The potential of a microneedle patch for reducing obesity

KEYWORDS:

• Obesity
• browning
• microneedle
• intradermal delivery

1. Introduction

Obesity has been identified as a chronic disease by the American Medical Association since 2013. The worldwide prevalence of obesity is spreading rapidly during the past few decades, affecting billions of people (~15% of the population), especially in developing countries. The metabolic disorders associated with obesity such as diabetes and cardiovascular diseases severely threaten public health. Moreover, obesity has significantly increased the risk of cancer incidence and mortality, which accounts for an estimated ~20% death in adults [1]. Hence, there is an urgent demand for weight management and obesity treatment.

Obesity most often results from excessive accumulation of fat, caused by the imbalance of fat absorption and energy expenditure. Meanwhile, environmental and genetic factors also play important roles in the development of obesity [2]. Dietary and lifestyle adjustments can facilitate weight management, but it is difficult to maintain for a long period. Besides, bariatric surgeries are also performed for weight loss in some cases.

A few pharmacological agents have been approved by US FDA to help control weight through suppressing appetite (e.g. dexfenfluramine) or absorption of fats (e.g. orlistat), or promoting energy expenditure (e.g. β3-adrenoceptor agonists) along with diet and exercise. However, they often show limited efficacy and systemic side effects as a large dosage is usually required by conventional administration routes, including oral, nasal, pulmonary, and intravenous delivery, strongly limiting their applications [3]. Therefore, a safe and effective therapeutic strategy against obesity is urgently needed.

2. Targeting delivery to adipose tissue

One of the approaches to reducing systemic adverse effects is targeted delivery of drugs to adipose tissue. Nanoparticles have been widely applied in the site-specific drug delivery systems such as tumor-targeted delivery for cancer treatment [4]. For adipose tissue targeting, prohibitin-homing peptides have been employed as a targeting motif, which can selectively bind to prohibitin that highly expressed on the membrane of adipocytes. Kim group combined the targeting peptide with 9-arginine to construct a carrier together with a short-hairpin RNA against fatty-acid-binding protein-4 with ~75% silencing efficacy, thereby inhibiting the transport and accumulation of lipid in adipocytes [5]. More recently, Langer, Farokhzad, and coworkers designed a peptide-functionalized nanoparticle to deliver browning agents, rosiglitazone or prostaglandin E2 analog, to adipose tissue vasculature [6]. Browning agents have been investigated as promising therapeutics to regress obesity, since they are able to transform adipose tissue from energy storing (white) to energy expenditure (brown/beige-like). Upon intravenous injection, targeted nanoparticles released agents specifically to the adipose tissue and stimulated angiogenesis as well as upregulated browning markers. Besides using peptide modified carriers for systemic targeted delivery, Jiang et al. directly injected drug-loading nanoparticles to the subcutaneous inguinal adipose tissue for locally sustained drug release [7]. Drug-loaded nanoparticles were retained in the adipose tissue, resulting in the subsequent browning of the treated inguinal fat tissue.

3. Microneedle-assisted drug delivery

Microneedle-based delivery provides an alternative administration method and has been clinically used in delivering small molecule drugs [8]. A microneedle patch usually consists of arrays of microscopic needles that transport therapeutics into the skin in a minimally invasive means. These micron-scale needles can be fabricated by a variety of materials and methods for diverse sizes, shapes, and purposes. Integrating with the microneedle patch, it is possible to achieve localized drug delivery and decrease systemic side effects. For example, our group applied microneedle array patch to locally deliver immune checkpoint inhibitors or tumor antigen into tumor environment for enhanced therapeutic efficacy toward melanoma [9,10].

More recently, Zhang et al. developed a local delivery system to minimize the side effects of the anti-obesity therapeutics, which is based on a polymeric microneedle patch (Figure 1) [11]. They employed glucose-responsive nanoparticles to encapsulate rosiglitazone as the browning agents for sustained release. These drug-loaded particles were further integrated into the microneedle array to restrict the nanoparticles within the device for localized delivery in the subcutaneous adipose tissue. Under the physiological glucose condition, the pH-sensitive nanoparticle gradually degraded in an enzyme-induced acidic environment to subsequently release the embedded browning agents to adipocytes and promote their transformation from energy storing (white) to energy expenditure (beige). The in vivo results on a diet-induced obese mouse model indicated a significant inhibition of weight gain (~15%) compared to the untreated group. Interestingly, they demonstrated a local treatment effect using the microneedle patch with a ~10% difference in the inguinal fat pad size observed between the treated and nontreated side in the same mouse.

Figure 1. Schematic showing the microneedle assisted local delivery of the browning agent to adipose tissue for obesity control. Adapted with permission from ref [11] Copyright (2017) American Chemical Society.

In another work explored by Than et al., the researchers also took the advantage of the microneedle patch to deliver anti-obesity compounds targeting on the subcutaneous adipose tissue [12]. They tailored the release kinetics of the drugs by changing the degradation rate of the needle with various components. Their results presented much lower effective dosage compared to systemic administration, indicating a decreased risk of adverse effects.

4. Expert opinion

Pharmacotherapy plays an important role in obesity treatment, while most treatments are limited due to the low therapeutic efficacy and significant side effects caused by high-dosage of medication through oral administration. In order to achieve high therapeutic efficacy, a desirable anti-obesity treatment requires adipocytes-specific delivery of drugs with a low dose.

The microneedle-based device provides a localized and bloodless delivery strategy, which is able to maximize the therapeutic effect with a minimal drug dosage. In addition, it can also serve as a safe reservoir for the compounds (such as microRNAs) that are not able to survive through systemic administration. Anti-obesity drug delivery utilizing microneedle patch has been demonstrated potential in weight management. This painless administration method can not only enhance the therapeutic efficiency due to the concentrated drug level within adipose tissue, but also overcome the adverse effects caused by systemic administration.

Furthermore, bioresponsive patch models that are capable of releasing drugs in response to internal-signals have been developed for controlled and on-demand drug delivery recently [13]. For example, glucose-responsive microneedles that could release insulin in response to blood glucose level were demonstrated to effectively adjust normoglycemia for diabetes treatment [14]. Such bioresponsive microneedle approach could be a promising way to move forward for anti-obesity drug delivery. The biosignals associated with the chronic inflammatory environment in adipose tissue such as hypoxia and high reactive oxygen species (ROS) levels may provide new insights for the design of adipocyte-targeting drug delivery with a precise dosage control [15].

In addition, the feasibility of the low-cost fabrication process also benefits the mass production of microneedles for further clinical applications. In summary, we envision that such microneedle device could offer an effective, safe, and simple approach for the management of obesity and associated diseases.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by a grant from the Alfred P. Sloan Foundation (Sloan Research Fellowship) to Zhen Gu, NC TraCS, NIH’s Clinical and Translational Science Awards (CTSA, NIH grant 1UL1TR001111) at UNC-CH.