Review articleEngineered non-invasive functionalized dendrimer/dendron-entrapped/complexed gold nanoparticles as a novel class of theranostic (radio)pharmaceuticals in cancer therapy
Introduction
In medicine, nanomedicine which is an interdisciplinary field of science have sparked an extraordinary growing interest to achieve medical benefit. Also, nanotechnology in nanomedicine can overcome biological obstacles to treat severe diseases like complex cancers, which are presently difficult to cure completely. The most widespread cancers are breast, colorectal, lung, prostate as well stomach and liver cancer. [1] Importantly, over the last decade, remarkable steps forward have been made in advancing cancer diagnosis and treatment with a move toward increased sensitivity, speed, and cost-effectiveness. [2] Nanomedicine has made a very significant contribution to current cancer treatments, in addition to surgical intervention; importantly, radiation and chemotherapeutic agents unfortunately also kill normal cells by inducing highly deleterious and often life-threatening side effects in the patient. [3] Consequently, to overcome these problems, within the nanomedicine domain, the development of highly efficient platforms for cancer therapy based on engineered nanoparticles (NPs) for drug delivery has been investigated as so-called “magic bullets”. [4] Indeed, in order to decrease the side effects of highly toxic anti-cancer drugs, the development of drug delivery systems for cancer chemotherapy have been employed.
Liposomes, micelles, polymeric nanoparticles, nanocrystals, solid lipid nanoparticles, nanocages, metal nanoparticles (e.g. gold, iron), nanocrystals, graphene oxide, carbon nanotubes, and dendrimers have been used extensively as nanocarriers, and several of them have been approved for clinical use. [5] The two NPs in clinic are the first FDA approved (1995) PEGylated liposome injections Doxil® and Caelyx® (doxorubicin (DOX) HCl (Adriamycin®)), and paclitaxel albumin-bound particles called Abraxane™. [6]
Dendrimers are different in comparison to conventional polymers, and represent a unique class of macromolecules offering well-defined 3D nanoarchitectures. The spherical shape, the surface functionalities and size of which can be precisely controlled affording high degree of molecular uniformity. Size and surface characteristics are the most important features to be managed to develop safe and biocompatible dendrimers. Presently, a large variety of dendrimers have emerged as non-viral versatile nanocarriers. These radially symmetric monodisperse macromolecules are described as highly branched, star-shaped with nanometer size. Three major macromolecular architectural components can characterize dendrimers: a central core, interior dendritic structure including branches, and a peripheral surface with diverse functional groups. The drugs of interest can be entrapped by encapsulation within the cavities of dendrimers, or covalently conjugated with a cleavable linker sensitive to, for instance, acidic pH. [7] Dendrimers have been widely used to deliver anticancer drug by passive and active targeting strategies. Dendrimers represent ideal vectors for drugs for therapeutic purposes or imaging molecules for diagnostic use. Based on the different attributes of dendrimers including pharmacokinetic, pharmacodynamic and toxicological properties, the concept of dendrimer space has been presented and developed. [8] The main advantages of dendrimers are as follows: 1) strong functionalization of surface, 2) hydrophobic and hydrophilic drugs can be encapsulated, conjugated or complexed, 3) facile control of the synthesis as well degradation process, 4) high penetration into the cell membranes, 5) high structural homogenicity, 6) high water solubility with adequate surface functionalization, 7) meaningfully lower viscosity versus linear polymer, 8) higher ligand density on the surface than linear polymers, 9) multiple routes of administration: intravenous (iv), intraperitoneal (ip), ocular, transdermal, oral (po), intranasal, and pulmonary) [9] versus micelles and liposomes for which only the iv route is possible, 10) controlled biodistribution, 11) high drug loading capacity (local concentration effect), 12) enhanced permeability and retention (EPR) effect for the accumulation in tumor tissues, [10,11] whereas the main disadvantages are 1) few examples in clinic due to translational issues including good manufacturing practices (GMP) production and quality control. This aspect is general for any nanoparticles in medicine [12], 2) high cost of production, and 3) challenged EPR effect: ‘the EPR effect works in rodents but not in humans’. [13] All these advantages have contributed to the development of dendrimers in nanomedicine.
The historical applications of gold in art and ancient medicine dates back to the dawn of time. Naturally, the body does not have gold nanoparticles, but several formulations in biomedicine with gold molecule are generally non-toxic and non-immunogenic, and consequently suitable for in vivo studies [14,15]. Importantly, the tailored chemical (e.g. facile surface chemistry), and physical (e.g. comparable size relative to proteins) properties of gold nanoparticles allow their accumulation, for instance in tumor tissues and cells, and they can be detected and quantified with high sensitivity [16,17]. Importantly, based on the ability of gold nanoparticles to intensively absorb X-ray radiation, they can be used as in cancer radiation therapy, as well as imaging contrast agents in diagnostic CT (computed tomography) scans [18].
