Core-shell microneedle devices and uses thereof
The present disclosure relates to microneedle devices and methods for treating a disease (for example, diabetes) using a degradable cross-linked gel for self-regulated delivery of a therapeutic agent (for example, insulin).
1 . A microneedle patch, comprising:
a plurality of microneedles each having a base end and a tip; and
a substrate to which the base ends of the microneedles are attached;
wherein the microneedles comprise:
a shell, comprising:
a first poly (vinyl alcohol) (PVA) polymer cross-linked with a first peroxide-sensitive linker; and
a peroxide scavenging enzyme encapsulated within a first nanogel, wherein the first nanogel is embedded in the first PVA polymer;
and
a core, comprising:
a second poly (vinyl alcohol) (PVA) polymer cross-linked with a second peroxide-sensitive linker;
a glucose-responsive agent encapsulated within a second nanogel, wherein the second nanogel is embedded in the second PVA polymer; and
a therapeutic agent, wherein the therapeutic agent is covalently attached to the second PVA polymer with a third peroxide-sensitive linker;
wherein the glucose-responsive agent comprises glucose oxidase; and
wherein the therapeutic agent is insulin.
2 . The microneedle patch of claim 1 , wherein the first peroxide-sensitive linker comprises a boronic ester.
3 . The microneedle patch of claim 1 , wherein the first peroxide-sensitive linker is N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1,N1,N3,N3-tetramethylpropane-1,3-diaminium (TSPBA).
4 . The microneedle patch of claim 1 , wherein the second peroxide-sensitive linker comprises a boronic ester.
5 . The microneedle patch of claim 1 , wherein the second peroxide-sensitive linker is N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1,N1,N3,N3-tetramethylpropane-1,3-diaminium (TSPBA).
6 . The microneedle patch of claim 1 , wherein the third peroxide-sensitive linker comprises a boronic ester.
7 . The microneedle patch of claim 1 , wherein the third peroxide-sensitive linker is 4-nitrophenyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl carbonate (NBC).
8 . The microneedle patch of claim 1 , wherein the peroxide scavenging enzyme is catalase.
9 . The microneedle patch of claim 1 , wherein the microneedles further comprise hyaluronic acid (HA).
10 . A method of delivering a therapeutic agent to a subject, comprising:
administering to the subject the microneedle patch of claim 1 ; and
releasing the therapeutic agent from the microneedle patch in the presence of hyperglycemic levels of glucose.
11 . The method of claim 10 , wherein the subject has diabetes.
12 . The method of claim 10 , wherein the glucose-responsive agent produces a peroxide when exposed to hyperglycemic levels of glucose.
13 . The method of any one of claim 10 , wherein the method further comprises detaching the first peroxide-sensitive linker from the first PVA polymer upon exposure to the peroxide.
14 . The method of claim 10 , wherein the method further comprises detaching the second peroxide-sensitive linker from the second PVA polymer upon exposure to the peroxide.
15 . The method of claim 10 , wherein the method further comprises detaching the third peroxide-sensitive linker from the second PVA polymer upon exposure to the peroxide.
16 . The method of claim 15 , wherein the detaching of the third peroxide-sensitive linker from the second PVA polymer releases the therapeutic agent from the microneedle patch.
17 . The method of claim 10 , wherein the method further comprises reducing blood glucose levels.
18 . The method of claim 10 , wherein the method further comprises terminating release of the therapeutic agent prior to causing hypoglycemia.