Polymeric carriers for controlled drug delivery in obesity treatment

Abstract

The global rise in the prevalence of obesity and affiliated metabolic syndrome pose a significant threat to human health. Various approaches, including bariatric surgery and pharmacotherapy, have been used in the clinical setting for obesity treatment; however, these conventional options remain ineffective and carry risks of side effects. Treatments with higher efficacy and specificity are therefore urgently required. Emerging drug delivery systems use polymeric materials and chemical strategies to improve therapeutic efficacy and specificity through stabilization and spatiotemporally controlled release of anti-obesity agents. This review provides insights into current treatment for obesity with a focus on recent developments of polymeric carriers for enhanced anti-obesity drug delivery.

Status of Obesity Management

Obesity is a chronic and complex disease, characterized by ectopic and excessive accumulation of adipose tissue (AT, commonly known as fat) that significantly increases the body weight and compromises the normal physiological function of AT [1]. Various therapeutic approaches for the treatment of obesity, such as lifestyle intervention, pharmacotherapy, and bariatric surgery, have been developed [2]. Lifestyle changes are the cornerstones of weight management, but they are difficult to achieve and to maintain. As a result, pharmacotherapy is typically considered an adjunctive treatment option [3].

Several anti-obesity drugs and their therapeutic targets have been investigated in animals and humans. Six major therapeutic agents have been approved by the US Food and Drug Administration (FDA) for obesity treatment, including phentermine (Adipex-P^®), orlistat (Xenical^®), lorcaserin (Belviq^®), liraglutide (Saxenda^®), naltrexone/bupropion sustained release (Contrave^®), and phentermine/topiramate extended release (Qsymia^®). Most of these drugs work through central nervous system pathways that reduce appetite or enhance satiety, with the exception of orlistat, which decreases the absorption of fat [4]. However, inefficacy and risks of side effects have cast a long shadow over development of many obesity therapeutic agents, leading to their withdrawn from the market [5]. Examples of side effects include pulmonary hypertension (aminorex), stroke (phenylpropanolamine), and neuro-psychiatric issues (rimonabant) [6]. These undesirable experiences highlight the importance of risk-benefit assessment and necessitate the development of new drug delivery strategies to achieve safer and more efficient obesity treatment options.

Advanced drug delivery systems have been developed over recent decades using a wide array of materials and chemical strategies. Biocompatible polymers are particularly attractive drug carrier matrix due to the versatility in polymer chemistry and ease of tailoring their physicochemical and biological properties [7]. Polymeric carriers offer benefits in controlled and sustained delivery, extended drug bioactivity, and enhanced dissolution. Additionally, these carriers are gaining encouraging prospects in medicine as they could stabilize drugs and localize their effect to improve the therapeutic efficacy and specificity [8]. Several carriers have been designed to deliver anti-obesity drugs to target different metabolic pathways (Figure 1). Compared to conventional pharmacotherapeutics, these new approaches have improved therapeutic efficiency and reduced side effects; and exhibit great potential for clinical translation. Here, we summarize some of the recent key developments in polymeric carriers for enhanced anti-obesity drug delivery.

Figure 1.

Key anti-obesity strategies and pharmacological agents. Reduced energy intake can be achieved through A) appetite suppression: leptin secreted by adipocytes penetrates across BBB and binds to neurons in the hypothalamus. JAK-STAT signaling has been identified as a key pathway involved in activation of leptin receptor in the hypothalamus. Upon activation of leptin pathway, synthesis of agouti-related neuropeptide and neuropeptide Y is inhibited, resulting in appetite suppression and decrease in food intake; and B) decrease in fat absorption: large dietary fat breaks down and feeds pool of dissolved monoglycerides and fatty acids. Once uptake by absorptive intestinal cells, they are packaged into chylomicrons and released into the lymphatic system. EGCG has previously shown to suppress fat absorption with possible mechanisms including modified surface transport barriers and altered intraluminal digestion as well as intestinal production of lipoproteins. On the other hand, strategies to increase energy expenditure include C) exercise mimetics such as AMPK and PPAR agonists that increase energy expenditure by muscle cells, which in turn release myokines to regulate adipose tissues; D) stimulation of thermogenesis by brown adipocytes, which can be achieved through activation of β3-adrenal receptor (Adrb3) that relays sympathetic nerve signal to activate brown adipocytes, or activation of intracellular cAMP, a downstream mediator Adrb3 signaling; and E) white to brown fat conversion (termed “browning”). For example, activation of Notch signaling leads to the release of Notch intracellular domain (NICD) via γ-secretase-mediated proteolytic cleavage. NICD translocates to the nucleus where it binds RBPJ transcriptional complex to activate the transcription of HES and HEY family genes. HES directly binds to the promoter regions of PRDM16 and PGC1α to inhibit beige adipogenesis. Since the proteolytic cleavage of NICD is necessary for activation of Notch signaling, pharmacological blocking using a γ-secretase inhibitor DBZ inhibits Notch signaling transduction and promotes browning of white adipocytes. This figure was created using BioRender (https://biorender.com/).

