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Crossing barriers towards improving cancer nanomedicine

Devika Chithrani

Department of Physics and Astronomy, University of Victoria, Victoria, British Columbia, Canada; British Columbia Cancer agency, Victoria, British Columbia, Canada

E-mail : aa

DOI: 10.15761/FNN.1000178

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Opinion

The flexibility of cancer nanotechnology allows for the development of safer yet more effective nanoparticle-based tools for diagnostic and therapeutic applications in cancer research [1-3]. The ultimate goal of nanoparticle (NP)-based platforms will be the targeted delivery and monitoring of therapeutics to tumors while causing minimum side effects [4-8]. In addition to this, NP-based technology has the capability to develop novel multiplex systems to combine more than one treatment and imaging modalities for creating a more aggressive and effective approach in eradicating cancer [3,9,10]. The first generation of NP-based therapies approved by the FDA consists of lipid based NP-systems, such as liposomes and micelles [11]. However, recently more attention is given to the development of inorganic NP-based systems, such as gold NPs (GNPs) for drug delivery and therapeutics [12-15]. The successful delivery of NPs into tumor depends on efficiency of crossing few boundaries effectively which involves in vivo delivery, tissue transport, and internalization within individual tumor cells as discussed in this article.

In vivo delivery of nanoparticles

The rapid growth of tumor results in leaky vessels allowing NPs to leak into the tumor. In addition, the NPs are retained due to the lack of a functional lymphatic system [16-18]. This Enhanced permeability and retention EPR effect has been exploited to passively accumulate NPs within tumors [16-18]. This process is known to be strongly dependent on the size of the NPs [19,20]. The lack of lymphatic drainage within the tumor also increase interstitial fluid pressure (IFP) which can also limit delivery of therapeutic agents [21]. Administration of agents that inhibit angiogenesis temporarily could improve the blood flow and reduce IFP by pruning immature vessels [21,22].

Penetration of nanoparticles through extracellular tumor matrix

A tumor with a well-developed collagen network can be considered to be physically resistant to transport of NP-based therapies [23,24]. Using in vitro tissue models, it was shown that NP transport is dependent on their size, tumor cell type, and surface functionality [25-27]. The more aggressive and invasive tumour cells secrete matrix-degrading proteinases that serve to break down collagen and attribute to the differences in the difference in extracellular matrix (ECM) and cell layer organizations [28,29]. It was observed that the GNPs penetrated deeper through more aggressive tumor tissue models [25]. For tumors with a relatively well-developed collagen network, treatments that reverse or inhibit collagen production and assembly can be performed prior to NP-based therapies [23]. For example,  Ji, et al. down-regulated ECM levels and observed an enhanced penetration of a therapeutic agent and suggested that the regulation of ECM may become a promising adjuvant therapeutic strategy for ECM-rich tumors [24]. Other studies have shown that ECM-degrading enzymes and hormones can be used to modify the collagen structure to further improve the distribution of NPs in solid tumors [30,31].

Uptake of nanoparticles at individual cell level

Cellular uptake of NPs is dependent on their size, shape, and surface properties. Among the size range 10-100 nm, NPs of diameter 50 nm have the highest uptake [32-34]. However, it is shown that adding polyethylene glycol (PEG) onto NP for in vivo applications would change the size dependent NP uptake dynamics at individual cell level.(PEG) is a commonly used molecule to decrease the NP surface exposure to proteins, such as opsonin, while improving the blood circulation of the NPs [35,36]. The limitations of mortifying GNPs with PEG molecules is that accumulation at cellular level is decreased. This is due to the lowering of binding ability of NPs onto cell surface receptors [35-37]. Peptides containing the targeting moieties are being used to improve the accumulation of PEGylated NPs [36,38]. It was shown that the 50 nm was not the optimum size anymore and smaller NPs had a higher uptake. It is believed that the higher surface curvature of smaller NPs can expose targeting molecules to receptors on the tumor cell membrane.

Figure 1. The successful delivery of NPs into tumor depends on optimizing size and surface properties for in vivo delivery (A) followed up by their release into the tumor through it leaky vasculature (B), transport through the tumor extra cellular matrix (C), and internalize within the individual tumor cells effectively (E). Successful clinical translation of nanomedicine requires NPs to be accumulated in the tumor tissue

It is known that in vitro data cannot be extrapolated directly to in vivo or clinical settings [39]. However, these in vitro models provide useful information in a less complex environment. As a first step in this direction, a recent study has shown that NP complexes optimized using in vitro models ultimately produced a higher accumulation within the tumor [27]. Accumulation of the NPs into the cells becomes a more complicated process as they must pass more barriers before entering the cells as discussed in this article. Successful clinical translation of nanomedicine requires NPs to be accumulated in the tumor Cells [40].

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Editorial Information

Editor-in-Chief

Article Type

Opinion Article

Publication history

Received date: December 22, 2018
Accepted date: December 28, 2018
Published date: December 31, 2018

Copyright

©2018 Chithrani D. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Chithrani D (2018) Crossing barriers towards improving cancer nanomedicine. Front Nanosci Nanotech 4: doi: 10.15761/FNN.1000178.

Corresponding author

Chithrani D

Department of Physics and Astronomy, University of Victoria, Victoria, British Columbia, Canada, British Columbia Cancer agency, Victoria, British Columbia, Canada

Figure 1. The successful delivery of NPs into tumor depends on optimizing size and surface properties for in vivo delivery (A) followed up by their release into the tumor through it leaky vasculature (B), transport through the tumor extra cellular matrix (C), and internalize within the individual tumor cells effectively (E). Successful clinical translation of nanomedicine requires NPs to be accumulated in the tumor tissue