Muscular Dystrophies (MDs) are a group of rare inherited genetic muscular pathologies encompassing a variety of clinical phenotypes, gene mutations and mechanisms of disease. MDs undergo progressive skeletal muscle degeneration causing severe health problems that lead to poor life quality, disability and premature death. There are no available therapies to counteract the causes of these diseases and conventional treatments are administered only to mitigate symptoms. Recent understanding on the pathogenetic mechanisms allowed the development of novel therapeutic strategies based on gene therapy, genome editing CRISPR/Cas9 and drug repurposing approaches. Despite the therapeutic potential of these treatments, once the actives are administered, their instability, susceptibility to degradation and toxicity limit their applications. In this frame, the design of delivery strategies based on nanomedicines holds great promise for MD treatments. This review focuses on nanomedicine approaches able to encapsulate therapeutic agents such as small chemical molecules and oligonucleotides to target the most common MDs such as Duchenne Muscular Dystrophy and the Myotonic Dystrophies. The challenge related to in vitro and in vivo testing of nanosystems in appropriate animal models is also addressed. Finally, the most promising nanomedicine-based strategies are highlighted and a critical view in future developments of nanomedicine for neuromuscular diseases is provided.

Targeted radionuclide therapy is a revolutionary tool for the treatment of highly spread metastatic cancers. Most current approaches rely on the use of vectors to deliver radionuclides to tumor cells, targeting membrane‐bound cancer‐specific moieties. Here, we report the embryonic navigation cue netrin‐1 as an unanticipated target for vectorized radiotherapy. While netrin‐1, known to be re‐expressed in tumoral cells to promote cancer progression, is usually characterized as a diffusible ligand, we demonstrate here that netrin‐1 is actually poorly diffusible and bound to the extracellular matrix. A therapeutic anti‐netrin‐1 monoclonal antibody (NP137) has been preclinically developed and was tested in various clinical trials showing an excellent safety profile. In order to provide a companion test detecting netrin‐1 in solid tumors and allowing the selection of therapy‐eligible patients, we used the clinical‐grade NP137 agent and developed an indium‐111‐NODAGA‐NP137 single photon emission computed tomography (SPECT) contrast agent. NP137‐ ¹¹¹ In provided specific detection of netrin‐1‐positive tumors with an excellent signal‐to‐noise ratio using SPECT/CT imaging in different mouse models. The high specificity and strong affinity of NP137 paved the way for the generation of lutetium‐177‐DOTA‐NP137, a novel vectorized radiotherapy, which specifically accumulated in netrin‐1‐positive tumors. We demonstrate here, using tumor cell‐engrafted mouse models and a genetically engineered mouse model, that a single systemic injection of NP137‐ ¹⁷⁷ Lu provides important antitumor effects and prolonged mouse survival. Together, these data support the view that NP137‐ ¹¹¹ In and NP137‐ ¹⁷⁷ Lu may represent original and unexplored imaging and therapeutic tools against advanced solid cancers.

