Abstract
Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as [68Ga]Ga-labelled FAPI-02, 04, 46, and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging point of view. FAP inhibitors introduced via bifunctional DOTA and DOTAGA chelators offer the possibility to complex Lutetium-177 due to an additional coordination site, and are suitable for theranostic applications owing to the increased tumor accumulation and prolonged tumor retention time. However, for therapeutic applications, very little has been accomplished, mainly due to residence times of the compounds. In an attempt to develop a promising therapeutic radiopharmaceutical, the present study aimed to evaluate and compare the biodistribution, pharmacokinetics, and dosimetry of [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in patients with various cancers. The FAPi agents, [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were administered in two different groups of patients. Three patients (mean age—50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2–3 GBq) [177Lu]Lu-DOTA.SA.FAPi and seven (mean age—51 years) were treated with 1.48 GBq (IQR: 0.6–1.5) of [177Lu]Lu-DOTAGA.(SA.FAPi)2. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 h and 168 h post-injection (p.i.). The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Physiological uptake of [177Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [177Lu]Lu-DOTAGA.(SA.FAPi)2 involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. In the [177Lu]Lu-DOTA.SA.FAPi group, the highest absorbed doses were noted in the kidneys (0.618 ± 0.015 Gy/GBq), followed by the colon (right colon: 0.472 Gy/GBq and left colon: 0.430 Gy/GBq). In the [177Lu]Lu-DOTAGA.(SA.FAPi)2 group, the colon received the highest absorbed dose (right colon: 1.160 Gy/GBq and left colon: 2.870 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [177Lu]Lu-DOTA.SA.FAPi (p < 0.011). [177Lu]Lu-DOTAGA.(SA.FAPi)2 had significantly longer median whole-body Te compared to that of [177Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5–70.1) vs. 23.1 h (IQR: 17.8–31.5); p-0.0167]. The Te of tumor lesions was significantly higher for [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi [86.6 h (IQR: 34.3–94.6) vs. 14 h (IQR: 12.8–15.5); p-0.0004]. The median absorbed doses to the lesions were 0.603 (IQR: 0.230–1.810) Gy/GBq and 6.70 (IQR: 3.40–49) Gy/GBq dose per cycle in the [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 groups, respectively. The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.
Highlights
The tumor microenvironment (TME) plays a crucial role in tumor remodelling andThe tumorcontributor microenvironment plays crucial roledrug in tumor remodelling is an important to tumor(TME)growth andapromoting resistance.Within and the is an important contributor to tumor growth andapromoting drug resistance. theTME, cancer-associated fibroblasts (CAFs) have multifaceted function and Within are majorTME, cancer-associated fibroblasts have a multifaceted and of aretumors major contributors to TME remodelling.The(CAFs) high abundance of CAFs in function a wide range contributors to TME remodelling.The various high abundance offers important implications to target cancers. of CAFs in a wide range of tumors offers important implications to target variousThe fibroblast activation protein (FAPα), a cancers.type II transmembrane serine protease, is fibroblast protein (FAPα), a typereported
It is of interest to know whether in vitro results of homodimers still hold true from the clinical aspect; the aim of the present study was to compare the in vivo biodistribution, pharmacokinetics, absorbed dose estimates, and effective half-lives of
Introduced a squaramide linker containing bifunctional DATA5m and DOTA chelators and a FAP targeting moiety abbreviated as DATA5m .SA.FAPi and DOTA.SA.FAPi, that were labelled with gallium-68
Summary
The tumor microenvironment (TME) plays a crucial role in tumor remodelling andThe tumorcontributor microenvironment plays crucial roledrug in tumor remodelling is an important to tumor(TME)growth andapromoting resistance.Within and the is an important contributor to tumor growth andapromoting drug resistance. theTME, cancer-associated fibroblasts (CAFs) have multifaceted function and Within are majorTME, cancer-associated fibroblasts have a multifaceted and of aretumors major contributors to TME remodelling.The(CAFs) high abundance of CAFs in function a wide range contributors to TME remodelling.The various high abundance offers important implications to target cancers. of CAFs in a wide range of tumors offers important implications to target variousThe fibroblast activation protein (FAPα), a cancers.type II transmembrane serine protease, is fibroblast protein (FAPα), a typereported. The tumor microenvironment (TME) plays a crucial role in tumor remodelling and. The tumorcontributor microenvironment plays crucial roledrug in tumor remodelling is an important to tumor(TME). Within and the is an important contributor to tumor growth andapromoting drug resistance. TME, cancer-associated fibroblasts (CAFs) have multifaceted function and Within are major. TME, cancer-associated fibroblasts have a multifaceted and of aretumors major contributors to TME remodelling. The(CAFs) high abundance of CAFs in function a wide range contributors to TME remodelling. The various high abundance offers important implications to target cancers. Of CAFs in a wide range of tumors offers important implications to target various. The fibroblast activation protein (FAPα), a cancers. Type II transmembrane serine protease, is fibroblast protein (FAPα), a typereported
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