Microneedle-Based Intradermal Delivery Enables Rapid Lymphatic Uptake and Distribution of Protein Drugs

Harvey, Alfred; Kaestner, Scott A.; Sutter, Diane; Harvey, Noel G.; Mikszta, John A.; Pettis, Ronald J.

doi:10.1007/s11095-010-0123-9

Cited by 133 publications

(90 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The matrix of MNs was made from cross-linked HA to improve the stiffness of MNs and restrict the loss of GRVs from needles. With transcutaneous administration, the GRVs loaded in MNs disassembled when exposed to high interstitial fluid glucose in vascular and lymph capillary networks (35), thereby promoting the release of insulin, which was then taken up quickly through the regional lymph and capillary vessels (36). We demonstrated that this "smart insulin patch" with a novel glucoseresponsive mechanism displayed rapid responsiveness for glucose regulation and reliable avoidance of hypoglycemia in a mouse model of type 1 diabetes.…”

Section: Significancementioning

confidence: 96%

Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

715

551

View full text Add to dashboard Cite

A glucose-responsive "closed-loop" insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch ("smart insulin patch") containing glucoseresponsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GO x ) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy.diabetes | drug delivery | glucose-responsive | hypoxia-sensitive | microneedle

show abstract

Section: Significancementioning

confidence: 96%

Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

715

551

View full text Add to dashboard Cite

show abstract

“…In the case of lymphedema, in particular, a major limitation in the development of new treatments has been the lack of in vivo imaging diagnostics capable of quantifying differences in the dynamic pump function of lymphatic vessels in real time. 3 Recently, the lymphatic system has garnered increased interest, as its roles in tumor metastasis, 4 dermal drug delivery, 5 chronic inflammation, 6 and lipid transport 7 are beginning to be appreciated. With the new understanding of the role of lymphatic vessels in disease processes and therapies, there is now a greater need for major advances in the diagnostic imaging tools available to adequately visualize and quantify lymphatic pump function.…”

Section: Introductionmentioning

confidence: 99%

Sensitivity analysis of near-infrared functional lymphatic imaging

2012

View full text Add to dashboard Cite

Abstract. Near-infrared imaging of lymphatic drainage of injected indocyanine green (ICG) has emerged as a new technology for clinical imaging of lymphatic architecture and quantification of vessel function, yet the imaging capabilities of this approach have yet to be quantitatively characterized. We seek to quantify its capabilities as a diagnostic tool for lymphatic disease. Imaging is performed in a tissue phantom for sensitivity analysis and in hairless rats for in vivo testing. To demonstrate the efficacy of this imaging approach to quantifying immediate functional changes in lymphatics, we investigate the effects of a topically applied nitric oxide (NO) donor glyceryl trinitrate ointment. Premixing ICG with albumin induces greater fluorescence intensity, with the ideal concentration being 150 μg∕mL ICG and 60 g∕L albumin. ICG fluorescence can be detected at a concentration of 150 μg∕mL as deep as 6 mm with our system, but spatial resolution deteriorates below 3 mm, skewing measurements of vessel geometry. NO treatment slows lymphatic transport, which is reflected in increased transport time, reduced packet frequency, reduced packet velocity, and reduced effective contraction length. NIR imaging may be an alternative to invasive procedures measuring lymphatic function in vivo in real time.

show abstract

“…10,53 The drugs can be subsequently absorbed into the blood stream or lymphatic circulation. 11,54 It is expected that the protein released will accumulate in the subepidermal tissues and be rapidly absorbed from the highly vascularized regions lying underneath.…”

Section: In Vitro Release Of Bsa From Microneedlesmentioning

confidence: 99%

Protein encapsulation in polymeric microneedles by photolithography

Kochhar¹,

Zou²,

Chan³

et al. 2012

IJN

View full text Add to dashboard Cite

Background: Recent interest in biocompatible polymeric microneedles for the delivery of biomolecules has propelled considerable interest in fabrication of microneedles. It is important that the fabrication process is feasible for drug encapsulation and compatible with the stability of the drug in question. Moreover, drug encapsulation may offer the advantage of higher drug loading compared with other technologies, such as drug coating. Methods and results:In this study, we encapsulated a model protein drug, namely, bovine serum albumin, in polymeric microneedles by photolithography. Drug distribution within the microneedle array was found to be uniform. The encapsulated protein retained its primary, secondary, and tertiary structural characteristics. In vitro release of the encapsulated protein showed that almost all of the drug was released into phosphate buffered saline within 6 hours. The in vitro permeation profile of encapsulated bovine serum albumin through rat skin was also tested and shown to resemble the in vitro release profile, with an initial release burst followed by a slow release phase. The cytotoxicity of the microneedles without bovine serum albumin was tested in three different cell lines. High cell viabilities were observed, demonstrating the innocuous nature of the microneedles. Conclusion:The microneedle array can potentially serve as a useful drug carrier for proteins, peptides, and vaccines.

show abstract

Microneedle-Based Intradermal Delivery Enables Rapid Lymphatic Uptake and Distribution of Protein Drugs

Cited by 133 publications

References 45 publications

Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

Sensitivity analysis of near-infrared functional lymphatic imaging

Protein encapsulation in polymeric microneedles by photolithography

Contact Info

Product

Resources

About