Control of polymeric nanoparticle size to improve therapeutic delivery

Abstract

As nanoparticle (NP)-mediated drug delivery research continues to expand, understanding parameters that govern NP interactions with the biological environment becomes paramount. The principles identified from the study of these parameters can be used to engineer new NPs, impart unique functionalities, identify novel utilities, and improve the clinical translation of NP formulations. One key design parameter is NP size. New methods have been developed to produce NPs with increased control of NP size between 10 and 200nm, a size range most relevant to physical and biochemical targeting through both intravascular and site-specific deliveries. Three notable techniques best suited for generating polymeric NPs with narrow size distributions are highlighted in this review: self-assembly, microfluidics-based preparation, and flash nanoprecipitation. Furthermore, the effect of NP size on the biological fate and transport properties at the molecular scale (protein-NP interactions) and the tissue and systemic scale (convective and diffusive transport of NPs) are analyzed here. These analyses underscore the importance of NP size control in considering clinical translation and assessment of therapeutic outcomes of NP delivery vehicles.

Keywords: Drug delivery; Nanomedicine; Polymeric nanoparticles; Size control.

Figure 1. Methods have been developed for precise control of NP size

(a) Fabrication of polymer NPs containing anticancer drugs using a simple diffusion based continuous-flow microfluidic device (top left panel, adapted with permission from [17]. Copyright (2008) American Chemical Society) or a hydrodynamic flow focusing device (top right panel, adapted with permission from [19]. Copyright (2010) National Academy of Sciences of the USA). (b) Preparation of block copolymer stabilized-NPs using confined precipitation geometries of four (MIVM) or two (CIJ) impinging fluid streams. Reprinted from [38], copyright (2011), with permission from Elsevier. Hydrophobic solute and block copolymers are dissolved in a water miscible organic solvent and brought together with water into a confined space to generate NPs. The final concentration of organic solvent is <10%. (c) Schematic representation of NPs prepared using LbL method with controlled size and surface characteristics. Reprinted with permission from [29]. Copyright (2013) American Chemical Society. Sequential layers of oppositely charged macromolecules can be added to the NP core, allowing for the delivery of therapeutics, including DNA and RNA, and coating with an outer layer for long circulation and targeting capabilities.

Figure 2. Environmental factors that influence contextual size of NPs

(a) NP surface characteristics after fabrication in PBS or water changes drastically upon incubation in biological media, such as serum. (b) Schematic representation of PLGA-PEG-alendronate NPs with various amounts of alendronate conjugated to the surface for bone targeting. NP size increases were observed after incubation in serum, particularly for high alendronate surface modification. Reprinted with permission from [63]. Copyright (2014) National Academy of Sciences of the USA. (c) NP rigidity influences the ability to be cleared by the kidney. For stiffer nanoparticles, only those smaller than pores in the capillaries could be filtered. Softer and more flexible nanoparticles could deform through the capillary bed, allowing larger particles to be cleared. Reprinted with permission from [72]. Copyright (2011) American Chemical Society.

Figure 3. NP size influences tumor delivery via i.v. administration

(a) Schematic representation of the EPR effect for NP delivery to solid tumors through fenestrations in tumor-associated blood vessels. Reprinted with permission from [80]. (b) Fluorescent microscopy image of distribution of 30-nm (green) and 70-nm (red) polymeric micelles in metastatic LN 24 h after systemic injection of micelles. B16-F10 melanoma cells are shown in blue, and micelle co-localization is shown in yellow. Fluorescent intensity of micelles was quantified in both the metastatic region and normal region of the LN, and the ratio was plotted to compare the size-dependent distribution. Adapted with permission from [82]. Copyright (2015) American Chemical Society. (c) Fluorescent microscopy images showing distribution of 30-nm (green) and 70-nm (red) micelles in C26 and BxPC3 tumors. Co-localization of micelles is shown in yellow. Graphs depict the fluorescent intensity of the two micelles in the white rectangle box, with the 0 – 10 µm region characterizing the distribution inside the blood vessel and the 10 – 100 µm region characterizing the distribution in the tumor tissue. Values are expressed as a maximum of the fluorescent intensity in the blood vessel region. Reprinted by permission from Macmillan Publishers Ltd: Nature Nanotechnology [83], copyright 2011.

Figure 4. NP size affects tissue biodistribution in tissue-based injections

(a) Schematic illustration depicting transport of 1 – 100 nm NPs versus larger NP within fibrous ECM matrix highlighting increased ability of smaller NPs to navigate the ECM. Upon transport to LNs, size also significantly influences NP retention. Reprinted by permission from Macmillan Publishers Ltd: Nature Materials [99], copyright 2013. (b) Administration route influences the immune response of different sized NPs. Reprinted from [100], copyright (2010), with permission from Elsevier. (c) NPs encounter tissue ECM barriers to transport upon reaching target tissues and exhibit further NP size dependent properties such as tumor accumulation. Reprinted by permission from Macmillan Publishers Ltd: Nature Communications [98], copyright 2013.