposomes, silicon particles, and gold nanoshells, in terms of their individual function as well as their synergistic use. Active and passive targeting, photothermal ablation, and drug controlled release constitute some of the crucial functions identified to achieve a medical purpose. Current limitations in targeting, slow clearance, and systemic as well as local toxicity are addressed in reference to the recent studies that attempted to comprehend and solve these issues. The demand for a more sophisticated understanding of the impact of nanomaterialson the body and of their potential immune response underlies this discussion. Combined components are then discussed in the setting of multifunctional nanocarriers, a class of drug delivery systems we envisioned, proposed, and evolved in the last 5 years. In particular, our third generation of nanocarriers, the multistage vectors, usher in the new field of nanomedicine by combining several components onto multifunctional nanocarriers characterized by emerging properties and able to achieve synergistic effects.

Keywords: cancer; drug delivery; multifunctional; multistage; nanomedicine; nanoparticle; porous silicon; third generation nanocarriers.

Figure 1. Hierarchy of Nanocarriers

A. First-generation nanocarriers (e.g., liposomes, micelles) primary role is to enclose therapeutic or diagnostic agents and then localize in tumors by the EPR effect; B. Second-generation nanocarriers improved by incorporating further modifications allowing for specific targeting via antibodies or other recognition biomolecules or “stealthing” from MPS sequestration; C. Third-generation nanocarriers advanced the field by creating platforms capable of incorporating and preforming multiple complex functions due to their nanoscale features (e.g., multistage silicon nanocarriers ability to deploy multiple waves of nanoparticles). Reproduced with permission, © Wiley-VCH Verlay GmbH & Co. KGA [22].

Figure 2. Third-generation nanocarrier platforms

A. Gold nanoshells and rods display unique photothermal properties and can enhance fluorescent and magnetic properties when coupled to their surface. B. Au-phage networks are the result of the unique synergism yielded upon the incorporation of gold nanoparticles with bacteriophages, schematic is shown here displaying the effect of charge. Adapted from [41] and reproduced by permission from Jonathan O. Martinez, Methods in Bioengineering: Nanoscale Bioengineering and Nanomedicine, Norwood, MA: Artech House, Inc., 2009. © 2009 by Artech House, Inc. C. Nanocells are comprised of two compartments (nucleus and envelope) which allows for the temporal release of agents enabling time-dependent delivery of therapeutics, adapted from [43]. D. Protocells are nanoporous silica cores supported by a lipid bilayer. The porous core allows for the incorporation of a diverse array of cargoes, while the lipid bilayer enables for further conjugation of targeting and fusogenic peptides yielding an agent capable of providing a “one nanoparticle, one kill”. Reproduced with permission from NPG [44] E. Embedded nanoparticles enable the concentrated delivery of smaller nanoparticles deep within the tumor site by taking advantage of the responsive nature of larger nanoparticles to tumor microenvironment cues (e.g., Gelatin & MMP-2). Reproduced from [49] with permission from National Academy of Sciences, U.S.A. F. Communicating nanoparticles benefit from the amplification of signals created through biological cascades resulting in significant increases in nanoparticle tumor accumulation. Using the increases in factors involved in the coagulation cascade, via the heating of gold nanorods, one could effectively increase the accumulation of targeted therapeutic and diagnostic agents. Reproduced with permission from NPG [50].

Figure 3. Schematic and SEM micrographs describing the process and shape of multistage silicon nanocarriers

A. MSN is initially loaded with second-stage NP into the pores of the silicon nanocarriers. Upon systemic administration, the rational design of MSN allows them to travel within the blood stream, avoid MPS sequestration, and preferentially drift towards the target’s endothelium and firmly adhere. Once docked, MSN can release their cargo (i.e., second stage NP) that will infiltrate into the target’s microenvironment where they can specifically target diseased cells and fulfill their final objective. B. Overall view of a view MSN illustrating the uniform size and shape within each fabrication batch. C. Magnified image of the nano-sized pores of MSN, which can serve to accommodate a variety of NP. Reproduced with permission from [51].

Figure 4. Loading and release of nanoparticles from MSN

A–C. Loading of NP (liposomes, quantum dots) into MSN. A,B. Flow cytometry of loading comparing the fluorescence of MSN, either unloaded (black) or with NP-loaded (A, green, liposomes; C, red, quantum dots). C. Fluorescent image of MSN containing FITC labeled nanoliposomes. D. Release profiles of quantum dots from oxidized (blue) and APTES modified (red) MSN.

Figure 5. Coating and delayed release of biomolecules from MSN

A–D. SEM micrographs demonstrating the coating of MSN with agarose (A,B) and gelatin (C,D) at the single particle scale (A,C) and pore scale (B,D). E. Release profiles of BSA-FITC from uncoated (black), agarose (blue), and gelatin (red) coated MSN. The coating of MSN yielded a delay in the release of BSA enabling kinetics not possible without a coating.