Conventional Treatments for Obesity and Their Limitations

Current treatments for obesity are generally prescribed based on the severity of excess weight and coexisting chronic conditions. Healthy lifestyle choices are considered the foundation of obesity treatment, given their low costs and minimal risks. However, weight loss might lead to physiological adaptations that promote weight regain [2]. As a result, lifestyle modifications alone typically induce modest weight loss that is difficult to sustain. Additional treatment options for obesity have therefore been used in the clinical setting, principally including bariatric surgery (Box 1) and pharmacotherapy (Box 2) [3] [9].

Text Box 1: Commonly Used Bariatric Surgery Procedures.

Bariatric surgery is an effective treatment for severe obesity that results in the improvement and remission of many obesity-related comorbidities and sustained weight loss [70]. The use of surgical procedures has dramatically escalated in recent years with technical refinement of bariatric operations and initiation of an accreditation system to standardize the surgery outcomes [71]. Currently, four types of bariatric surgery are commonly performed in the U.S. Roux-en-Y gastric bypass is one of the first bariatric procedures developed and still considered the gold-standard weight-loss operation [9]. This operation restricts food intake by creating a small pouch in the upper gastric fundus anastomosed to a Roux limb of jejunum and facilitating the consumption of less food and fewer calories [72]. Weight loss with Roux-en-Y gastric bypass is around 70% of excess weight at 1 year [73]. Laparoscopic adjustable gastric banding is the least invasive and safest procedure without inducing any anatomical gut changes. It involves an inflatable silicone band placed around the gastric fundus to create a small pouch and to result in a reduction of hunger [74]. Weight loss after laparoscopic adjustable gastric banding has been reported to be 34% of the excess weight at 1 year [75]. Laparoscopic sleeve gastrectomy, the most commonly used bariatric procedure in the U.S., is constructed by removing 80% of the lateral aspect of the stomach in a vertical fashion and leaving a remaining long, tubular gastric pouch or sleeve. Weight loss from the sleeve gastrectomy has been reported to be 51-70% of excess weight at 1 year [75]. Lastly, biliopancreatic diversion with duodenal switch involves two distinct components. A vertical gastrectomy is firstly performed followed by bypassing a large portion of the small intestine to create malabsorption. Unlike the other procedures, a substantial amount of small bowel is bypassed with biliopancreatic diversion with duodenal switch, which results in a considerable decrease in the absorption of calories [76][77]. Although bariatric surgery yields short-term improvements in weight control, these procedures are generally associated with high costs, variations in outcomes, weight regain in 5 to 20% of patients, and great risks of complications ranging from 10 to 17% [72][78]. Additionally, questions remain regarding the long-term safety, such as micronutrient deficiencies, the possibility of future abdominal procedures, potentially higher incidence of suicide, and excess skin that may require additional surgery for removal [79][80][81][82].

Text Box 2: Current Pharmacotherapy Options.

Pharmacotherapy is indicated as an adjunct to a reduced-calorie diet and increased activity for long-term weight management, bridging the gap between lifestyle modifications and invasive bariatric surgery [83]. Currently available medications in the market achieve their anti-obesity effects via single or multiple mechanisms, principally including appetite suppression, decrease in fat absorption, and increase in energy expenditure [84]. Although efficacy has been found with monotherapies that target a single protein or pathway involved in obesity, with four monotherapy options (i.e. phentermine, orlistat, lorcaserin, and liraglutide) approved by the FDA, physiological counter-regulation mechanisms involving alternate pathways pose major limitations and lead to safety issues associated with cardiovascular and psychiatric complications [85]. Consequently, combined therapy is considered a more efficient way to treat a disease with multiple etiologies and two FDA-approved anti-obesity combination products (i.e. phentermine/topiramate and naltrexone/bupropion) are currently in the market.

However, the magnitude of weight loss may be modestly effective and insufficient to eliminate the possibility for the development of comorbidities, necessitating the development of novel therapeutic candidates and targets. Most new drugs in the pipeline, including centrally acting agents and gut hormones as well as incretin targets, achieve their anti-obesity effect via energy intake control [86]. Recently, a therapeutic strategy of boosting energy expenditure through stimulating thermogenesis receives more attention. Various factors have been identified to induce the transformation from white to beige adipose tissue (termed “browning”) and different browning agents, including PPARγ activator, β3-adrenoceptor agonist, and Notch signaling inhibitor, have been investigated as potential anti-obesity drugs [87][88][39].

Despite great efforts made to achieve therapeutic benefits, anti-obesity drugs have considerable safety concerns that are attributed to the multifactorial pathogenesis and the complex neuro-hormonal regulation of energy balance, thereby influencing patient persistence and in some cases leading to withdrawal or restricted use of approved agents. For example, sibutramine, a combined serotonin and noradrenaline reuptake inhibitor, was withdrawn from the market in 2010 due to increased cardiovascular events in patients with pre-existing cardiovascular conditions [89]. Furthermore, numerous studies addressing the efficacy and safety of these pharmacological agents are still in their infancy and drugs currently under development appear unable to change this situation in the near future. As a result, a significant portion of obese patients have limited treatment options due to the minimal weight loss and adverse effects associated with current pharmacotherapies.

