Bridging the gap between lab and clinic for nanodiagnostics

NanomedicineAhead of Print EditorialOpen AccessBridging the gap between lab and clinic for nanodiagnosticsRoger M Pallares, Fabian Kiessling & Twan LammersRoger M Pallares *Author for correspondence: E-mail Address: rmoltopallar@ukaachen.dehttps://orcid.org/0000-0001-7423-8706Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, 52074, GermanySearch for more papers by this author, Fabian Kiessling https://orcid.org/0000-0002-7341-0399Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, 52074, GermanySearch for more papers by this author & Twan Lammers https://orcid.org/0000-0002-1090-6805Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen, 52074, GermanySearch for more papers by this authorPublished Online:28 Mar 2023https://doi.org/10.2217/nnm-2023-0067AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInReddit Keywords: clinical trialsdiagnosticsimaging nanoparticlesmedical imagingnanoparticlesNanodiagnostics have been used in clinical diagnosis for over 60 years [1]. The nanoparticles tend to be either intrinsically (optically or magnetically) active or labeled with radioisotopes or dyes. For example, sulfur colloids radiolabeled with 99mTc started to be used in the mid-1960s for planar scintigraphy and later for single-photon emission computed tomography (SPECT) imaging [2], while spherical gold nanoparticles were initially used in colorimetric assays, such as pregnancy tests [3].Both nanoparticle types are still clinically relevant: 99mTc sulfur and albumin colloids continue to be used to image lymphatic flow and identify sentinel lymph nodes in multiple tumor types, and gold and silver nanoparticles are commonly used in rapid antigen tests for influenza and COVID-19. The latter rely on their plasmonic properties, which provide strong extinction coefficients and permit naked-eye assessment with detection limits in the ng/ml range [4]. Moreover, their strong electromagnetic fields near the nanoparticle surface can enhance the spectroscopic signatures of nearby molecules; for example, in surface-enhanced Raman spectroscopy, which results in high sensitivity, rapid analysis speed and low water interference [5]. Nevertheless, even with recent translational progress, such as identification of surgical tumor margins with surface-enhanced Raman spectroscopy nanotags [6], this sensing modality is uncommon in routine clinical practice and significant challenges still exist for widespread use, including measurement variability and non-optimal reproducibility.Regarding imaging nanodiagnostics, despite strong research efforts carried out in the last 30–40 years, only a few nanoprobes have moved to clinical settings. This lack of translational success is due to multiple factors. First, many nanodiagnostics display inadequate pharmacokinetics for clinical imaging. The level of contrast enhancement needed for disease differentiation should ideally be achieved fast (within minutes to a few hours) after contrast agent administration, which is not in line with nanoparticles’ slow compartment exchange (except in specific organs, such as the liver or spleen).Second, imaging agents are not meant to cause any toxicological effects as they are potentially administered to healthy patients, and they should therefore be biodegraded and/or eliminated from the body as rapidly and as completely as possible. However, nanoparticles tend to accumulate in highly perfused tissues with large phagocytic capacity, including (besides tumors and sites of inflammation) the liver, spleen, lungs and lymph nodes, remaining in these organs for relatively long periods of time [7].Third, an important reason explaining the low numbers of nanoparticles used for imaging in the clinic is that most nanodiagnostic designs are too complex. The vast majority of nanoparticle research is materials science-driven and focuses on developing multifunctional nanoformulations with exotic properties. Nevertheless, those are not the main characteristics needed in the clinic and integrated in successful products. Nanoparticles that are used in clinical settings tend to be simple and made of only a few components [8], as their scaled-up production is less challenging and their in vivo behavior (including side effects) easier to predict. However, simple nanodiagnostics are uncommon in basic research, as they are frequently perceived to be of low scientific value, and studies focused on those nanoparticles are less likely to be published in multidisciplinary journals with high impact factors.Fourth, although many preclinical nanodiagnostics possess scientific merits, they often lack key features necessary for clinical translation. Those include parameters that are usually beyond the scope of basic science, such as the need for a big potential market size to compensate for the high development costs. Other features are frequently overlooked because of the lack of communication between basic scientists and physicians. For instance, nanodiagnostics need to tackle real clinical needs (e.g., providing a conclusive diagnosis), be competitive with current clinical standards, have no alternative means for obtaining diagnostic information, and really impact clinical decision-making, contributing to potential improvements in therapeutic outcomes. Despite not being a nanoparticle-based diagnostic, Locametz® is a good