A gene-coated microneedle patch based on industrialized ultrasonic spraying technology with a polycation vector to improve antitumor efficacy

Author(s): Xinfang Li ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Qinan Xu ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Jing Wang ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Peng Zhang ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Youxiang Wang ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Jian Ji ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵

Publication date (Electronic): 2021

Journal: Journal of Materials Chemistry B

Publisher: Royal Society of Chemistry (RSC)

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Abstract

Two-step ultrasonic spraying can make an interpenetrating structure composed of p53 DNA and PEI on coated microneedle patch (P@D@MNP); P@D@MNP shows good anti-tumor efficiency, and it has potential to be a drug/gene transdermal delivery platform.

Abstract

A coated microneedle patch is a reliable way to load gene on a surface as a transdermal gene delivery platform. But there are many limitations to the traditional methods to fabricate a coated microneedle patch, such as the fact that they are time consuming or the difficulty in controlling the loading content. In this research, ultrasonic spraying technology, as an industrialized production method, was first used to fabricate a gene-coated microneedle patch. First, the p53 expression plasmid (p53 DNA) was ultrasonically sprayed on a polycaprolactone (PCL) microneedle patch (D@MNP). To promote the transfection efficiency, polycation polyethylenimine (PEI), as a vector, was then ultrasonically sprayed on D@MNP (P@D@MNP). From the experimental results, although two layers were sprayed step by step, no obvious stratification could be observed. The vector PEI interweaved with genes and inhibited the gene release profile, but it changed the released naked genes to positively charged complexes, which would promote gene transfection efficiency. In subsequent in vivo experiments, the anti-tumor efficacy of the “P@D@MNP treated group” could reach 84.7%, although it had the lowest gene release profile. In contrast, the anti-tumor efficacy of the “intravenous injection group” and “D@MNP treated group” was only 24.3% and 59.3%, respectively. Overall, P@D@MNP was a safe and efficient device to treat the subdermal tumor. Ultrasonic spraying technology provided an industrialized method to fabricate the coated microneedle patch as a transdermal gene/drug delivery platform.

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Most cited references 44

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Microneedles for drug and vaccine delivery.

Yeu-Chun Kim, Jung-Hwan Park, Mark Prausnitz (2012)

Microneedles were first conceptualized for drug delivery many decades ago, but only became the subject of significant research starting in the mid-1990's when microfabrication technology enabled their manufacture as (i) solid microneedles for skin pretreatment to increase skin permeability, (ii) microneedles coated with drug that dissolves off in the skin, (iii) polymer microneedles that encapsulate drug and fully dissolve in the skin and (iv) hollow microneedles for drug infusion into the skin. As shown in more than 350 papers now published in the field, microneedles have been used to deliver a broad range of different low molecular weight drugs, biotherapeutics and vaccines, including published human studies with a number of small-molecule and protein drugs and vaccines. Influenza vaccination using a hollow microneedle is in widespread clinical use and a number of solid microneedle products are sold for cosmetic purposes. In addition to applications in the skin, microneedles have also been adapted for delivery of bioactives into the eye and into cells. Successful application of microneedles depends on device function that facilitates microneedle insertion and possible infusion into skin, skin recovery after microneedle removal, and drug stability during manufacturing, storage and delivery, and on patient outcomes, including lack of pain, skin irritation and skin infection, in addition to drug efficacy and safety. Building off a strong technology base and multiple demonstrations of successful drug delivery, microneedles are poised to advance further into clinical practice to enable better pharmaceutical therapies, vaccination and other applications. Copyright © 2012 Elsevier B.V. All rights reserved.

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Dissolving microneedles for transdermal drug delivery.

Jeong Lee, Jung-Hwan Park, Mark Prausnitz (2008)

Microfabrication technology has been adapted to produce micron-scale needles as a safer and painless alternative to hypodermic needle injection, especially for protein biotherapeutics and vaccines. This study presents a design that encapsulates molecules within microneedles that dissolve within the skin for bolus or sustained delivery and leave behind no biohazardous sharp medical waste. A fabrication process was developed based on casting a viscous aqueous solution during centrifugation to fill a micro-fabricated mold with biocompatible carboxymethylcellulose or amylopectin formulations. This process encapsulated sulforhodamine B, bovine serum albumin, and lysozyme; lysozyme was shown to retain full enzymatic activity after encapsulation and to remain 96% active after storage for 2 months at room temperature. Microneedles were also shown to be strong enough to insert into cadaver skin and then to dissolve within minutes. Bolus delivery was achieved by encapsulating molecules just within microneedle shafts. For the first time, sustained delivery over hours to days was achieved by encapsulating molecules within the microneedle backing, which served as a controlled release reservoir that delivered molecules by a combination of swelling the backing with interstitial fluid drawn out of the skin and molecule diffusion into the skin via channels formed by dissolved microneedles. We conclude that dissolving microneedles can be designed to gently encapsulate molecules, insert into skin, and enable bolus or sustained release delivery.

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Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery.

Jung-Hwan Park, Mark Allen, Mark Prausnitz (2005)

To overcome the skin's barrier properties that block transdermal delivery of most drugs, arrays of microscopic needles have been microfabricated primarily out of silicon or metal. This study addresses microneedles made of biocompatible and biodegradable polymers, which are expected to improve safety and manufacturability. To make biodegradable polymer microneedles with sharp tips, micro-electromechanical masking and etching were adapted to produce beveled- and chisel-tip microneedles and a new fabrication method was developed to produce tapered-cone microneedles using an in situ lens-based lithographic approach. To replicate microfabricated master structures, PDMS micromolds were generated and a novel vacuum-based method was developed to fill the molds with polylactic acid, polyglycolic acid, and their co-polymers. Mechanical testing of the resulting needles measured the force at which needles broke during axial loading and found that this failure force increased with Young's modulus of the material and needle base diameter and decreased with needle length. Failure forces were generally much larger than the forces needed to insert microneedles into skin, indicating that biodegradable polymers can have satisfactory mechanical properties for microneedles. Finally, arrays of polymer microneedles were shown to increase permeability of human cadaver skin to a low-molecular weight tracer, calcein, and a macromolecular protein, bovine serum albumin, by up to three orders of magnitude. Altogether, these results indicate that biodegradable polymer microneedles can be fabricated with an appropriate geometry and sufficient strength to insert into skin, and thereby dramatically increase transdermal transport of molecules.