Advanced Drug Delivery Systems for the Treatment of Obesity

Despite great efforts made over the past decades, conventional therapeutic methods for obesity are often insufficient for preserving metabolic equilibrium and preventing life-threatening complications. New strategies to improve the efficacy and to reduce the side effects are therefore critically needed for the management of obesity. Advances in biomaterials for drug delivery are enabling significant progress in medicine with many polymeric carriers designed to release therapeutics for extended periods of time and further engineered to target specific locations or cell types within the body [10]. These polymeric carriers include polymer conjugates [11], hydrogels [12], microneedles [13], micro- and nano-particles [14][15], and liposomes [16] (Figure 2). The utility of various drug delivery systems for obesity treatment are summarized in Table 1.

Figure 2.

Advanced drug delivery carriers for the treatment of obesity. Drugs can be conjugated to the polymer chain (e.g. polymer conjugates), encapsulated into the polymers (e.g. micro-/nano-particles) or lipids (e.g. liposomes), or embedded within the carrier matrix (e.g. hydrogels and microneedles) to form the drug delivery system.

Table 1.

Summary of advanced material carriers applied in the treatment of obesity.

Formulation	Advantages	Disadvantages	Applications in the treatment of obesity
			Administration route	Carrier matrix	Modification	Therapeutic agents	Experimental model	Ref.
Chemical conjugates	Drug release in controlled and sustained manner; Improvement in aqueous solubility of drug and its bioavailability; Prolong blood plasma half-life of drug	Low drug loading; Large sized conjugates have the potential for long-term accumulation, resulting in toxicity; Conjugates are taken up slowly by endocytosis	N.A.	Low molecular weight protamine	N.A.	ASO for HIF1α	3T3-L1 cell line	[60]
			Intraperitoneal injection	Low molecular weight protamine	N.A.	ASO for HIF1α	Lean or HFD-induced obese mice	[11]
			Local injection	D-form 9-arginine	Adipose homing peptide (CKGGRAKDC)	shRNA silencing FABP-4	HFD-induced obese mice	[61]
			Intravenous injection	Dextran	PEG	Dexamethasone	Lean or HFD-induced obese mice	[22]
			Intracerebroventricular injection or intravenous injection or subcutaneous injection	Pluronic P85	N.A.	Leptin	Ob/ob mice or HFD-induced obese mice	[18]
			Intracerebroventricular injection or intranasal injection	Pluronic P85	N-terminal group	Leptin	Lean mice	[19]
Hydrogels	Drug release in controlled and sustained manner; Good diffusional properties; Biocompatibility and biodegradability; In situ gelling systems at body temperature can be made	Low mechanical resistance; Difficult to control pore size and degradation rate; Potential toxicity posed by the chemical crosslinkers	Subcutaneous injection	PLGA	N.A.	EGCG	Mice fed with HFD or normal diet	[26]
			N.A.	Methylcellulose-gold nanoparticles	N.A.	Leptin	3T3-L1 cells	[27]
Microneedles	Non-invasive administration; Ease of administration; Specific tissue area can be targeted for desired drug delivery with minimized systemic side effects	Difficult insertion into the target tissue by hand without external device; Local inflammation may be induced if the amount of drug is high; Limited choice of appropriate biomaterials and lack of mechanical strength	Intradermal insertion	HA and PLGA	N.A.	CL316243 or T3	HFD-induced obese mice	[30]
			Intradermal insertion	HA	N.A.	Caffeine	HFD-induced obese mice	[31]
			Intradermal insertion	Gelatin	N.A.	Glycerol	HFD-induced obese rats	[32]
			Intradermal insertion	Methacrylated HA-dextran nanoparticles	Glucose oxidase and catalase	Rosiglitazone or CL316243	Lean or HFD-induced obese mice	[13]
Microparticles	Drug release in controlled and sustained manner; Protection of drugs against the environment; Aid in dispersion of water-insoluble drugs in aqueous media; Localizing at the application site	Limited ability to cross biological barriers and enter the cells due to relatively large particle size; Inflammatory response might be elicited due to slow degradation of particulate materials	Oral administration	PCL	N.A.	Capsaicinoids	Obese rats induced by hypothalamic lesion using monosodium L-glutamate	[36]
			Oral administration	Chitosan	N.A.	Capsaicinoids	HFD-induced obese rats	[37]
			Oral administration	Chitosan or water-soluble chitosan	N.A.	N.A.	Rats fed with HFD or normal diet	[62]
			Local injection	PLGA	N.A.	DBZ	Lean mice	[14]
			Bilateral injection into the paraventricular hypothalamic nucleus	Human serum albumin-alginate	N.A.	α-MSH	Lean rats	[38]
Nanoparticles	Drug release in controlled and sustained manner; Tunable physicochemical properties; Easy to functionalize; Excellent ability to penetrate across biological barriers	Difficulty for scale-up; Insufficient of toxicity assessment in the literature	Oral administration	Chitosan or water-soluble chitosan	N.A.	N.A.	Rats fed with HFD or normal diet	[62]
			Intraperitoneal injection	Cerium oxide	N.A.	N.A.	Lean rats	[63]
			Local injection	PLGA	N.A.	DBZ	HFD-induced obese mice	[49]
			N.A.	PLGA-b-PEG	TPP	2,4-DNP	3T3-L1 cell line	[48]
			Intravenous injection	PLGA-b-PEG	iRGD or P3	Rosiglitazone or prostaglandin E2 analog	Lean or HFD-induced obese mice	[47]
			Intravenous injection	Gold	Biotinylated adipose homing peptide (CKGGRAKDC) and PEG	N.A.	Mice fed with HFD or normal diet	[64]
			Retro orbital injection	PLGA	N.A.	Rosiglitazone	Ldlr−/− mice fed with HFD	[44]
			Intravascular injection	Bifidobacterium shuttle vector	N.A.	OXM	Normal or overweight mice	[65]
			Intravenous injection	Cadmium-based quantum dots	Adipose homing peptide (CKGGRAKDC)	N.A.	Rats fed with HFD or normal diet	[66]
			Retro-orbital injection	PCL or mesoporous silica	N.A.	N.A.	Lean or HFD-induced obese mice	[59]
Liposomes	Drug release in controlled and sustained manner; Biocompatibility and biodegradability; Low toxicity and antigenicity	Low stability; Phospholipids may undergo oxidation and hydrolysis; Leakage of encapsulated drugs during storage	Orally	Linseed oil	N.A.	Capsaicine and phenylalaninol oleamide or oleoylethanolamide	HFD-induced obese mice	[67]
			N.A.	Soy L-α-phosphatidylcholine	N.A.	Resveratrol	3T3-L1 cell line	[16]
			Intraperitoneal injection	DSPC and CDAN	PEG	Acetate	Lean or HFD-induced obese mice	[68]
			N.A.	Egg yolk phosphatidylcholine	Adipose tissue-specific circular peptide (KGGRAKD)	N.A.	Primary endothelial cells derived from white adipose tissue	[52]
			Intravenous injection	Egg yolk phosphatidylcholine	Adipose tissue-specific circular peptide (KGGRAKD)	N.A.	Lean or HFD-induced obese mice	[53]
			Intravenous injection	Egg yolk phosphatidylcholine	Adipose tissue-specific circular peptide (KGGRAKD)	D(KLAKLAK)2	Lean or HFD-induced obese mice	[54]
			Intravenous injection	Egg yolk phosphatidylcholine	Adipose tissue-specific circular peptide (KGGRAKD)	Cytochrome C	Mice fed with HFD or normal diet	[55]
			Intravenous injection	Lipid-latex	Phosphatidylserine and cholesterol-9-carboxynonanoate	Rosiglitazone, paclitaxel, and tamoxifen	FmsYFP+ mice fed with HFD or normal diet; ApoE−/− or wild type mice	[69]

