Improving drug pharmacokinetics and bio-distribution: nanotechnology helps address the issue

The human society today is facing a difficult situation in the form of the corona pandemic and scientists across the world have been striving to find different ways to deal with this new SARS-CoV-2 virus that seems to present with varied respiratory symptoms. Nevertheless, there are other predominant infectious diseases, cancers and several health disorders that are widely prevalent. The need for improved drugs and their delivery methods are of greater importance now, than ever before. Having said that, the limiting factors for a drug molecule to be effective are its pharmacokinetic properties and bio-distribution.

The candidate compounds that were found to be excellent when screened in silico and tested in vitro failed to show the same efficacy when tested in vivo; which could be due to different factors per se. In an in vitro scenario it would be only a single cell type that the drug interacts with, but, in a multi-cellular organism the drug has to cross several barriers and interact with several cell types, before it reaches the target cells, this makes it difficult for the drug molecule to show the expected efficacy. The other reasons for the poor pharmacokinetics and bio-distribution would include the reduced half-life of the compounds in the blood stream, clearance from the circulation, and sequestration in liver, spleen and kidneys. In order to improve these properties of drug molecules; nanoparticles or nanoparticle preparations are being employed.

Gold nanoparticles seem to be a good choice, given, their multi-functionality, optical and photo-thermal properties and biocompatible nature. Gold nanoparticles that are synthesised with different surface coatings have been conjugated to drug compounds and used to improve the pharmacokinetics by administering through oral or parenteral routes. Here we would discuss a couple of interesting studies that were carried out in that direction.


Figure 1: The synthetic versatility of AuNPs. Courtesy: Sciencedirect.com 

In a study conducted on immune-competent CD1 mice and immune-deficient athymic mice (mice that have a deteriorated or no thymus, with an inhibited immunity due to lack of T cells), the authors reported their findings of how the surface charge of the gold nanoparticles modulated the pharmacokinetics, tumour cell uptake and bio-distribution. The study showed that the neutral and zwitterion nanoparticles had higher systemic exposure and low clearance but positively charged nanoparticles were cleared rapidly from the system, and negatively charged nanoparticles had moderate clearance. With this observation it could be noted that mere alteration of the surface charge of the nanomaterials could differentially affect the pharmacokinetics and bio-distribution of the drug load to the target tumour cells. [1] 

There have been studies conducted to see if conjugating the drug to gold nanoparticles or coating the gold nanoparticles with the drug has any effect on the drug delivery, bio-distribution and pharmacokinetics. Du et al., reported that intravenous administration of doxorubicin conjugated gold nanoparticles improved stability of the drug under the physiological conditions, and also showed no observable histopathological lesions in various organs as in case of the mice administered the same dose of doxorubicin. This could indicate that conjugation of gold nanoparticles to doxorubicin not just improves the half-life but also could make them more biocompatible. [2] Another interesting study conducted on mice demonstrated the use of gold nanoparticles conjugated with cancer drug paclitaxel and a diagnostic agent indocyanine green to be exploited for theranostics (simultaneous therapy and diagnosis), a dual functional approach. The pharmacokinetics data revealed the size dependent clearance of the nanoparticles from the blood by higher localisation of the larger nanoparticles in the liver, after intravenous administration of the nanofabricated drug load. [3] 


Figure 2: Applications of gold nanoparticles. Courtesy: Sciencedirect.com

A more recent study to evaluate the safety, pharmacokinetics and bio-distribution of the laser-ablated dextran-coated gold nanoparticles (AuNPds) showed the intravenous administration of AuNPds promptly cleared them from bloodstream and that the AuNPds were localized in liver, kidney and spleen. The histological observation of these tissues indicated no atrophy, necrosis, hyperplasia or inflammation. This was further supported by biochemical and inflammatory marker levels in the plasma, which did not have any significant change as compared to the control. This study gives evidence of the good pharmacokinetics, biocompatibility and non inflammatory nature of the AuNPds prepared using laser ablation.[4] Although this was a non drug conjugated gold nanoparticles study, it does give use some useful insights into the bio-distribution of laser ablated gold nanoparticles and their future use as drug delivery agents.

From afore mentioned studies one could conclude that conjugating the drug molecules with the gold nanoparticles not only stabilizes the drug molecule by improving the half-life of the compounds in bloodstream but also help better the bio-distribution to the target cells with possibly improved biocompatibility. Also, optimising the size and the surface charge of the drug conjugated gold nanoparticles could improve the pharmacokinetics of the drug molecules.

References

1. Arvizo R.R, et al., Modulating Pharmacokinetics, Tumor Uptake and Biodistribution by Engineered Nanoparticles. PLoS ONE 2011, 6 (9). 

2. Du Y, et al., Synthesis and Evaluation of Doxorubicin-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery. Bioconjugate Chemistry 2018, 29 (2).

3. Liu, R., et al.,. Theranostic size-reducible and no donor conjugated gold nanocluster fabricated hyaluronic acid nanoparticle with optimal size for combinational treatment of breast cancer and lung metastasis. Journal of Controlled Release, 2018, 278, (127).

4. Bailly A, et al., In vivo evaluation of safety, biodistribution and pharmacokinetics of laser synthesized gold nanoparticles. Scientific reports 2019, 9 (12890)

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