example of a recently US FDA-approved imaging agent that displays all those characteristics [9]. It is a 68Ga-labeled peptide that targets PSMA, a protein that is overexpressed in many cancer cells. Locametz is used to identify metastatic castration-resistant prostate cancer patients whose tumors express PSMA before they receive targeted radiotherapy (clinical need). It provides diagnostic information that is hardly achievable by other means, as the gold standard technique is biopsy, which would require sampling every metastatic site. Finally, Locametz impacts therapeutic decision-making, because only patients with PSMA-positive lesions are selected to be treated with Pluvicto™ (a radiopharmaceutical made of the same targeting peptide as Locametz and 177Lu) [9].Considering all of the above, it is important to learn from the nanodiagnostics that have already moved to the clinic, and identify the characteristics that facilitated their translation. The initial paradigm that multifunctional nanoparticles can be universally used to detect a wide range of diseases has shifted toward a more realistic approach, in which nanodiagnostics can be useful for the detection of very specific diseases. These diagnosable disorders are determined by the pharmacokinetics and biodistribution of nanoparticles. For example, their tendency to be picked up by the lymphatic system and accumulate in lymph nodes is routinely exploited for the mapping of sentinel lymph nodes with 99mTc colloids. Superparamagnetic iron oxide nanoparticles (SPIONs), fluorescent silica dots (also known as Cornell dots) and lipidic microbubbles have been clinically explored as alternative probes for sentinel lymph node mapping [10–12], as they can provide similar diagnostic performance to 99mTc colloids, while not relying on radioisotopes.The potential use of nanoparticles as imaging probes also depends on the lack of alternative small-molecule contrast agents for the specific pathology. For example, SPIONs were initially approved by the FDA in 1996 [2]. The magnetic moment of SPIONs affects the transverse relaxation time (T2) of nearby water protons, decreasing (darkening) their signal intensity in T2- and T2*-weighted MRI. Because around 80% of intravenously administered SPIONs are cleared via Kupffer cells in the liver, SPIONs were primarily used to identify liver lesions, such as carcinomas and dysplastic nodules, as those usually display lower phagocytic capacity [13]. However, most SPION formulations for liver imaging have been discontinued in favor of a gadolinium-based alternative, Primovist®/Eovist®. The reasons for this are improved end-user (clinician) acceptance, better pharmacokinetics and excretion profiles, as well as positive signal generation in T1-weighted MRI by gadolinium chelates [13]. Consequently, the current use of SPIONs in clinical diagnosis is restricted to specific niche applications, such as sentinel lymph node mapping with magnetometers, such as Sentimag® (approved by both FDA and EMA), and tumor-associated macrophage imaging (in clinical studies). The latter takes advantage of the large phagocytic capacity of macrophages, which allows for in situ imaging of tissue-resident macrophages at pathological sites [14].Many preclinical nanoparticles are developed to be stimuli-responsive, meaning that they modulate their imaging characteristics depending on specific environmental conditions, such as pH or temperature. These nanoformulations, however, are rarely (if ever) translated into clinical studies because of the reasons explained above, particularly nanoconstruct complexity. An exception worth mentioning in this regard is ONM-100, a micellar formulation that contains pH-sensitive polymers conjugated to fluorescent indocyanine green. In the acidic tumor microenvironment, ONM-100 irreversibly disassociates, releasing the dye, which fluoresces as a result. Unlike many preclinical formulations, ONM-100 is relatively simple, as it is made of one dye (indocyanine green) and two polymers, namely PEG and poly(methyl methacrylate), all three of which are already routinely used in clinical practice. In a recent clinical study, ONM-100 was used for intraoperative imaging of four different solid tumor types and allowed the detection of cancer-positive resection margins [15].Beyond their use in diagnostics, imageable nanoparticles are starting to be explored for patient stratification in cancer nanomedicine. To facilitate clinical translation, patients are routinely stratified in oncological trials based on different pathological biomarkers. For example, only patients with high expression levels of HER2 were included in the pivotal clinical trials that resulted in the approval of trastuzumab and pertuzumab, as those are the patients most likely to benefit from antibody-based therapy [16]. Remarkably, stratification strategies are uncommon in clinical trials exploring the use of nanomedicines, despite the notion that the therapeutic benefits of nanoformulations strongly depend on their tumor accumulation, which is highly variable between and within patients [16]. Lack of patient stratification and poor study design are believed to have caused several nanomedicine failures in clinical trials [17]. Taking the above into consideration, several studies have started to incorporate either companion nanodiagnostics or nanotheranostics to characterize tumor