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 (0.25-10μL) 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 50μm and a bevel length of 66±26μm were successfully fabricated via hydrofluoric acid etching. Upon piercing these microneedles into the skin using a protrusion length of 400μm, microneedles were inserted at a depth of 350±55μm. Micro-injections of 1-10μL had an accuracy between 97 and 113% with a relative standard deviation (RSD) of 9%, and lower volumes (0.25 and 0.5μL) 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.

Heterosubtypic influenza protection elicited by double-layered polypeptide nanoparticles in mice

“…The NP-peptide/4M2e-layered nanoparticle group showed much higher levels of NP 147 -and NP 55 -specific IFN-γ-secreting splenocytes. In previous studies, peptide mixture reactivation of splenocytes indicated the successful induction of vaccine-specific cellular immune responses (34,35). We measured levels of IFN-γ, IL-4, and IL-2 from the splenocyte culture medium in the presence of a peptide pool containing equal amounts of 4M2e and the NP peptide 3 wk after the boosting immunization.…”

Recent advances of microneedles for biomedical applications: drug delivery and beyond

“…To induce strong functional cytotoxic and potent T-cell responses, van der Maaden et al. 75 developed hollow microneedle injection system combined with the synthetic long peptide as a therapeutic cancer vaccine. As compared to intradermal injections, the promising strategy enables much lower volumes, further leading to improve immunogenicity and effectiveness of tumor vaccine formulations.…”

Engineering Microneedles for Therapy and Diagnosis: A Survey

“…Drug dispersion can be filled into the hollow MNs and deposited into the epidermis following MN insertion. An extra pump can be utilized to change the speed of drug solution carefully and refill the drug without removing the MNs, which makes continuous delivery of the drug possible [99]. Hollow MNs are also widely used to collect ISF [34] and blood [18].…”