Laser-engineered dissolving microneedle arrays for protein delivery: potential for enhanced intradermal vaccination

McCrudden, Maeliosa; Torrisi, Barbara M.; Al-Zahrani, Sharifah; McCrudden, Cian M.; Zaric, Marija; Scott, Christopher J.; Kissenpfennig, Adrien; McCarthy, Helen; Donnelly, Ryan F.

doi:10.1111/jphp.12248

Cited by 35 publications

(34 citation statements)

References 57 publications

(108 reference statements)

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“…MNs were prepared by using Gantrez ® , a poly(methyl vinyl ether-co-maleic anhydride) polymer, which has been extensively employed for pharmaceutical applications, such as denture adhesives, thickening, suspending agents, or carriers for oral delivery, due to its mucoadhesive properties and low oral toxicity [31]. More recently, it has been used for the preparation of transdermal patches, showing good properties to form dissolving MNs [14,32]. Among the different types of Gantrez ® polymers used, Gantrez ® AN119 has not been reported to perform MNs.…”

Section: Discussionmentioning

confidence: 99%

Dissolving Microneedles for Intradermal Vaccination against Shigellosis

et al. 2019

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Intradermal (ID) immunization is of increasing interest due to the easy accessibility and excellent immunogenic properties of the skin. Among ID immunization methods, dissolving microneedles (MNs) have appeared as an alternative to traditional hypodermic immunization, offering many advantages, such as being an easily administered method, with no need for health personnel, painless, and avoiding the use of needles and sharp wastage. In this study, an affordable and easy-to-produce MNs method was developed based on aqueous blends of 30% w/w poly (methyl vinyl ether-co-maleic anhydride). As an antigen model, a subunit vaccine candidate based on outer membrane vesicles from Shigella flexneri was used. Both unloaded and antigen-loaded MNs were synthetized and characterized. The MNs were successfully validated in an in vitro Parafilm M ® skin model and in a pig skin ex vivo model. Biodistribution studies were performed in BALB/c mice using 99m TcO 4 − radiolabeled samples. Results indicated that the vesicle vaccine was successfully released from the MNs and targeted gastrointestinal tract after 6 h post-administration. In vivo immunization and protection studies were performed in BALB/c mice. Mice were intradermally immunized through ear skin with one single dose of 200 µg antigenic complex, eliciting the production of specific systemic IgG and mucosal IgA. Moreover, MNs were able to protect mice from an experimental infection with 1×10 6 CFU/mouse of S. flexneri four weeks after immunization. This work demonstrates for the first time the potential of outer membrane vesicle-loaded dissolving MNs for ID vaccination against enteropathogens like Shigella.Vaccines 2019, 7, 159 2 of 15 (SALT), formed by a great network of immune cells, including Langerhans cells (LC), lymphocytes, and dendritic cells (DCs), which recognize the antigens and present them in the proximal lymph nodes [3]. Different ID vaccination methods have been used already, such as the Mantoux technique, microinjection systems, or jet injectors, used for smallpox, rabies, or Bacillus Calmette-Guérin (BCG) vaccines. However, they require the use of needles [4]. Microneedle patches (MNs) have appeared as a novel and attractive approach for ID immunization [5]. They are painless devices formed by arrays of micron-size projections that can pass through the stratum corneum and epidermis without reaching the nerves of the dermis layer [6]. Thus, they are a self-administered, minimally invasive method, well tolerated by human patients in proof of concept trials [7,8], that can directly target the skin immune cells [9].Several types of MNs have been developed for the delivery of antigens: solid, coated, hollow, and dissolving MNs [10]. Among them, and based on their self-disabling properties, dissolving MNs (MNs) have been selected for this work. These MNs are made of a soluble matrix, generally a biocompatible polymer or polysaccharide, which includes the antigenic complex. After the array insertion into the skin, the needle tips dissolve and the antigenic cargo i...