CDAN: N¹-cholesteryloxycarbonyl-3,7-diazanonane-1,9-diamine; DSPC: 1,2-distearoyl-sn-glycero-3-phosphocholine; N.A.: Not available.

Polymer Conjugates

Polymer conjugates are commonly characterized by the presence of a rationally designed covalent bond between a polymer carrier and a bioactive drug molecule (Figure 2). These complexes release drugs as the polymers break down naturally over time or due to specific stimuli. The conjugated drug remains its bioactivity but also acts as a building block in the assemblies. Polymer conjugates offer advantages over native therapeutics with functional modifications allowing tunable release and enhanced stability of native drugs.

Polymer conjugates capable of crossing biomembranes are a new strategy to improve delivery efficacy for appetite control and thermogenesis induction. Leptin is a regulatory protein secreted by adipocytes and acting within the brain to suppress appetite (Figure 1), but it generally shows resistance in the blood-brain barrier (BBB) due to impaired BBB transport and leptin receptor function in the hypothalamus that develop with obesity [17]. To overcome this challenge, leptin was conjugated with amphiphilic pluronic triblock copolymers [18]. Compared to unmodified leptin, leptin-pluronic P85 conjugates exhibited improved peripheral bioavailability and brain accumulation along with increased efficiency in reducing food intake in both ob/ob and high fat diet (HFD)-induced obese mice. These results demonstrate that leptin analogs could be developed through chemical modification to facilitate penetration across BBB, thus improving the efficacy for appetite control. To further optimize the chemical structure of conjugates, leptin was conjugated with pluronic P85 at various random lysine amino groups or specifically at its N-terminal amine [19]. It was shown that low-dose N-terminal conjugates with a reduced steric hindrance to leptin receptor binding were more efficiently transported to the brain and accumulated in the hypothalamus and hippocampus to a greater extent than the native leptin and random conjugates.

Obesity has been linked to chronic systemic inflammation initiated by pro-inflammatory macrophages in visceral AT [20]. However, conventional anti-inflammatory therapeutics at high doses may induce serious side effects in off-target tissues, particularly in hepatocytes, myocytes, and adipocytes. Specific targeting visceral AT macrophages could therefore substantially reduce toxicity. Dexamethasone, a corticoid with a half-life of 36-72 h, binds to the glucocorticoid receptor that inhibits the transcription of pro-inflammatory genes in M1 macrophages [21]. Dexamethasone-dextran conjugates were designed for selective uptake by macrophages due to their expression of dextran-binding C-type lectins and scavenger receptors [22]. It was observed that up to 63% of the injected conjugates remained in visceral AT 24 h after administration, especially for those conjugated with high molecular weight dextran (70 and 500 kDa). The conjugated dexamethasone was slowly released after esterase hydrolysis and bound to the glucocorticoid receptor that inhibits the transcription of pro-inflammatory genes in AT of obese mice.

