Degradable Hydrogel for Sustained Localized Delivery of Anti-Tumor Drugs.

Autor:	Lessmann T; Ascendis Pharma GmbH; Im Neuenheimer Feld 584, 69120 Heidelberg, Germany., Jones SA; Ascendis Pharma GmbH; Im Neuenheimer Feld 584, 69120 Heidelberg, Germany., Voigt T; Ascendis Pharma GmbH; Im Neuenheimer Feld 584, 69120 Heidelberg, Germany., Weisbrod S; Ascendis Pharma GmbH; Im Neuenheimer Feld 584, 69120 Heidelberg, Germany., Kracker O; Ascendis Pharma GmbH; Im Neuenheimer Feld 584, 69120 Heidelberg, Germany., Winter S; Ascendis Pharma GmbH; Im Neuenheimer Feld 584, 69120 Heidelberg, Germany., Zúñiga LA; Ascendis Pharma, Inc., 1200 Bridge Parkway, Redwood City, CA 94065, USA., Stark S; Ascendis Pharma GmbH; Im Neuenheimer Feld 584, 69120 Heidelberg, Germany., Bisek N; Ascendis Pharma GmbH; Im Neuenheimer Feld 584, 69120 Heidelberg, Germany., Sprogøe K; Ascendis Pharma A/S, Tuborg Boulevard 12, 2900 Hellerup, Denmark. Electronic address: ks@ascendispharma.com.
Jazyk:	angličtina
Zdroj:	Journal of pharmaceutical sciences [J Pharm Sci] 2023 Nov; Vol. 112 (11), pp. 2843-2852. Date of Electronic Publication: 2023 Jun 04.
DOI:	10.1016/j.xphs.2023.05.018
Abstrakt:	Disadvantages of systemically administered immunomodulatory anti-tumor therapies include poor efficacy and high toxicity. Direct intratumoral injection of a drug is often associated with rapid efflux from the site of administration, thus reducing local exposure and therapeutic efficacy, while potentially increasing systemic adverse events. To address this, a sustained release prodrug technology was developed using a transient conjugation (TransCon TM ) technology to provide long-term high local drug exposure after injection in the tumor while minimizing systemic exposure. TransCon technology for systemic delivery is clinically validated, with multiple compounds in late-stage clinical development and approval of a once-weekly growth hormone for pediatric growth hormone deficiency. As a further application of this technology, this report describes the design, preparation, and functional characterization of hydrogel microspheres as insoluble, yet degradable carrier system. Microspheres were obtained after reaction of PEG-based polyamine dendrimers and bifunctional crosslinkers. Resiquimod, a TLR7/8 agonist, and axitinib, a vascular endothelial growth factor tyrosine kinase inhibitor, were chosen as anti-cancer drugs. The drugs were covalently attached to the carrier by linkers, which released the drugs under physiological conditions. Essentially all resiquimod or axitinib was released over weeks before physical degradation of the hydrogel microsphere was observed. In summary, TransCon Hydrogel technology allows localized sustained-release drug delivery for cancer therapy enabling high local drug concentrations while at the same time ensuring low systemic drug exposure over weeks with a single injection, which may improve the therapeutic index and improve efficacy, while minimizing systemic adverse events. A hydrogel prodrug of resiquimod, TransCon TLR7/8 agonist, is currently being investigated in clinical trials of patients with solid tumors (NCT04799054). Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kennett Sprogoe reports a relationship with Ascendis Pharma that includes: employment. Torben Lessmann reports a relationship with Ascendis Pharma that includes: employment. Seth A. Jones reports a relationship with Ascendis Pharma that includes: employment. Tobias Voigt reports a relationship with Ascendis Pharma that includes: employment. Samuel Weisbrod reports a relationship with Ascendis Pharma that includes: employment. Oliver Kracker reports a relationship with Ascendis Pharma that includes: employment. Steffen Winter reports a relationship with Ascendis Pharma that includes: employment. Luis Alejandro Zuniga reports a relationship with Ascendis Pharma that includes: employment. Sebastian Stark reports a relationship with Ascendis Pharma that includes: employment. Nicola Bisek reports a relationship with Ascendis Pharma that includes: employment. Kennett Sprogoe has patent pending to Ascendis Pharma A/S. Torben Lessmann has patent pending to Ascendis Pharma A/S. Samuel Weisbrod has patent pending to Ascendis Pharma A/S. Nicola Bisek has patent pending to Ascendis Pharma A/S. Sebastian Stark has patent pending to Ascendis Pharma A/S. Tobias Voigt has patent pending to Ascendis Pharma A/S. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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