Drug delivery to hair follicles

1. Introduction

2. Structure and biology of the

hair follicle and its functions

3. Investigation of follicular

penetration

4. Drug delivery to hair follicles

5. Drug delivery via hair follicle:

current applications

6. Conclusion

7. Expert opinion

Review

Drug delivery to hair folliclesAlexa Patzelt† & Juergen LademannCenter for Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venerology

and Allergology, Charite - Universitatsmedizin Berlin, Berlin, Germany

Introduction: The optimization of drug delivery to and via the hair follicles is

gaining more and more importance as it has been recognized that the hair

follicles are an interesting target site for topical applications. They are closely

surrounded by capillaries and antigen-presenting cells, are associated with

the sebaceous glands and are the host of stem cells in the bulge region of

the hair follicle.

Areas covered: The present review shortly summarizes the complexity of the

structure, biology and functions of the hair follicle and presents the models

and methods suitable to investigate follicular penetration. Drug delivery to

hair follicles was clearly shown to be dependent on the physicochemical prop-

erties of the applied substances and vehicles as well as on the activity status,

size and density of the hair follicles. Especially particulate substances were

demonstrated to be proficient drug carriers into the hair follicles, whereas

dependent data for transfollicular penetration into the deeper viable skin

layers could only be found for non-particulate substances which then, how-

ever, received rapid access to the circulation when the follicular pathway

was accessible.

Expert opinion: Promising concepts to optimize hair follicle delivery and to

beneficially utilize particulate substances for efficient follicular drug delivery

are the application of external or internal stimuli for controlled drug release

from the particles such as the combined application with protease or the

usage of gold nanoparticles in combination with near-infrared irradiation.

Keywords: controlled release, drug delivery, hair follicle, particles

Expert Opin. Drug Deliv. [Early Online]

1. Introduction

Since the end of the 18th century, attempts have been made to administer drugstransdermally and to improve skin absorption by various methods includingmechanical, physical and chemical manipulations to reduce the barrier function ofthe skin [1]. Particularly, researchers and physicians quickly understood that themajor function of the skin is providing a protective barrier at the interface betweenthe hostile external environment and the organism [2] thus impeding the uptake oftopically applied substances. However, the skin does not represent a completelyimpermeable barrier but provides physiologically available accesses. Potential entriesto overcome the skin barrier are the intercellular route within the stratum corneum,the hair follicles and the transcellular route as depicted in Figure 1. The transcellularpenetration pathway seems to play a subordinate role, yet.

The respective relevance of these routes for percutaneous absorption of com-pounds depends on their density and path length, as well as the diffusivity and sol-ubility of the compound in each domain [3]. For the intercellular penetrationpathway, Bos and Meinardi [4] proposed the 500 Da rule for skin penetration ofchemical compounds and drugs, hypothesizing that molecules larger than 500 Daare not able to penetrate the skin. They based their assumption on their observationthat all common contact allergens, commonly used dermatopharmaceutics andtopical drugs have molecular weights smaller than 500 Da.

10.1517/17425247.2013.776038 © 2013 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 1All rights reserved: reproduction in whole or in part not permitted

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For the follicular penetration pathway the situation is dif-ferent. While its relevance has been neglected for years, thehair follicle is now gaining increasing importance as specifictarget for topical drug delivery by providing additional fea-tures compared with intercellular penetration, such as fastdelivery into the blood flow and long-term intrafollicularstorage [5,6].

2. Structure and biology of the hair follicleand its functions

The hair follicle itself is a very complex and dynamic three-dimensional structure underlying cyclical activity [7]. Eachhuman individual displays an estimated number of 5 millionhair follicles [8]. In principle, it has to be distinguished betweenthe smaller vellus hair follicles and larger terminal hair follicles.Their morphometry has been already well documented [9].However, the enormous number of the hair follicles recordedemphasizes their important role in penetration processes.

Whereas original functions of the hair follicles seemed to bethose of a sensory organ and instrument of psychosocial com-munication, sebum excretion and protection [8], coincidentaladditional functions seem to be penetration and reservoirfunctions which are due to their architectural structure.

The upper part of the hair follicle is the infundibulumwhich represents an area of additional absorption andincreases the surface area of the skin depending on the skinsites, which provide different follicular densities and sizes.The highest density of vellus hair follicles can be found onthe forehead, whereas the highest average size of the follicularorifice is represented in the calf region [10]. Thus, the com-bined follicular orifices of the face and the scalp can cover10% of the total surface area [11], whereas in other body sites,the follicular openings only constitute about 0.1% [3].Otberg et al., for example, found that the reservoir volumesof the stratum corneum and the hair follicles in the regionof the forehead were approximately comparable [10].