Hydrogels

Hydrogels are three-dimensional, cross-linked networks of water-soluble polymers (Figure 2). As drug carriers, hydrogels can provide spatiotemporal control over the release of therapeutics and leverage therapeutically beneficial outcomes of drug delivery. Owing to their tunable physicochemical properties, controllable degradability and capability to protect drugs from degradation, hydrogels serve as a platform on which various physiochemical interactions with the biomolecules occur to control drug release and enhance therapeutic efficacy [23].

Epigallocatechin gallate (EGCG), the most abundant catechin in green tea with half-lives ranged from 1.9 to 4.6 h, has shown great potential of anti-obesity treatment via decrease in fat absorption (Figure 1) [24][25]. However, the poor bioavailability limits its clinical application. Zhang et al. developed EGCG-loaded in situ hydrogel implants using poly(lactic-co-glycolic acid) (PLGA) and administered the implants to HFD-induced obese mice [26]. Over a 30-day period, the hydrogel-EGCG implant group showed 35.6% reduction in body weight gain compared to the control group. Also, the hydrogel-EGCG implant treated mice had lower levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglyceride; and higher levels of high-density lipoprotein (HDL)-cholesterol. These findings suggest that in situ hydrogel implants could be a promising drug delivery system for prolonged anti-hyperlipidemic and anti-obesity treatment.

Hybrid hydrogels can also be fabricated to offer opportunities for controlled drug release. Liao et al. loaded leptin in methylcellulose-based hydrogels with incorporation of gold nanoparticles [27]. The temperature-dependent degradation of hydrogels was controlled by the proportion of gold nanoparticles. Leptin released from hydrogels was accumulated in AT, inhibiting fat storages in adipocytes following a tunable light irradiation response. Considering the encouraging in vitro results, further studies on the in vivo feasibility of this stimuli-responsive hydrogel system are warranted.

Microneedles

Microneedles as a drug delivery system provide an alternative administration method through surface skins and have been used in the clinic [28]. A microneedle patch usually consists of arrays of microscopic needles typically with a height ranged from 500-800 μm that can overcome the transport barrier posed by epidermis and directly localize therapeutic agents in a minimally invasive manner (Figure 2). These needles can be made of water-soluble or biodegradable polymers encapsulating drug that is released in the insertion site upon microneedle dissolution or degradation. The local diffusion and accumulation of transdermally delivered drugs allow targeted delivery into subcutaneous AT and minimize systemic side effects [29].

Than et al. developed microneedle patches using hyaluronic acid (HA) and PLGA to deliver an anti-obesity compound to the subcutaneous white AT [30]. Specifically, β3-adrenoceptor agonist CL316243 that has been widely used to convert white fat to brown fat (browning, Figure 1) was released from microneedles. The released drugs reached inguinal AT underneath the insertion sites, promoted browning of white AT, and suppressed body fat as well as weight gain in HFD-induced obese mice. Also, the microneedle delivery requires much lower effective dosage compared to systemic administration, thus minimizing potential side effects of over-activating β3-adrenoceptors. HA-based microneedles were also used to deliver caffeine, shown to be able to reduce body weight through stimulating lipolysis but exhibit low bioavailability due to its polymorphic transformation from anhydrous to hydrous form [31]. Loading caffeine into dissolvable HA microneedles inhibited its crystal growth and significantly improved lipolysis, which reduces the levels of triglyceride, total cholesterol, and LDL-cholesterol, leading to a weight loss of 12.8% in HFD-induced obese mice. More recently, microneedle-mediated delivery of natural polymers for obesity treatment was reported by An et al [32]. Their results showed that gelatin microneedles alone, without entrapping any therapeutics, reduced the amount of subcutaneous AT by ~60%, through inducing lipolysis and inhibiting lipogenesis in an HFD-induced obese rat model. This effect might be mediated by glycine, which constitutes 30% of amino acids in gelatin and has previously been shown to reduce body weight and adipose tissue [33]. The potential of drug loaded gelatin formulations for obesity treatment is enormous considering these current results, however, safety (immunogenicity) profile and pharmacological mechanism should be carefully evaluated in the future.

Microneedles can also be an effective vehicle for intradermal delivery of nanoparticles, where the microconduits in the epidermis produced by microneedles serve as channels for nanoparticles to enter the therapeutic sites. Zhang et al. developed a transcutaneous patch based on polymeric microneedles to locally deliver anti-obesity therapeutics and induce AT transformation [13]. They employed pH-sensitive acetal-modified dextran nanoparticles to encapsulate browning agents CL 316243 or rosiglitazone for sustained release. These drug-loaded particles were further embedded into the cross-linked HA-based microneedle array to penetrate the skin and restrict the agents in the inguinal AT. Under the physiological glucose condition, pH-sensitive nanoparticles gradually degraded to release the agent into the AT and to promote browning. The in vivo results on HFD-induced obese mice indicated that this microneedle formation increased systemic energy expenditure and fatty acid oxidation, improved insulin sensitivity, and inhibited weight gain (~15%).

