Hollow microneedle‐mediated micro‐injections of a liposomal HPV E743–63 synthetic long peptide vaccine for efficient induction of cytotoxic and T‐helper responses

Abstract Recent studies have shown that intradermal vaccination has great potential for T cell‐mediated cancer immunotherapy. However, classical intradermal immunization with a hypodermic needle and syringe has several drawbacks. Therefore, in the present study a digitally controlled hollow microneedle injection system (DC‐hMN‐iSystem) with an ultra‐low dead volume was developed to perform micro‐injections (0.25–10 &mgr;L) into skin in an automated manner. A synthetic long peptide derived from human papilloma virus formulated in cationic liposomes, which was used as a therapeutic cancer vaccine, was administered intradermally by using the DC‐hMN‐iSystem. Fused silica hollow microneedles with an inner diameter of 50 &mgr;m and a bevel length of 66 ± 26 &mgr;m were successfully fabricated via hydrofluoric acid etching. Upon piercing these microneedles into the skin using a protrusion length of 400 &mgr;m, microneedles were inserted at a depth of 350 ± 55 &mgr;m. Micro‐injections of 1–10 &mgr;L had an accuracy between 97 and 113% with a relative standard deviation (RSD) of 9%, and lower volumes (0.25 and 0.5 &mgr;L) had an accuracy of 86–103% with a RSD of 29% in ex vivo human skin. Intradermal administration of the therapeutic cancer vaccine via micro‐injections induced strong functional cytotoxic and T‐helper responses in mice, while requiring much lower volumes as compared to classical intradermal immunization. In conclusion, by using the newly developed DC‐hMN‐iSystem, very low vaccine volumes can be precisely injected into skin in an automated manner. Thereby, this system shows potential for minimally‐invasive and potentially pain‐free therapeutic cancer vaccination. Graphical abstract Figure. No Caption available.