Clinical translation of quantum dots

Quantum dots (QDs) are semiconductor nanocrystals with unique optical and electronic properties that depend on the nanoparticle morphology [1]. When the nanocrystal size is in the same range or smaller than the exciton Bohr radius (usually under 10 nm), the electron-hole pairs of the semiconductor get spatially confined within the material [2]. In practice, as the QD size decreases, the quantum confinement of the excitons increases, yielding larger band gaps and blue-shifted absorption and emission bands. As a result of these tunable properties, QDs are being used in multiple fields and applications, including commercialized electronic products, such as QD-based displays in televisions and portable electronics [3].

Although the field of QDs is over 40 years old, and pioneer work by Professors Ekimov, Bawendi, and Brus was recently recognized with the 2023 Nobel Prize in Chemistry, there are still a lot of ongoing efforts in improving the synthesis (either through top-down or bottom-up approaches [4]) and performance and expanding the applications of these nanocrystals. For instance, while traditional QDs were primarily made of II-VI (e.g. CdS, CdSe, CdTe, and ZnS), III-V (e.g. InP, GaP, and InAs) and IV-VI (e.g. PbS, PbSe, and SnS) compounds, in the last decade, improvements in colloidal chemistry have yielded new QD designs based on perovskites, carbon, and dichalcogenides (for a more extensive description of these new QDs, we refer to [5,6]), which have found applications in lasing, solar energy harvesting, and diagnostics [7].

Considering their unique optical features, QDs were proposed early on as potential imaging and biosensing probes [8]. To a certain extent, this was sensible, since QDs possess certain competitive advantages over synthetic and biological fluorophores [9]. For instance, QDs tend to display higher quantum yields (>15%) and resist photobleaching. Furthermore, QDs have broad excitation bands and narrow emission peaks, which can be shifted by controlling the nanocrystal size, endowing multiplexing applications. Moreover, several QDs have been developed that emit in the first (700–900 nm) and second (1000–1800 nm) near-infrared (NIR) biological window [10], where light penetrates deeper into tissue and autofluorescence is lower.

Despite these strengths, as preclinical studies started to be published, essential limitations that challenged the use of QDs as universal nanodiagnostics were recognized. First, QDs display inadequate pharmacokinetics and biodistribution profiles for clinical imaging [11]. Contrast agents and probes are expected to provide enough signal to discriminate the pathological conditions within minutes (to a few hours) after administration. However, colloidal particles display slow compartment exchange except with organs in the reticuloendothelial and mononuclear phagocytic systems [12,13].

Second, imaging agents should be excreted or degraded quickly without causing any toxicity, since they are also administered to healthy individuals. Nevertheless, QDs display significantly longer blood circulation times than small contrast agents (i.e. circulation half-lives of small molecule agents and QDs are in the minute and hour range, respectively) [14]. Moreover, QDs also show long-term accumulations in phagocyte-rich and highly perfused tissues, such as the liver, spleen, lymph nodes, kidneys, and lungs [15], rising toxicological concerns and compromising (potential) follow-up imaging. Although their biodistribution and pharmacokinetics can be improved by decreasing their size below the renal clearance cut-off, they are still worse than those shown by small-molecule contrast agents. In addition, there are serious concerns regarding the long-term toxicity of QDs [16], which partially originate from the heavy metals commonly used in many nanocrystals, and the generation of reactive oxygen species under light irradiation [17]. Hence, despite all the extensive preclinical work carried out in imaging (e.g. intracellular imaging and vascular imaging) and therapy (e.g. drug delivery and photodynamic therapy), only those applications that do not require the intravenous administration of the QDs may have clinical potential.