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Section: Discussionmentioning

confidence: 99%

Dissolving Microneedles for Intradermal Vaccination against Shigellosis

et al. 2019

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“…The advantages of MN technology include pain free administration, simplicity of use, lack of needle stick injury, patient compliance and low manufacturing costs 25 . MNs are designed to painlessly breach the skin's stratum corneum (SC) barrier and dissolve upon contact with the skin's interstitial fluid to release the cargo in the needle tips 26,27 . Herein we build upon the delivery of DNA from this system 28 and report for the first time on a functional HPV-16 E6/E7 DNA vaccine candidate.…”

Section: Introductionmentioning

confidence: 99%

DNA vaccination for cervical cancer; a novel technology platform of RALA mediated gene delivery via polymeric microneedles

Ali

McCrudden

McCaffrey

et al. 2017

Nanomedicine: Nanotechnology, Biology and Medicine

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HPV subtypes (16, 18) are associated with the development of cervical cancer, with oncoproteins E6 and E7 responsible for pathogenesis. The goal of this study was to evaluate our 'smart system' technology platform for DNA vaccination against cervical cancer. The vaccination platform brings together two main components; a peptide RALA which condenses DNA into cationic nanoparticles (NPs), and a polymeric polyvinylpyrrolidone (PVP) microneedle (MN) patch for cutaneous delivery of the loaded NPs. RALA condensed E6/E7 DNA into NPs not exceeding 100nm in diameter, and afforded the DNA protection from degradation in PVP. Sera from mice vaccinated with MN/RALA-E6/E7 were richer in E6/E7-specific IgGs, displayed a greater T-cell-mediated TC-1 cytotoxicity and contained more IFN-γ than sera from mice that received NPs intramuscularly. More importantly, MN/RALA-E6/E7 delayed TC-1 tumor initiation in a prophylactic model, and slowed tumor growth in a therapeutic model of vaccination, and was more potent than intramuscular vaccination.

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“…Thus, the modification of trypsin with hydrophilic polymers to prevent autolysis is promising [14,[18][19][20]. The vinylmethylether-maleic acid copolymer (VEMAC) is obtained by hydrolyzing the maleic anhydride moiety from the commercially available vinylmethylether-maleic anhydride copolymer, and has been extensively tested for medical and pharmaceutical applications due to its hydrophilicity, biocompatibility, and non-toxicity [21][22][23][24][25][26]. In addition, we have reported the cell compatibility of VEMAC immobilized on polystyrene cell culture dishes [27], and abundant carboxyl groups on the VEMAC backbone can be used for multi-point conjugation of enzymes.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Highly Stabilized Polymer–Trypsin Conjugates with Autolysis Resistance

et al. 2016

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Abstract:Protein digestion by trypsin has been widely used in many industrial and research applications. However, extensive use of trypsin is limited because of the rapid decrease in enzymatic activity caused by autolysis at optimal pH and temperature. To improve the enzymatic performance of trypsin, we synthesized highly stabilized polymer-trypsin conjugates using vinylmethylether-maleic acid copolymer (VEMAC) via multi-point attachment. The VEMAC modification significantly enhanced the thermal stability of trypsin, and the resulting conjugates showed a strong resistance to autolysis. VEMAC-modified trypsin (VEMAC-Tryp) showed maximum activity at 55 • C and at 1.4-fold higher levels than that of unmodified trypsin. Bovine serum albumin was effectively digested by VEMAC-Tryp, indicating that the modified trypsin can be used for digestion of high molecular weight substrates. VEMAC modification is a simple and cost-effective strategy to obtain fully active modified enzymes, and may be used to develop bioreactors.

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Laser-engineered dissolving microneedle arrays for protein delivery: potential for enhanced intradermal vaccination

Abstract: While enhanced manufacturing strategies are required to improve delivery efficiency and reduce waste, dissolving MN are a promising candidate for 'reduced-risk' vaccination and protein delivery strategies.

Cited by 35 publications

References 57 publications

Dissolving Microneedles for Intradermal Vaccination against Shigellosis

Dissolving Microneedles for Intradermal Vaccination against Shigellosis

DNA vaccination for cervical cancer; a novel technology platform of RALA mediated gene delivery via polymeric microneedles

Synthesis and Characterization of Highly Stabilized Polymer–Trypsin Conjugates with Autolysis Resistance

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