Over the past decades, nanotheranostic nanoparticles (TNPs) that simultaneously transmit diagnostic information and monitor the therapy process in situ have been developped mainly in nano-oncology realm. [19] These TNPs dispose of unique physical and chemical properties to target desired cells and tissues producing therapeutic and imaging action against the disease. [20] Multiple imaging approaches were used such as optical imaging, ultrasound (US), magnetic resonance imaging (MRI), computed tomography (CT), single-photon computed tomography (SPECT) and positron emission tomography (PET). [21] Importantly, NPTs are able to increase the accumulation and delivery of encapsulated or conjugated biologically active compounds in tumors, which enhances therapeutic efficacy and reduces side effects on healthy tissue. [22] An interesting analysis to develop ideal TNPs was advocated by Chen et al. [23] The Table 1 shows few selected TNPS in oncology therapeutic domain, and consequently does not present exhaustive list of TNPS. To extend a panoramic view about the development of TNPS in the oncology field, itltt is important to note, that for example, mesoporous silica nanoparticles (MSN) in the theranostic strategy were developped with several imaging technique including photoacustical (near infrared radiation, NIR) [24], ultrasound [25], magnetic resonance (Table 1), optical (e.g. NIR, visible light) [26], and radionucleotide-based (NIR). [27] In vitro and in vivo advances in theranostic nanocarriers of doxorubicin based on iron oxide and gold nanoparticles were highlighted by Gautier et al. including hybrid and metallic nanocarriers. [28] Recently, hybrid mesoporous silica and hydroxyapatite nanoparticles nanocarriers for theranostic applications were described. [29,30] Table 2 depicts selected therapeutic applications of theranostic principle with dendrimers in oncoly except gold NPs which is the aim of this review. [31]
Several examples of the design of targeted dendrimers and dendrons for theranostic applications in oncology were highlighted, and selected examples were depicted in Table 2. In brief, using dendrimers or dendrons as stabilizers or templates, on one hand, the size of the in-situ formed Au NPs can be readily controlled by dendrimers/dendrons through a reducing reaction; on the other hand, with the combination of dendrimers/dendrons and Au NPs, both properties of dendrimers/dendrons and Au NPs can be rendered. Hence, there are many opportunities that can be explored for theranostic applications in cancer therapy based on the dendrimer/dendron-complexed Au NPs. [51] These are the biggest advantages of dendrimer/dendron-complexed Au NPs. The only disadvantage of the combination could be the high cost of commercially available such as PAMAM dendrimers, limiting their uses in some developing countries.
In spite of the large amount of research carried out over decades, few dendrimers have crossed the milestone of entering the clinic. In the dendrimer field, the pharmaceutical company Starpharma Holdings Ltd. (Melbourne, Australia) succeeded in introducing dendrimers, as first-in-class NPs, in the market under the brand name Vivagel™ (SPL7013). This dendrimer have 32 sodium 1-(carboxymethoxy)naphthalene-3,6-disulfonate groups on its surface. Phase II double-blind trials demonstrated retention and duration of activity against HIV and HSV-2, as well as prevention of bacterial vaginosis. VivaGel™ demonstrated statistically significant efficacy in pivotal Phase III trials to treat bacterial vaginosis. [70,71] Another interesting dendrimer Givosiran (Givlaari™) for the treatment of adults with acute hepatic porphyria, was developed by Alnylam. Givosiran bears a double-stranded siRNA containing 16 2’-F-ribonucleosides units and six thiophosphate linkages. [72]
This review will describe the recent developments in the design, synthesis, functionalization, in biomedicine of engineered functionalized dendrimer-entrapped gold(0) and dendrimer-complexed gold(III) nanoparticles in cancer therapy. The therapeutic applications of dendrimer-stabilized AuNPs and AuNP-cored dendrimers are not within the scope of this review.
Section snippets
Dendrimers encapsulating gold(0) nanoparticles (Au DENPs): general principles
The molecular luminescent AuNPs are chemically inert NPs with a size from 0.3 to 2 nm, and generally showed high X-ray attenuation intensity, higher than the CT contrast media Omnipaque [73].
With the use of non-invasive theranostic functional nanoprobes [74], the major objective of specialized nuclear medicine is to 1) characterize and quantify biological processes involved, for instance, in the diagnosis of early cancer, 2) to stimulate specific drug delivery to tackle cancer, and 3) to track
Dendrimer/dendron-complexed gold(III) nanoparticles: technologies to take down cancer cells
Majoral and Mignani were pioneers in the development of dendrimer-complexed gold(III) nanoparticles to take down tumor cells. Biocompatible phosphorus dendrimers were selected as templates. In the cancer chemotherapy field, cisplatin, oxaliplatin, carboplatin, and Pt(IV) complexes as prodrugs are usually used, but with main drawbacks encompassing resistance and severe toxicity. In addition, other metal complexes to tackle tumors have been developed including, Ru(II/III)-, Au(I/III)-, Ga(III)-,
Conclusion and future directions
There are many types of cancer treatments, and nanomedicine is part of this strategy. [134] One of the main challenges in nanomedicine is to increase delivery efficiency to the tumor, which is typically less than 1%. [135] Within the nanotechnology domain, a theranostic strategy has been developed to treat cancers. Promising theranostic agents/tools include metal nanoparticles, such as iron, gold, silver, zinc, and titanium, as these play crucial dual roles as 1) diagnostic and 2) active
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgements
X. Shi, S. Mignani and J-P. Majoral thank the PRC NSFC-CNRS 2019 (21911530230 for X.S. and 199675 for S.M. and J-P.M). J. Rodrigues, H. Tomas S. Mignani and X. Shi acknowledge the support of FCT-Fundação para a Ciência e a Tecnologia (Base Fund UIDB/00674/2020 and Programmatic Fund UIDP/00674/2020, Portuguese Government Funds) and ARDITI-Agência Regional para o Desenvolvimento da Investigação Tecnologia e Inovação through the project M1420-01-0145-FEDER-000005-CQM+ (Madeira 14-20 Program). S.
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