Radiolabeled OTSA101, a monoclonal antibody targeting synovial sarcoma (SS) developed by OncoTherapy Science, was used to treat relapsing SS metastases following a theranostic procedure: in case of significant 111In-OTSA101 tumor uptake and favorable biodistribution, patient was randomly treated with 370/1110 MBq 90Y-OTSA101. Monte Carlo-based 3D dosimetry integrating time-activity curves in VOI was performed on 111In-OTSA101 repeated SPECT/CT. Estimated absorbed doses (AD) in normal tissues were compared to biological side effects and to the admitted maximal tolerated absorbed dose (MTD) in normal organs. Results in the tumors were also compared to disease evolution. Biodistribution and tracer quantification were analyzed on repeated SPECT/CT acquisitions performed after injection of 111In-OTSA101 in 19/20 included patients. SPECT images were warped to a common coordinates system with deformable registration. Volumes of interest (VOI) for various lesions and normal tissues were drawn on the first CT acquisition and reported to all the SPECT images. Tracer quantification and residence time of 111In-OTSA101 in VOI were used to evaluate the estimated absorbed doses per MBq of 90Y-OTSA101 by means of Monte Carlo simulations (GATE). A visual scale analysis was applied to assess tumor uptake (grades 0 to 4) and results were compared to the automated quantification. Results were then compared to biological side effects reported in the selected patients treated with 90Y-OTSA101 but also to disease response to treatment. After screening, 8/20 patients were treated with 370 or 1110 MBq 90Y-OTSA101. All demonstrated medullary toxicity, only one presented with transient grade 3 liver toxicity due to disease progression, and two patients presented with transient grade 1 renal toxicity. Median absorbed doses were the highest in the liver (median, 0.64 cGy/MBq; [0.27 −1.07]) being far lower than the 20 Gy liver MTD, and the lowest in bone marrow (median, 0.09 cGy/MBq; [0.02 −0.18]) being closer to the 2 Gy bone marrow MTD. Most of the patients demonstrated progressive disease on RECIST criteria during patient follow-up. 111In-OTSA101 tumors tracer uptake visually appeared highly heterogeneous in inter- and intra-patient analyses, independently of tumor sizes, with variable kinetics. The majority of visual grades corresponded to the automated computed ones. Estimated absorbed doses in the 95 supra-centimetric selected lesions ranged from 0.01 to 0.71 cGy per injected MBq (median, 0.22 cGy/MBq). The maximal tumor AD obtained was 11.5 Gy. 3D dosimetry results can explain the observed toxicity and tumors response. Despite an intense visual 111In-OTSA101 liver uptake, liver toxicity was not the dose limiting factor conversely to bone marrow toxicity. Even though tumors 111In-OTSA101 avidity was visually obvious for treated patients, the low estimated tumors AD obtained by 3D dosimetry explain the lack of tumor response.

Background: Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). ¹⁷⁷Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. Methods: This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of ¹⁷⁷Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of ¹⁷⁷Lu-PSMA-1 (phase I) and the efficacy of ¹⁷⁷Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). Discussion: Our prospective study may lead to new potential indications for the use of ¹⁷⁷Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of ¹⁷⁷Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. Trial registration: ClinicalTrials.gov: NCT06059014.

Introdution: [⁶⁸Ga]Ga-prostate specific membrane antigen (PSMA)-11 showed a clear gain in sensitivity for lesion detection in the biological recurrence of prostate cancer as compared to the standard [¹⁸F]fluorocholine radiopharmaceutical. To meet the strong demand for [⁶⁸Ga]Ga-PSMA-11, we aimed to optimize an automated radiolabeling process by evaluating the influence of different key parameters on radiochemical purity and radiochemical yield. Methods: The radiosynthesis of [⁶⁸Ga]Ga PSMA-11 was performed using a Trasis MiniAio synthesizer and a ⁶⁸Ge/⁶⁸Ga GalliaPharm generator supplied by Eckert & Ziegler, Berlin, Germany. Optimized labeling parameters were evaluated by variation of sodium acetate concentrations and temperature of radiolabeling as well as the purification process. Results: For each condition tested, radiochemical purity was higher than 99% in the final vial without batch failure, indicating a robust and fast radiosynthesis process. Radiosynthesis without the solid phase extraction purification process at room temperature in less than 5 min resulted in a radiolabeling efficiency of over 99% and remained stable at least 4 h without manual processing to limit operator radiation exposure. Conclusion: The procedure was completely automated and provided a high radiochemical yield. It can be performed several times a day, facilitating the clinical demand of this radiopharmaceutical.

Peritoneal carcinomatosis (PC) is a common outcome of epithelial ovarian carcinoma and is the leading cause of death for these patients. Tumor location, extent, peculiarities of the microenvironment, and the development of drug resistance are the main challenges that need to be addressed to improve therapeutic outcome. The development of new procedures such as HIPEC (Hyperthermic Intraperitoneal Chemotherapy) and PIPAC (Pressurized Intraperitoneal Aerosol Chemotherapy) have enabled locoregional delivery of chemotherapeutics, while the increasingly efficient design and development of advanced drug delivery micro and nanosystems are helping to promote tumor targeting and penetration and to reduce the side effects associated with systemic chemotherapy administration. The possibility of combining drug-loaded carriers with delivery via HIPEC and PIPAC represents a powerful tool to improve treatment efficacy, and this possibility has recently begun to be explored. This review will discuss the latest advances in the treatment of PC derived from ovarian cancer, with a focus on the potential of PIPAC and nanoparticles in terms of their application to develop new therapeutic strategies and future prospects.