Long-acting injectable formulation technologies: challenges and opportunities for the delivery of fragile molecules.

INTRODUCTION: The development of long-acting injectables (LAIs) for protein and peptide therapeutics has been a key challenge over the last 20 years. If these molecules offer advantages due to their high specificity and selectivity, their controlled release may confer several additional benefits in terms of extended half-life, local delivery, and patient compliance. AREA COVERED: This manuscript aims to give an overview of peptide and protein-based LAIs from an industrial perspective, describing both approved and promising technologies (with exceptions of protein engineering strategies and devices), their advantages and potential improvements to aid their access to the market. EXPERT OPINION: Many LAIs have been developed for peptides, with formulations on the market for several decades. On the contrary, LAIs for proteins are still far from the market and issues related to manufacturing and sterilization of these products still need to be overcome. In situ forming depots (ISFDs), whose simple manufacturing conditions and easy administration procedures (without reconstitution) are strong advantages, appear as one of the most promising technologies for the delivery of these molecules. In this regard, the approval of ELIGARD® in the early 2000's (which still requires a complex reconstitution process), paved the way for the development of second-generation, ready-to-use ISFD technologies like BEPO® and FluidCrystal®.

Intracellular Delivery of an Antibody Targeting Gasdermin-B Reduces HER2 Breast Cancer Aggressiveness.

PURPOSE: Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers. EXPERIMENTAL DESIGN: We have developed a new targeted nanomedicine based on hyaluronic acid-biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo. RESULTS: Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMB-overexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB. CONCLUSIONS: Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.

Prospective analysis of the surgical outcomes and patients' satisfaction rate after the AMS Spectra penile prosthesis implantation.

OBJECTIVE: To evaluate the outcomes, the patients', and their partners' satisfaction concerning the AMS Spectra penile prosthesis implantation. METHODS: Twenty-two unresponsive or dissatisfied patients with phosphodiesterase 5 inhibitor oral therapy or prostaglandin intracavernous injection underwent a Spectra penile prosthesis implantation. No major intraoperative or postoperative complications were observed. The preoperative erectile dysfunction (ED) was rated by the International Index of Erectile Function (IIEF) questionnaire. The patients and their partners were submitted to the IIEF and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaires through telephonic interviews at the third, sixth, and 12th months after the penile surgery. RESULTS: This study demonstrates that 86.4% of the patients and 52.6% of their partners are satisfied by the AMS Spectra penile prosthesis. The preoperative average IIEF score was equal to 28.5 (range 13-39). The postoperative IIEF rates were 47.7 (43-53), 51.8 (48-58), and 53.9 (50-58) at the third, sixth, and 12th months, respectively. The patient average EDITS score amounted to 39.5 (31-48), 43.4 (36-50), and 45.2 (38-50) at the third, sixth, and 12th months, respectively. The increase between the preoperative and postoperative IIEF parameters resulted to be statistically significant (P <.05) as well as the increase in EDITS at the third, sixth, and 12th months postoperatively. CONCLUSION: The AMS Spectra is a reliable device to treat ED as shown by the high grade of the patients' satisfaction. Moreover, the AMS Spectra is highly convenient in terms of cost savings in comparison to an inflatable device. In selected patients, this prosthesis should be considered as an effective solution to treat severe ED.