As presented in Figure 1, the infundibulum consists ofupper and lower parts. Whereas in the upper infundibulum,the epithelium is continuous with the keratinized epidermisand covered by an intact stratum corneum, the barrier of thelower infundibulum is interrupted as the differentiationpattern switches from epidermal to a tricholemmal differen-tiation [12] facilitating transfollicular penetration. As thisupper part of the hair follicle is additionally supplied by adense capillary network, transfollicularly penetrated sub-stances can permeate into the central circulation [12] mean-ing a rapid systemic uptake becomes feasible [13], whichwas shown to be significantly faster in comparison withpure intercellular penetration [14,15]. In this study, caffeineneeded around 20 min to be detectable in the blood afteronly intercellular and occluded transfollicular penetration,whereas it took only 5 min when the hair follicles wereaccessible [15].

In addition to the capillary network, the upper hair follicleis also surrounded by a high density of immune cells suggest-ing that the hair follicle might be a promising target for top-ical vaccination [16] but also a potential entry point for typeI allergens, which might play a pathophysiological role inthe development or aggravation of atopic dermatitis [17].

Moreover, the hair follicles provide additional target sites oftherapeutic interest (Figure 1), such as the sebaceous gland andthe bulge region where the epithelial stem cells are hostedwhich provide a high proliferative capacity and multipo-tency [18] but which can also be the origin of skin tumorssuch as the basal cell carcinoma [19]. For the improved treat-ment of pathologies associated with these structures, such asacne or alopecia areata for the sebaceous gland, it may beimportant to increase the distribution of certain drugs in thehair follicles [20]. For diverse substances such as adapalene [20],erythromycin--zinc complexes [21] and tretinoin [22], respectiveefforts have been made. Being highly proliferative and multi-potent, the bulge cells provide opportunities as a stem cellsource for cutaneous regenerative medicine. Promising goals

Article highlights.

. The optimization of topical drug delivery represents aresearch topic of highest priority.

. The hair follicle represents a relevant target site fortopical drug delivery as it is easily accessible andprovides a diversity of structures which are oftherapeutic interest such as the infundibulumsurrounded by blood capillaries and antigen-presentingcells, the sebaceous gland or the bulge region hostingstem cells.

. Particulate substances would be ideal transportersystems for topical delivery as they offer severaladvantages such as high surface-to-volume ratio, deepintrafollicular penetration, selective targeted delivery tospecific sites within the hair follicle and sustainedrelease, however, for at least larger particulatesubstances, a transfollicular or intercellular penetrationor permeation in deeper skin layers could not beobserved due to their size.

. Therefore, different approaches to take advantage ofthe positive attributes of particulate delivery systems areunder investigation.

. Next to targeted delivery directly to the site of actionwithin the hair follicle by choosing the correct particlesize, also particles equipped with specific releasemechanisms have been proposed, which release thedrugs actively from the particles after penetration fromwhereupon the drugs can translocate independently intothe viable skin or to other desired targets.

. Future investigations should focus on i) thedetermination of a size threshold below whichtransfollicular and intercellular penetration becomesfeasible, ii) the definition of adequate models andmethods to investigate follicular particle penetrationwithout over- and underestimation with regard to riskassessment and iii) the optimization of controlled drugrelease with all possible modifications.

This box summarizes key points contained in the article.

A. Patzelt & J. Lademann

2 Expert Opin. Drug Deliv. [Early Online]

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might be the gene delivery to specific bulge stem cells to facil-itate long-term gene correction of congenital hair diseases orgenetic skin disorders such as epidermolysis bullosa, which isassociated with extensive wounding [23]. As hair follicles areeasily accessible, it has been demonstrated that they can betargeted by liposomes loaded with DNA [24].

Summarized, by improving the targeted delivery of drugsor substances to these specific sites, therapeutic strategiesrelated to these structures may be significantly enhancedand side effects may be minimized as systemic uptake canbe reduced.

The complex structure of the hair follicle, however, eluci-dates that ‘follicular penetration’ represents a complex processand is still rarely understood. Follicular penetration has to bedivided at least into two penetration steps. First, penetrationinto the hair follicle can be observed, and in a second step,transfollicular penetration may be detected, as demonstratedin Figure 1. Here, similar to the assumption of Bos andMeinardi [4] for the intercellular penetration, the size of thesubstances seems to play a superior role.

