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Review
. 2018 Mar 1:127:106-118.
doi: 10.1016/j.addr.2018.01.015. Epub 2018 Jan 31.

Polymeric microneedles for transdermal protein delivery

Yanqi Ye  1 , Jicheng Yu  1 , Di Wen  1 , Anna R Kahkoska  2 , Zhen Gu  3
Affiliations
Review

Polymeric microneedles for transdermal protein delivery

Yanqi Ye et al. Adv Drug Deliv Rev. .

Abstract

The intrinsic properties of therapeutic proteins generally present a major impediment for transdermal delivery, including their relatively large molecule size and susceptibility to degradation. One solution is to utilize microneedles (MNs), which are capable of painlessly traversing the stratum corneum and directly translocating protein drugs into the systematic circulation. MNs can be designed to incorporate appropriate structural materials as well as therapeutics or formulations with tailored physicochemical properties. This platform technique has been applied to deliver drugs both locally and systemically in applications ranging from vaccination to diabetes and cancer therapy. This review surveys the current design and use of polymeric MNs for transdermal protein delivery. The clinical potential and future translation of MNs are also discussed.

Keywords: Drug delivery; Microneedle; Protein delivery; Transdermal; Vaccine.

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Figures

Fig. 1
Fig. 1
Representative types of polymeric MNs for protein delivery. A) Solid MNs coated with polymeric drug formulation on the MNs surface for direct delivery. B) Dissolvable polymeric MNs that remain in the skin and dissolve to deliver the drug encapsulated within. C) Degradable polymeric MNs that remain in the skin and degrade over time. Drug delivery occurs via passive diffusion or degradation of the polymeric matrix. D) Bioresponsive polymeric MNs. Drug release is dependent on the degradation or dissociation of MN matrix and/or formulations from the MN matrix.
Fig. 2
Fig. 2
A) Schematic illustration of multilayers deposited onto the PLGA MN surfaces. MNs transfer coatings into the skin as an initiation of adaptive immunity. B) Anti-OVA IgG titers in serum over time with MN-based and control immunizations on days 0, 28, and 56. Quantification of C) anti-OVA IgG1 and D) IgG2c subtypes in serum at day 107. Adapted with permission from Ref [116].
Fig. 3
Fig. 3
A) Side view of dissolvable polymeric MNs. B) Top view of porcine cadaver skin after insertion and removal of MNs with encapsulated sulforhodamine. C) Fluorescence image of pig skin cross section after insertion of one MNs. D) Brightfield image of the skin section with hematoxylin and eosin staining. Quantification of serum influenza-specific E) IgG titers F) IgG1 titers G) IgG2a titers at the indicated days after immunization. Mice were immunized intramuscularly with inactivated influenza virus or via an MN patch encapsulating the same amount of virus. Adapted with permission from Ref [12].
Fig. 4
Fig. 4
A) Schematic illustration of transdermal delivery of insulin using starch/gelatin MNs, which could rapidly dissolve in the skin to release encapsulated insulin. B) Plasma glucose levels and C) plasma insulin concentrations of diabetic rats after administration of control and insulin-loaded MNs. Adapted with permission from Ref [132].
Fig. 5
Fig. 5
Fabrication and characterizations of silk/PAA composite MNs. A) Schematic of MN fabrication. B) Optical micrograph of silk/PAA MN array with silk (blue) in the tips and PAA (red) in the pedestals (scale bar 500 μm). C) Confocal micrographs of composite MNs (scale bar 500 μm). D) SEM micrographs of a single silk tip following 30 s exposure to water. Micrographs show the MN tip structure and silk hydrogel structure (left, scale bar 500 μm, center, scale bar 20 μm, and right, scale bar 5 μm). E) Quantitative analysis of programmed release profiles of fluorescent OVA from silk and PAA portions of the MNs over time. Adapted with permission from Ref [135].
Fig. 6
Fig. 6
A) Schematic of dissolvable MN arrays laden with antigen-loaded NPs to increase vaccine immunogenicity by targeting antigen specifically to DC networks within the skin. B) The antigen-encapsulated NP vaccination via MNs generated robust antigen-specific cellular immune responses in mice. Adapted with permission from Ref [140].
Fig. 7
Fig. 7
A) Schematic of the smart insulin patch composed of HA and GRVs composed of HA. B) Formation and mechanism of glucose-responsive MN patch. C) The indicated mouse skin was applied with an MN-array patch (Scale bar: top right 500 μm, bottom 100 μm). D) In vivo BG level changes E) and plasma human insulin concentrations in diabetic mice after indicated treatments. Adapted with permission from Ref [41].
Fig. 8
Fig. 8
A) Schematic of the anti-PD-1 antibody delivery by an MN patch loaded with self-dissociated NPs. B) The blockade of PD-1 by anti-PD-1 antibody activates the immune system to destroy cancer cells. C) Quantified tumor signals according to in vivo bioluminescence imaging of the B16F10 tumors in different treatment groups. D) Kaplan-Meier survival curves for the treated mice. Adapted with permission from Ref [157].
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