Objectives

Camelid nanobodies (single-domain antibodies) are emerging as a promising tool in nuclear medicine for both molecular imaging and theranostics.
Nanobodies have a low molecular mass (12-15 kDa), allowing for deep tumor penetration and rapid renal clearance.
They can be labeled with various emitters (gamma, beta, alpha) for imaging and therapy, targeting specific cell-surface biomarkers.
Nanobodies can also cross the blood-brain barrier (BBB), offering potential for diagnosing and treating diseases like Alzheimer's disease (AD).
Nanobodies show promise in combating infectious diseases and imaging inflammation.

Methodology

Nanobodies are selected from phage, bacterial, or yeast display libraries generated from immunized Camelids.
Radiolabeling with gamma, beta, or alpha emitters is used for molecular imaging and theranostics.
Preclinical studies have utilized Tc-99m, and clinical studies have used Tc-99m and Ga-68 labeled nanobodies.
Astatine-211 labeled nanobodies have been used in preclinical studies for radionuclide therapy.
Two-photon microscopy has been used to demonstrate nanobody extravasation across the BBB.

Preclinical studies with anti-HER2 nanobodies in breast cancer (Vaneycken et al., 2011).
Clinical data on Tc-99m labeled HER2 nanobodies in diverse cancer types (Altunay et al., 2023).
Clinical data on Ga-68 HER2 in breast cancer (Gondry et al., 2024).
Preclinical studies using Tc-99m NM-01 showed uptake in PD-L1 bearing cancer cell-lines (Wong et al., 2021).
Preclinical studies using anti-HER2 nanobodies labeled with Astatine-211 for radionuclide therapy (Dekempeneer et al., 2019).
In vivo two-photon microscopy showed nanobody extravasation across the BBB (Li et al., 2016).

The review provides a good overview of the potential of camelid nanobodies in nuclear medicine. However, it lacks specific quantitative data from the cited studies (e.g., tumor-to-background ratios, sensitivity/specificity values, radiation dosimetry).
The discussion on nephrotoxicity could be expanded. Specifically, what are the measured levels of renal uptake, and what strategies beyond cationic amino acid co-injection are being explored to mitigate this?
The section on BBB penetration is intriguing, but further details on the mechanism of transport and the efficiency of delivery would strengthen the argument.
While various applications are mentioned, a more focused discussion on the most promising applications and the challenges that need to be overcome for clinical translation would be beneficial.