3. Investigation of follicular penetration

In general, the investigation of follicular penetration is chal-lenging as it requires spatial resolution. Initially, indirectdetection of follicular penetration by excluding the follicularpathway by comparing follicle-free and follicle-containingskin seemed to be the answer to this problem. The majordifficulty, however, was the lack of a quantitative model sys-tem that was truly follicle free but retained the structural, bio-chemical and barrier properties of normal skin [11]. Severalattempts have been made in this direction including the utili-zation of skins displaying different hair follicle densities [25] orof scarred or immature skin [26,27] or the usage of a sandwichmodel, where the top skin layer blocks the shunts in the bot-tom layer [28]. Nevertheless, these efforts could not fulfill thecriteria mentioned above.

In the meantime, several methods are available to investi-gate follicular penetration reasonably. The selective artificialhair follicle closing technique [29], as well as the differentialstripping methods [30] allow the quantitative estimation ofthe transfollicular and intrafollicular penetration in vivo,respectively. Both methods are schematically depictedin Figure 2. Also novel optical devices available on the marketare useful to investigate follicular penetration qualitativelyand also quantitatively, respectively, such as autoradiogra-phy [31], confocal laser scanning microscopy [32] or com-bined confocal laser scanning microscopy and confocalRaman spectroscopy [33]. The details as well as advantagesand disadvantages of each method for the investigation offollicular penetration have been recently summarized byMeidan [25].

Although several investigations on follicular penetrationhave been performed in vitro or ex vivo, there is increasing evi-dence of lacking in vitro--in vivo correlations. In a previousstudy, it could be shown that for experiments performed onthe same volunteers at the same skin site, the in vitro follicularreservoir of a specific topically applied substance was only10% of the in vivo follicular reservoir [34].

As a possible explanation, it was suggested that the elasticfibers surrounding the hair follicles contract during theexcision process. Whereas the removed sample can bere-stretched to its original size after cutting by expandingthe interfollicular elastic fibers, the elastic fibers surroundingthe hair follicle remain contracted reducing the follicular res-ervoir significantly. This contraction effect explains why diffu-sion cell experiments are not appropriate to investigatefollicular penetration as the follicular part of the penetrationprocess is significantly reduced by the contraction.

On the other hand, it might also explain why diffusioncells are still adequate models to investigate intercellularpenetration. For diffusion cell experiments, mostly splitskin or full epidermal skin is utilized, where at least thesubcutaneous tissue is removed, meaning that the bottompart of the hair follicle reaching into the subcutaneous tissueis cut off.

1

2

3

A

B

C D

?

1

2

Figure 1. Schematical illustration of the potential penetra-

tion pathways to overcome the skin barrier (1 -- 3) and of the

hair follicle morphology with its therapeutically interesting

target sites (A -- D). Penetration pathways: (1) intercellular

penetration pathway around the corneocytes within the

lipid layers, (2) follicular penetration pathway with transfol-

licular penetration option in dependence of skin condition

and physicochemical properties of the applied substance, (3)

intracellular penetration pathway across the corneocytes.

Hair follicle morphology: (A) infundibulum region with

increased permeability in the inferior part, (B) antigen-

presenting cells surrounding the infundibulum, (C) sebac-

eous gland being associated with the hair follicle, (D) bulge

region with stem cells.

Drug delivery to hair follicles

Expert Opin. Drug Deliv. [Early Online] 3

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Thus, the hair follicle is open at the bottom and the topi-cally applied substances can diffuse into the receptor medium,as also described by Senzui et al. [35] and illustrated in Figure 3.Due to the contraction, this effect seems to be minimized.Based on these results, the porcine ear model has been

introduced to be a suitable model to investigate follicular pen-etration ex vivo as the skin can remain fixed on the underlyingcartilage during the experiments [32]. Although, porcine hairfollicles are somewhat larger than human hair follicles, thismodel system has been well established to investigate thepenetration depths of substances into the hair follicles.

4. Drug delivery to hair follicles

Drug delivery to and via the hair follicles seems to depend onseveral aspects and ranges from the physicochemical proper-ties of the topically applied substances to the activity statusof the hair follicles.Thereby, it was suggested that the physicochemical proper-

ties of the substances might represent one of the importantinfluencing factors.

4.1 Physicochemical properties of topically applied

substancesThe effectiveness of follicular penetration can be affected byboth the active substance itself and by its vehicle. With regardto follicular penetration, vehicular optimization is still underdiscussion. Some authors suggest the use of volatile organicsolvents such as ethanol in order to dissolve and dry out thesebum from the follicular canal [36], whereas others showedthat lipophilic rather than hydrophilic vehicles are able toimprove follicular penetration [37]. In their own investigations,the authors investigated the influence of the vehicle of

particulate substances on the follicular penetration depthand found the deepest follicular penetration for aqueous andethanolic gel preparations, whereas aqueous or ethanolic sus-pensions showed significantly lower penetration depths [38].

