A platform technology for ultra-long acting intratumoral therapy.
Animals
Mice
Humans
Irinotecan
/ administration & dosage
Microspheres
Hydrogels
/ chemistry
Cell Line, Tumor
Topoisomerase I Inhibitors
/ administration & dosage
Drug Delivery Systems
Female
Neoplasms
/ drug therapy
Xenograft Model Antitumor Assays
Injections, Intralesional
Antineoplastic Agents
/ administration & dosage
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
18 Jun 2024
18 Jun 2024
Historique:
received:
18
02
2024
accepted:
06
06
2024
medline:
19
6
2024
pubmed:
19
6
2024
entrez:
18
6
2024
Statut:
epublish
Résumé
Intratumoral (IT) therapy is a powerful method of controlling tumor growth, but a major unsolved problem is the rapidity that injected drugs exit tumors, limiting on-target exposure and efficacy. We have developed a generic long acting IT delivery system in which a drug is covalently tethered to hydrogel microspheres (MS) by a cleavable linker; upon injection the conjugate forms a depot that slowly releases the drug and "bathes" the tumor for long periods. We established technology to measure tissue pharmacokinetics and studied MSs attached to SN-38, a topoisomerase 1 inhibitor. When MS ~ SN-38 was injected locally, tissues showed high levels of SN-38 with a long half-life of ~ 1 week. IT MS ~ SN-38 was ~ tenfold more efficacious as an anti-tumor agent than systemic SN-38. We also propose and provide an example that long-acting IT therapy might enable safe use of two drugs with overlapping toxicities. Here, long-acting IT MS ~ SN-38 is delivered with concurrent systemic PARP inhibitor. The tumor is exposed to both drugs whereas other tissues are exposed only to the systemic drug; synergistic anti-tumor activity supported the validity of this approach. We propose use of this approach to increase efficacy and reduce toxicities of combinations of immune checkpoint inhibitors such as αCTLA-4 and αPD-1.
Identifiants
pubmed: 38890412
doi: 10.1038/s41598-024-64261-8
pii: 10.1038/s41598-024-64261-8
doi:
Substances chimiques
Irinotecan
7673326042
Hydrogels
0
Topoisomerase I Inhibitors
0
Antineoplastic Agents
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
14000Informations de copyright
© 2024. The Author(s).
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