Clinical Trials Involving Gold Nanoparticles in Drug Delivery

Overview of ongoing clinical trials

Gold nanoparticles have special physicochemical properties that make them

potentially medicinal. Gold nanoconstructs are slowly but progressively
making their way into clinical trials following two decades of preclinical
advancement. While gold nanoformulations were once believed to be "magic
golden bullets" that could be used to treat a wide range of ailments, the
current consensus has shifted toward a more practical approach, wherein
specific conditions are being studied for treatment with gold nanoformulations.
The pharmacokinetics and biodistribution patterns of gold nanoparticles
determine their medicinal uses [1].Because of their localized surface plasmon
resonances—a collective oscillation of their conduction band electrons upon
interaction with particular wavelengths of light—AuNP exhibit distinctive
optoelectronic features [2]. Through colloidal chemistry and engineering,
these optoelectronic characteristics can be optimized.nanocrystal size and
shape [3]. For instance, anisotropic AuNP exhibits large extinction coefficients
in the near-infrared region (Fig. 1B) [4–7], where light demonstrates deeper
tissue penetration. Examples of these nanoparticles are thin gold nanoshells,
high aspect ratio gold nanorods, and gold nanostars.

Fig. 1 Fundamentals of gold nanoparticles. A Schematic representationof

localized surface plasmon resonance (i.e., collective oscillation of the
conduction band electrons of gold nanoparticles, when interacting with an
electromagnetic radiation), and the resulting extinction spectrum. B Gold
nanorods (AuNR), gold nanostars
key studies and their objectives

AuNP has significant potential to improve patient care. Because AuNP often
have simple compositions, it is easier to predict their behavior in vivo and to
scale up their production. When coupled on the surface of AuNP, these
nanoconstructs facilitate polyvalent interactions and improve the effectiveness
of therapeutic biomolecules like TNF. These features, along with the extended
circulation durations following PEG functionalization, result in nanoconstructs
that have enhanced therapeutic benefits and may aid in lowering therapeutic
dosages and mitigating side effects. However, given worries about the body's
long-term buildup of gold, AuNP-based therapy must manifestly outweigh any
possible hazards.Developing multifunctional NP with novel properties is the
goal, not advancing the qualities required in the clinic [8].

Challenges and limitations faced in clinical translation

 However, basic scientific investigations rarely use such basic

nanoconstructs. AuNP translation has also been hindered by their
inadequate excretion in vivo, since a large portion of injected AuNP
tends to concentrate in specific organs, like the spleen and liver [9].
While AuNP might not be hazardous in the short term, there are
worries about long-term negative effects.
 • siRNA has minimal therapeutic benefits due to its quick breakdown in
the bloodstream and poor distribution to and into malignant cells,
necessitating delivery devices.
 An allergic reaction that was treated with antihistamines and a brief
burning sensation in the epigastrium were two other adverse events
linked to the NP treatment.
Promising results and future implications

 Better therapeutic results have resulted from PEGylated TNF-AuNP.

Recombinant human tumour necrosis factor alpha (TNF), a pro-
inflammatory cytokine secreted by leukocytes upon activation, is
functionalized with CYT-6091, a PEGylated-AuNP (Fig. 2A) [10]. Due
to its ability to regulate the immune system and have an anticancer
effect, TNF has been extensively studied in preclinical and clinical
cancer research [11]. However, widespread TNF activation can cause
severe systemic inflammation and toxicity, which may lead to septic
shock and patient mortality since TNF receptors are extensively
expressed on a wide variety of cells in a wide range of tissues. TNF
administration locally may be able to provide the right amount of
therapeutic efficacy without having an adverse systemic effect. Without
any additional reagents, thiol residues can directly conjugate AuNP
with TNF Following PEGylation, TNF-AuNP circulation time increases
dramatically [12], corresponding with a decrease in particle uptake and
clearance by the reticuloendothelial system (Fig. 2B).However, given
worries about the body's long-term buildup of gold, AuNP-based
therapy must manifestly outweigh any possible hazards. Treatments for
fatal illnesses that depend on the usage of gold-based nanoconstructs,
 such as photothermal ablation of tumours and gold nanoshell
atherosclerosis plaques, are examples of this., using gold-based SNA
to penetrate the blood–brain barrier in glioblastoma (therefore
downregulating gene expression). All things considered, gold
nanoconstructs demonstrate encouraging clinical outcomes in
particular niche therapies where the special qualities of AuNP cannot
be duplicated by other formulations, despite not being the "magic
golden bullets" previously believed.

 Thiolated PEG is used to functionalize AuroShell particles, increasing

NP blood circulation durations and encouraging aggregation at tumour
locations. By concentrating the thermal ablation impact just in the
region of the irradiated AuNP, AuroShell NP utilises the high
photothermal conversion efficiency of gold to provide more therapeutic
selectivity [13]. AuroShell-based photoablation of prostate cancer was
evaluated in 16 patients as part of a follow-up clinical investigation that
commenced in 2016 [14]. AuroShell's effectiveness in treating patients
with primary and/or metastatic lung tumours (NCT01679470) and
recurring head and neck tumours (NCT00848042) was assessed in two
pilot studies, in addition to prostate cancer. The investigations ended
and were finished in 2014, respectively, but the findings haven't been
released yet. In addition to treating cancer, atherosclerotic plaques
have been photothermally destroyed and blood flow has been restored
in clinical settings using gold nanoshells. The safety of two NP delivery
techniques and subsequent photoablation therapy were assessed in a
first-in-man experiment utilising gold nanoshells that was started in
2007 and finished in 2016 (NCT01270139; study known as NANOM-
FIM and supported by the Ural State Medical University) [15].
 NU-0129, which is being investigated for the treatment of glioblastoma,
is composed of thiolated PEG and small interfering RNA (siRNA)
organised on the surface of AuNP (Fig. 2C). Compared to free RNA,
RNA in SNA exhibits much greater stability against nuclease
degradation because to the high-density topology of the oligonucleotide
shell [16]. Additionally, it has been reported that the SNA have
polyvalent contacts and can pass through the blood-brain barrier,
allowing siRNA to be delivered to glioblastoma lesions and Bcl2L12 to
be knocked down, which promotes apoptosis and tumour reduction.
Fig. 2 Representative therapeutic gold nanoconstructs in clinical trials. A
Schematic representation of CYT-6091. B Comparison of ex vivo organ
accumulation of non-PEGylated (TNF-AuNP) and PEGylated CYT-6091.
Adapted with permission of ref 22. Copyright 2012 CytImmune . C Schematic
representation of NU-0129
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