Microparticles

Particulate drug delivery overcomes the limitation of microneedles, which are typically used for local drug delivery. Particles share similar advantages with hydrogel implants and microneedles in direct deposition at the therapeutic site with a high local drug concentration and minimized systemic toxicity (Table 1). They can also be used as reservoirs, administered through a convenient route with the drug slowly released for systematic effect. Additionally, particles can be administered systemically but delivered to specific locations at which to release the encapsulated drugs through active or passive targeting approaches [34]. A distinction is often made between microparticles and nanoparticles, being particles with dimensions best described in the micrometer and nanometer ranges, respectively (Figure 2). The difference in particle size makes differences at many aspects, from in vitro characteristics to in vivo usage.

Consumption of capsaicinoids has been shown to increase energy expenditure by 50 kcal/day, which produces a clinically significant weight loss within 1-2 years [35]. However, their pungency limits the long-term use through the gastrointestinal tract. Almeida et al. encapsulated capsaicin into polycaprolactone (PCL) microparticles [36]. Capsaicin was slowly released from PCL microparticles in a controlled manner without changing its biexponential release kinetic. The optimized particulate formulation efficiently enhanced the gastric tolerability of capsaicin by preventing inflammation in the submucosal layer of stomach and decreased mesenteric and retroperitoneal fat deposits in obese rats. Capsaicin-encapsulated chitosan microspheres have also been developed and their anti-obesity effects following oral administration were evaluated in HFD-induced obese rats [37]. Compared to native capsaicin and commercial agent Orlistat, capsaicin-encapsulated microspheres exhibited enhanced ability to control body weight, body fat, and serum lipids.

Local injection into the target tissue is one promising approach to achieve site specificity. Microparticles have also been administered via local injections for obesity treatment due to their favorable characteristics to avoid rapid diffusion of drugs and prolong their local retention. Lucas et al. prepared human serum albumin-alginate microparticles encapsulating α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide that has anti-obesity effects [38]. It was found that microparticles administered via hypothalamic injections were capable to slowly release α-MSH in the hypothalamus to specifically target paraventricular nucleus and protected the peptide from degradation. Compared to blank particles and native α-MSH groups, the rats receiving α-MSH-loaded particles showed a sustained decrease in body weight gain.

PLGA microparticles have also been used to locally inhibit Notch signaling in AT [14]. Notch signaling has previously been shown to promote adipocyte browning and improve energy metabolism (Figure 1) [39][40]. Dibenzazepine (DBZ) is a well-established inhibitor of Notch signaling, but systemic inhibition of Notch may exhibit off-target toxicity in the gastrointestinal tract [41]. DBZ-loaded PLGA microparticles were prepared and their effects on locally induced browning of white AT were investigated in lean mice. Results show that the released DBZ from microparticles following local injections into the inguinal white AT retained its bioactivity and efficiently promoted browning of white adipocytes through inhibition of Notch signaling. More importantly, the localized release of DBZ in the inguinal white AT overcame the potential side effects induced by systemic administration. Although microparticles show great potential for controlled drug delivery by providing a high local drug concentration over an extended period, challenges remain to be addressed in the application (Table 1). For instance, microparticles are unlikely to cross most biological barriers due to the large size. Also, they can elicit acute and chronic inflammatory response resulting from slow degradation of particulate materials.

Nanoparticles

Nanoparticles overcome some of the limitations faced by microparticles (Table 1). They are characterized by several additional benefits, such as large surface-to-volume ratio, intracellular drug release, and tunable surface chemistry, making them promising delivery systems for disease treatments, including obesity [42]. Their geometrical and physicochemical properties can be finely tuned during their synthesis process to optimize drug loading and enhance specificity in reaching the target cells/tissues, thereby increasing the therapeutic efficacy and minimizing side effects [43].

Systemic administration is a powerful delivery route for obesity treatment. Mascolo et al. fabricated rosiglitazone-encapsulated PLGA nanoparticles, surrounded by an outer layer of steric repulsive polyvinyl alcohol (PVA) to reduce aggregation of nanoparticles and attenuate protein modification and opsonization in the blood after intravascular injection [44]. HFD fed Ldlr^−/− mice treated with nanoparticles showed alleviation of inflammatory macrophages in the white AT and liver, without side effects on lipid metabolism and cardiac tissues, which are typically observed following systemic administration of native rosiglitazone.

