Effects of Surface Protein Adsorption on the Distribution and Retention of Intratumorally Administered Gold Nanoparticles

Abstract

The heterogeneous distribution of delivery or treatment modalities within the tumor mass is a crucial limiting factor for a vast range of theranostic applications. Understanding the interactions between a nanomaterial and the tumor microenvironment will help to overcome challenges associated with tumor heterogeneity, as well as the clinical translation of nanotheranostic materials. This study aims to evaluate the influence of protein surface adsorption on gold nanoparticle (GNP) biodistribution using high-resolution computed tomography (CT) preclinical imaging in C57BL/6 mice harboring Lewis lung carcinoma (LLC) tumors. LLC provides a valuable model for study due to its highly heterogenous nature, which makes drug delivery to the tumor challenging. By controlling the adsorption of proteins on the GNP surface, we hypothesize that we can influence the intratumoral distribution pattern and particle retention. We performed an in vitro study to evaluate the uptake of GNPs by LLC cells and an in vivo study to assess and quantify the GNP biodistribution by injecting concentrated GNPs citrate-stabilized or passivated with bovine serum albumin (BSA) intratumorally into LLC solid tumors. Quantitative CT and inductively coupled plasma optical emission spectrometry (ICP-OES) results both confirm the presence of particles in the tumor 9 days post-injection (n = 8 mice/group). A significant difference is highlighted between citrate-GNP and BSA-GNP groups (** p < 0.005, Tukey’s multiple comparisons test), confirming that the protein corona of GNPs modifies intratumoral distribution and retention of the particles. In conclusion, our investigations show that the surface passivation of GNPs influences the mechanism of cellular uptake and intratumoral distribution in vivo, highlighting the spatial heterogeneity of the solid tumor.

Hyaluronate-Thiol Passivation Enhances Gold Nanoparticle Peritumoral Distribution When Administered Intratumorally in Lung Cancer

“…In previous studies, we demonstrate that GNP cellular uptake [20,21], as well as intratumoral distribution and retention [22,23], is strongly influenced by surface chemistry. We have shown that when GNPs are surface passivated with a bovine serum albumin (BSA) protein layer, internalization of the particles into cancer cells occurs through larger vesicle formation with reduced gold content per cell, and when injected intratumorally in a murine lung cancer model, the BSA passivated particles diffuse more overtime throughout the tumor tissue [22]. BSA modification shields the metal core and prevents unwanted non-specific adsorption of other agents onto the particles.…”

“…Evaluating the tumoral distribution of a drug or particle-drug conjugate is an important variable that is often neglected, as most drugs are assumed to distribute homogeneously into a tumor [19]. In previous studies, we demonstrate that GNP cellular uptake [20,21], as well as intratumoral distribution and retention [22,23], is strongly influenced by surface chemistry. We have shown that when GNPs are surface passivated with a bovine serum albumin (BSA) protein layer, internalization of the particles into cancer cells occurs through larger vesicle formation with reduced gold content per cell, and when injected intratumorally in a murine lung cancer model, the BSA passivated particles diffuse more overtime throughout the tumor tissue [22].…”

“…After synthesis, the GNPs have a native acidic pH due to their stabilization with citric acid (pH = 3.6). We previously demonstrated that in this condition, the particles lose their stability when immersed in biological media [22]. To increase particle stability, the pH of the solution was adjusted to 6.0 through dropwise addition of a 1 M NaOH solution.…”

Improvements in Gold Nanorod Biocompatibility with Sodium Dodecyl Sulfate Stabilization

“…To date, iodine is the most commonly used CT contrast agent to enhance contrast resolution in the body, but it results in short blood circulation time and rapid clearance from the kidneys [28]. Several studies demonstrated that gold nanoparticles have prolonged circulation times dependent on their surface chemistry, such that the particles can achieve a CT outcome with good efficiency with retention times in the body longer than other standard contrast agents [29][30][31]. Additionally, gold nanoparticles of different sizes are able to enhance the effects of radiation [32].…”

Improvements in Gold Nanorod Biocompatibility with Sodium Dodecyl Sulfate Stabilization

“…To date, iodine is the most commonly used CT contrast agent to enhance contrast resolution in the body tissues, but it results in short blood circulation time and rapid clearance from the kidneys [28]. Several studies demonstrated that gold nanoparticles have prolonged circulation times dependent on their surface chemistry, such that the particles can achieve a CT outcome with good efficiency with retention times in the body longer than other standard contrast agents [29][30][31]. Additionally, gold nanoparticles of different sizes are able to enhance the effects of radiation.…”