It is worth noting that beyond the inherent characteristics of the new agents, such as imaging performance, pharmacokinetics, biodistribution, and toxicity, other parameters also determine their translational potential, which are oftentimes overlooked in basic research. The new probes or contrast agents should address a real clinical need, be competitive with clinical gold standards, have a (potential) big market, impact decision-making, and improve therapeutic outcomes [18]. Considering all the above, QDs are not going to be universal imaging probes as initially hoped; however, they can provide value in niche applications where they can fulfill all the above requirements. For instance, in the healthcare market, QDs have found some success in liquid biopsy analysis and intraoperative imaging [19]. Nanoco commercializes NIR-emitting QDs (under the commercial name Heatwave) for the non-invasive quantification of clinically relevant biomolecules in blood samples via image sensors. Because blood contains many natural chromophores, the emissions of Heatwave QDs are centered in the first and second NIR biological window (from 900 to 1800 nm), minimizing matrix interferences. This application benefits from QDs high quantum yields and tunable emissions, as well as their narrow emission bands (compared with organic dyes), which endow multiplex analyte detection within the NIR biological windows. Vivodots are another commercial product by Nanoco, relying on QDs functionalized with antibodies to identify tumor margins in excised tissue during image-guided surgeries. Moreover, Vivodots are being explored to map overexpressed cancer biomarkers in suspected skin or mucosal lesions for early diagnosis. Beyond conventional diagnosis, QDs are also found in commercial products aimed at assisting patients with impaired vision. Visirium are QD-containing glasses developed by QD Laser, which project images onto the retina, improving the visual acuity of partially blind patients due to pathological conditions in the anterior part of the eye, including cornea and lens.

Consistent with their limited commercial landscape in healthcare, QDs are only explored in four clinical trials. For instance, in a phase I trial (NCT04138342) initiated in 2019 at the Al-Azhar University (Egypt), CdS/ZnS core-shell quantum dots functionalized with veldoreotide are being explored for the imaging and (potential) treatment of superficial breast cancers via topical administration. Veldoreotide is a somatostatin analog with a high binding affinity for somatostatin receptors 2, 4, and 5 (overexpressed in various cancers) and tumor growth inhibition activities [20]. On the surface of the QDs, veldoreotide is expected to act as a targeting agent and therapeutic agent, inducing antiproliferation activity and apoptosis by interacting with 5 G proteins coupled with somatostatin receptors. In another prospective randomized clinical study (NCT04390490) at the Xinhua Hospital (China), the precision, sensitivity, and effectiveness of a photoelectrochemical immunosensor based on graphene QDs and silica nanowires are being evaluated for the early diagnosis of acute myocardial infarction. The immunosensor quantifies the blood levels of cardiac troponin I, the gold standard biomarker for detecting acute myocardial infarction, since it is only produced in the myocardium and is highly specific to cardiac injury [21]. Because acute myocardial infarction may not induce substantial changes in electrocardiograms, the detection of cardiac troponin I is usually required for an accurate diagnosis [22]. Cardiac troponin I is quantified in the control group with an automatic chemiluminescence analyzer. In the other two studies (NCT03895437 and NCT04590872), QDs are being used as probes in immunologic assays to monitor the performance of two immunotherapeutics aimed at controlling type-1 diabetes, namely TOL-3021 and PIpepToIDC, by detecting autoantigen tolerance and CD8⁺ autoreactive cells, respectively.

In conclusion, although QDs have reached the healthcare market in the form of commercial products and a few formulations have even moved to clinical trials, these are very weak results considering the myriad of preclinical studies that every year are published on their biomedical uses. QD-based assays and ex vivo applications are (have been) much easier to translate as they avoid toxicity concerns. In the case of QDs being employed as imaging probes, these face significant challenges. Beyond transient issues, such as production, scalability, and regulatory hurdles, which could be overcome over time, QDs are unlikely to be translated as imaging probes since they present inadequate pharmacokinetics and biodistribution profiles, as well as long-term accumulations. Furthermore, alternative nanodiagnostics with better-perceived safety already exist for many proposed in vivo applications. Altogether, QDs cannot be the universal imaging probes initially hoped for; however, they can provide value in specific niche applications, such as NIR liquid biopsy analysis or ex vivo intraoperative imaging, as they tackle a real clinical need, (potentially) surpass the performance of clinical gold standards, and provide information that directs decision making.

Funding Statement

This work was funded by the Federal Ministry of Education and Research (BMBF) and the Ministry of Culture and Science of the German State of North Rhine Westphalia (MKW) under the Excellence Strategy of the Federal Government and the Länder through the Junior Principal Investigator (JPI) fellowship, by the European Research Council (ERC CoG 864121, Meta-Targeting), and the German Research Foundation (DFG: GRK 2375 (grant #331065168) and SFB 1066).

Financial disclosure

This work was funded by the Federal Ministry of Education and Research (BMBF) and the Ministry of Culture and Science of the German State of North Rhine Westphalia (MKW) under the Excellence Strategy of the Federal Government and the Länder through the Junior Principal Investigator (JPI) fellowship, by the European Research Council (ERC CoG 864121, Meta-Targeting), and the German Research Foundation (DFG: GRK 2375 (grant #331065168) and SFB 1066). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.