Efficient drug delivery to specific therapeutic targets is always challenging. Nanoparticles can be modified with surface ligands, targeting molecules, or peptides, for efficient navigation to the therapeutic sites. As angiogenic factors crosstalk among cells in AT and stimulation of angiogenesis results in browning of AT [45][46], vasculature directed targeting of AT could be a potential therapeutic intervention for obesity. Xue et al. used PLGA-b-poly(ethylene glycol) (PEG) nanoparticles to encapsulate rosiglitazone or prostaglandin E2 analog, and modified the nanoparticle surface with adipose vasculature-targeted peptides iRGD (CRGDK/RGPD/EC) or P3 (CKGGRAKDC), which binds to antigens specifically expressed on the endothelium of angiogenic vasculature [47]. As a result, more targeted nanoparticles localized in the AT to release drugs following intravenous injection compared to free drugs and non-targeted nanoparticles. This approach enhanced browning of white AT and inhibited body weight gain in HFD-induced obese mice.

AT mitochondrial dysfunction is generally linked to obesity, but to efficiently deliver drugs to the mitochondria is one of the most challenging tasks. Marrache et al. developed mitochondria-targeting polymeric nanoparticles by blending a targeted PLGA-b-PEG-triphenylphosphonium (TPP) polymer with either non-targeted PLGA-b-PEG-OH or PLGA-COOH [48]. Targeted nanoparticles achieved high endolysosomal escapability and mitochondrial uptake efficacy due to their high buffering capacity. In addition, the efficacy can be adjusted by fine-tuning the surface charge and size of nanoparticles. Moreover, targeted nanoparticles encapsulating mitochondrial uncoupler 2,4-DNP suppressed differentiation of 3T3-L1 preadipocytes at a lower dose compared to the free drug.

Local drug delivery for the treatment of obesity has recently been investigated due to its ability to maintain drug bioavailability and permit a reduction in dosage. Jiang et al. encapsulated DBZ into PLGA nanoparticles and locally injected them into the inguinal white AT in HFD-induced obese mice to stimulate browning of white adipocytes, improve the glucose homeostasis, and attenuate body weight gain through inhibition of Notch signaling pathway [49]. Notably, nanoparticles were preferentially endocytosed by adipocytes following local administration, limiting the therapeutic agent to be distributed throughout the body and reducing the side effects on non-adipocyte cells. It was also found that DBZ-loaded nanoparticles efficiently inhibited Notch signaling with a dosage 50 times lower than that through intraperitoneal injection and ten times lower than that using microparticles due to enhanced intracellular delivery.

Liposomes

Liposomes, sphere-shaped vesicles consisting of one or more concentric lipid bilayers, represent another carrier for drug delivery (Figure 2) [50]. These carriers tend to interact or fuse with cells indiscriminately during systemic circulation and can be used as contact-facilitated delivery through lipid-lipid exchange between cell membrane and the lipid layer of liposomes [51]. The non-specific cellular uptake and uncontrolled entrapment in non-targeted organs are undesired for liposomal drug delivery via systemic administration, but can be overcome by modifying a hydrophilic polymer, such as PEG, onto the surface of liposomes, which enables minimal uptake by the reticuloendothelial system, reduced renal clearance, and prolonged retention in circulation [43]. The therapeutic agent is therefore better able to be retained in the body to exert its therapeutic potency.

To achieve enhanced drug delivery efficacy to AT, a variety of ligand-based functionalized liposomes have been developed and appear to be superior in specificity and safety. Hossen et al. modified the surface of liposomes with PEG and a circular peptide (KGGRAKD), which specifically binds to endothelial cell-surface prohibitin in white adipose vessels [52] [53]. The liposomes were specifically taken up by primary endothelial cells isolated from inguinal white AT via prohibitin-mediated endocytosis and escaped from endosomes and lysosomes. Compared to non-PEGylated targeted liposomes, PEGylated targeted liposomes achieved enhanced accumulation in white adipose vessels of lean mice following intravenous administration, whereas the undesired particle accumulation in the liver was considerably reduced. Moreover, targeted liposomes exclusively accumulated in both adipose vessels and angiogenic clusters of adipocytes after systemic administration in obese mice. Surprisingly, PEGylated non-targeted liposomes were also observed in these clusters via an unexpected passive targeting mechanism, potentially due to enhanced tissue permeability and retention effect. In following studies, anti-obesity therapeutics, such as proapoptotic peptide _D(KLAKLAK)₂ and apoptosis-initiating protein cytochrome C, were encapsulated in the prohibitin-targeted nanoparticles [54] [55]. It was found that systemic administration of targeted nanoparticles in HFD-induced obese mice substantially reduced body weight gain, serum leptin levels, and ectopic fat deposits in the liver and muscle. Additionally, no detectable hepatotoxicity associated with this prevention was observed, suggesting this targeted liposomal formulation had good biocompatibility and safety.

Challenges and Future Opportunities of Advanced Drug Delivery Strategies

Given aforementioned advances, it is believed that controlled drug delivery strategies will revolutionize the treatment of obesity. However, there is an urgent need to fully understand the advantages and disadvantages of these formulations (Table 1) and to overcome challenges for clinical translation. It is key to discover the fate of carriers following administration and mechanisms underlying their toxicity, and how to achieve high reproducibility and scale-up in industry.