accumulation of nanomedicines. For instance, SPIONs have been used to characterize uptake and accumulation of nanoparticles in advanced solid tumors via MRI before treatment with liposomal irinotecan [18]. Interestingly, the patients who showed larger tumor accumulation of SPIONs were the ones who experienced greater lesion reductions after treatment with liposomal irinotecan. A follow-up study reported 74% accuracy of response prediction to liposomal irinotecan treatment in patients with metastatic breast cancer by using SPIONs as (pretreatment) nanodiagnostics [19]. These studies demonstrated the advantages of using companion nanodiagnostics to anticipate the therapeutic outcome of nanomedicines. It is worth highlighting that this strategy requires that both nanodiagnostic and nanotherapeutic display similar in vivo behaviors.An alternative to using companion nanodiagnostics is coloading nanoformulations with both therapeutic and diagnostic agents (nanotheranostics). Hence, nanomedicines can be administered at low doses, which ideally cause no physiological effects, and only if high tumor accumulation is observed is the treatment at high nanomedicine dose initiated. A representative example of nanotheranostics used in the clinic is 64Cu-labeled MM-302, a HER2-targeted PEGylated liposomal formulation containing doxorubicin, used in metastatic breast cancer patients. As expected, a retrospective analysis of patients identified a good correlation between tumor accumulation of 64Cu-MM-302 and therapeutic benefit [20]. Similarly, administration of low (diagnostic) doses of 89Zr-radiolabeled CPC634, a docetaxel-containing polymeric micelle used to treat solid tumors, accurately reflected the nanomedicine on-treatment (high dose) tumor accumulation [21]. Another nanotheranostic agent worth describing is AGulX, a 5-nm polysiloxane nanoparticle containing gadolinium chelates that is being used for whole-brain radiotherapy [22]. In addition to their radiosensitizer capabilities, the gadolinium ions inside the nanoformulation also allow for patient stratification and imaging-guided radiotherapy application.In summary, nanodiagnostics are slowly but steadily becoming available for clinical practice, despite the mismatch that often exists between clinical needs and basic research. Nanoparticle-based assays have been much easier to translate because their technology is in many cases well established, and the analyses are performed ex vivo, thus avoiding concerns regarding nanoparticle toxicity and long-term accumulation in the body. On the other hand, the translation of imageable nanodiagnostics has been significantly more challenging. The old paradigm of a single nanoformulation that can be used to detect a wide range of pathologies is not realistically achievable, because the pharmacokinetics and biodistribution of nanoparticles are only suitable for a few very specific applications, such as liver imaging, sentinel lymph node mapping or phagocytic cell imaging. Interestingly, companion nanodiagnostics or nanotheranostics – and using the imaging information that these formulations can provide regarding target site accumulation, biodistribution and retention – are an important feature avenue toward patient stratification and nanomedicine treatment optimization.Altogether, despite not being the ‘universal diagnostic tools’ initially aimed for, nanodiagnostic agents are slowly but steadily becoming relevant in clinical imaging and decision-making. The nanoparticle formulations that have been able to bridge the gap between lab and clinic provide solutions to specific clinical needs, are competitive enough to clinical standards and provide information that changes decision making.Financial & competing interests disclosureThis work is funded by the Federal Ministry of Education and Research (BMBF), by the Ministry of Culture and Science of the German State of North Rhine-Westphalia under the Excellence Strategy of the Federal Government and the Länder through the RWTH Junior Principal Investigator (JPI) fellowship scheme, by the European Research Council (ERC; 864121), and by the German Research Foundation (DFG; GRK2375 [331065168], FOR5011 and SFB1066).The authors have no 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.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. 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Adv. 6(29), eaay5279 (2020).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Ahead of Print Follow us on social media for the latest updates Metrics History Received 10 March 2023 Accepted 14 March 2023 Published online 28 March 2023 Information© 2023 Roger Molto PallaresKeywordsclinical trialsdiagnosticsimaging nanoparticlesmedical imagingnanoparticlesFinancial & competing interests disclosureThis work is funded by the Federal Ministry of Education and Research (BMBF), by the Ministry of Culture and Science of the German State of North Rhine-Westphalia under the Excellence Strategy of the Federal Government and the Länder through the RWTH Junior Principal Investigator (JPI) fellowship scheme, by the European Research Council (ERC; 864121), and by the German Research Foundation (DFG; GRK2375 [331065168], FOR5011 and SFB1066).The authors have no 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.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. 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