The primary aim of pre-clinical evaluation is to identify the therapeutic potential and risks, to select formulations that are safe and efficacious, and possess the required pharmacokinetic and biodistribution properties. Since the off-target toxicities of delivery systems may be different from the parent drug, it is important to accurately assess their biodistribution within the body after administration and their interaction with targeted cells before use. Obesity is often associated with chronic inflammation, reduced blood flow to the AT, increased glomerular filtration, and histological alterations of the liver. As a result, obesity could interfere carrier biodistribution, degradation, and loading dose parameters [56]. However, there are few studies investigating the fate of delivery systems in obesity with the factors dictating carrier interactions within living systems largely ignored. It is commonly believed that nanoparticles with a particle size ranged from 15-200 nm are typically captured by the liver Kupffer cells, whereas those larger than 200 nm are retained in the spleen after administration [57,58]. However, Felismino et al. recently found an opposite trend in obese subjects [59]. Large nanoparticles (280 nm) were principally taken up by Kupffer cells, while small nanoparticles (58 nm) preferentially deposited in the spleen. Their results also suggested that particle size of carriers seemed to have a predominant effect on biodistribution, especially regarding the deposition in spleen, which tends to be more permeable to small particles under pathological conditions associated with obesity. In addition to characteristics of drug carriers, fat depots and administration routes also affect their biodistribution [22]. For instance, the portal-drained visceral fat depots are more lipolytically active and more permeable to particles compared to the subcutaneous fat pads, particularly in obese patients. Also, drug carriers administered via intraperitoneal route can be directly deposited in the targeted AT through a positive hydrostatic pressure generated by injected liquids, which allows rapid physical access of the drug to the adipose interstitium. Further studies are required to understand the fate of both carrier and drug following application before translating these formulations into the clinic.

Despite growing attention to the advantages of novel drug carriers for obesity treatment, further studies are certainly needed to assess whether benefits outweigh risks. Also, the anti-obesity efficacy of these carriers has often not been investigated in larger mammals, the feasibility is therefore less clear compared to therapeutics themselves. The safety of drug carriers should be particularly considered, since formulations applied at a wrong dose or in a susceptible patient may give rise to unexpected toxicity. Luckily, recent research efforts are made towards establishing standardized in vitro assays for biocompatibility evaluation of carrier materials and ex vivo models for predicting the biological and toxicological responses of drug carriers through specific routes of administration [57].

Another challenge that requires consideration is detailed characterization of physicochemical properties of these delivery systems. Compared to native drugs, it is more complex to thoroughly characterize drug-encapsulated carriers. These systems might be intrinsically heterogeneous resulting from polydispersity and batch-to-batch variations. Also, the degradation rate and mechanism of biodegradable polymers are another complicating factor in many cases, particularly for hybrid materials. Despite the complexity in experimental designs, systematic physicochemical characterizations of these formulations could contribute to the understanding of their biological and toxicological responses, development of subsequent generations for enhanced therapeutic efficacy, and transfer of formulations into the clinic.

Closing Remarks

Pharmacotherapy plays an important role in the management of obesity, but the therapeutic efficacy of conventional medication is limited with undesirable side effects. A variety of novel drug delivery strategies for obesity treatment have been developed to provide a targeted or intelligent platform to release therapeutics in a spatiotemporally controlled manner, thereby achieving enhanced anti-obesity efficacy and reduced toxicity. Although clinical translation of these formulations remains challenging and further explorations that take industrial and clinical perspectives into account are warranted (see Outstanding Questions), there are already successful pre-clinical studies involving these delivery strategies, which could have a significant impact on bringing safe and effective therapies to obese patients in the future.

Outstanding Questions.

• Are the benefits of polymeric carriers shown in small animals applicable to large mammals?

• Can standardized in vitro and ex vivo assays for safety evaluation of carriers be performed to accurately predict their biological and toxicological properties?

• Can the encapsulation of anti-obesity agents into polymeric carriers achieve controlled pharmacokinetics and target specificity required for efficacious obesity treatment in humans?

• Will safety issues arise from the use of polymeric carriers or degraded materials in humans?

• Will polymeric carriers for the treatment of obesity in clinical trials result in beneficial long-term outcomes?

Highlights.

• Obesity is the most prevailing chronic disease, affecting 13% of adults worldwide.

• These is a critical unmet need for the treatment of obesity.

• Conventional obesity treatments often lack efficacy and specificity.

• Biodegradable polymeric carriers are designed to achieve spatiotemporally controlled release of small molecular drugs.

• Novel polymeric drug carriers have been shown to overcome many limitations of conventional obesity treatments.

Abbreviations

α-MSH

α-melanocyte-stimulating hormone

AT

Adipose tissue

BBB

Blood-brain barrier

CDAN

N1-cholesteryloxycarbonyl-3,7-diazanonane-1,9-diamine

DBZ

Dibenzazepine

DSPC

1,2-distearoyl-sn-glycero-3-phosphocholine

EGCG

Epigallocatechin gallate

FDA

Food and Drug Administration

HDL

High-density lipoprotein

LDL

Low-density lipoprotein

N.A.

Not available

PCL

Polycaprolactone

PEG

Poly(ethylene glycol)

PLGA

Poly(lactic-co-glycolic acid)

PVA

Polyvinyl alcohol

TPP

Triphenylphosphonium