In recent years, particulate substances such as liposomes,micro- and nanoparticles have attracted attention as a resultof their capability to improve follicular penetration. Liposomesare vesicular structures being able to envelop hydrophilic sub-stances in their inner compartment or to insert lipophilicsubstances in their membrane. Such liposomal formulationswere shown to enhance the penetration of substances into theskin [39] and specifically into the hair follicles [39-41].

For micro- and nanoparticles, a clear size-dependency forthe follicular penetration depth could be demonstrated inintact skin, whereby particulate penetration significantly sur-passed the penetration efficiency of non-particulate substan-ces with regard to follicular penetration depth [42]. Asillustrated in Figure 4, the optimum size for particles to pen-etrate deeply into the hair follicles was determined to be inthe range of 400 -- 700 nm, whereas smaller and larger par-ticles reached significantly lower penetration depths [13] orremained only on the skin surface of the follicular orifices,respectively [43,44]. This effect was shown for different par-ticles types. It was presumed that this observation may beexplained by a mechanical effect rather than by an effect spe-cific to different particle preparations [13]. Lademann et al.[45] hypothesized that the surface structure of the hair andthe hair follicle, which is determined by the thickness ofthe keratin cells (530 nm in human hair and around320 nm in porcine hair) might act as a pumping systemtransporting the particles deeply into the hair follicleswhen the hair is moving. Previous investigations could dem-onstrate that the movement of the hair, which occurs

1 2 3 4

A. B.

Figure 2. A. Selective follicular closing technique [29]. The hair follicles are closed with a special wax mixture prior to the

application of the substance under investigation and are therefore not accessible for the penetration process. Penetration

results can be compared with results obtained from skin areas with accessible hair follicles. Results of previous studies could

show that the permeation and systemic uptake is significantly accelerated if the hair follicles are accessible [15]. B. Differential

stripping method [30]: (1) intact skin with topically applied substance penetrating into the stratum corneum and the hair

follicle; (2) the stratum corneum is removed by tape stripping; (3) cyanoacrylate is applied distributing on the skin surface and

in the follicular infundibulum. Then, the treated skin surface is covered with a glass plate; (4) after polymerization of the

cyanoacrylate, the glass plate is removed containing the infundibular content and the hair. Subsequently, the amount of

substance penetrated into the stratum corneum and the hair follicle can be analyzed separately.



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physiologically in vivo, can be simulated in vitro by massageappliance [13,42]. The study mentioned above [13] moreoverrevealed that by choosing different particle sizes, different siteswithin the hair follicle can be selectively targeted, as presentedin Figure 4. By selecting PLGA (poly(lactic-co-glycolic acid))particles of 643 nm, for example, the authors depicted thateven the region of the bulge could be reached, which offersnew therapeutic options as due to their high surface-to-volumeratio, particles are ideal transporter systems.

Whereas the retention of the particulate substances in thefollicular duct has been well documented, researchers arecontroversially discussing whether or not particulate substan-ces penetrate the stratum corneum or transfollicularly intothe deeper skin layers, whereby the size seems to be againthe predominant parameter [46]. Recently, Labouta andSchneider [46] reviewed the recent literature focusing onskin penetration of inorganic particles. At first glance, actu-ally about half of the 40 analyzed studies reported particlepenetration or permeation. However, the results have to beconsidered carefully as most studies reporting particle pene-tration or permeation utilized either mechanical or chemicalenhancement approaches or the suitability of their model sys-tems used should be discussed. Penetration enhancementapproaches included increased UV exposure [47], hyperther-mia [48], iontophoresis [49], dermaportation [50], sonophore-sis [51], tape stripping [52] or dermabrasion and skinflexion [53]. As chemical permeation enhancers, substancessuch as oleic acid, ethanol, urea, sodium lauryl sulfate, poly-sorbate 80 and dimethyl sulfoxide were applied [46]. For stud-ies reporting particle penetration utilizing no penetrationenhancement strategies, the model systems utilized have tobe re-evaluated. As depicted by Labouta and Schneider [46],35% of the particle penetration studies were performed

in vitro on human skin. The respective studies showing parti-cle penetration without additional penetration enhancementwere all performed on excised or dermatomed skin at leastdiscarded from subcutaneous fat tissue and in diffusion cellexperiments. As stated above, this manipulation also includesa violation of the distal hair follicle so that topically appliedsubstances can just diffuse into the receptor medium as alsoreported by Senzui et al. [35] and illustrated in Figure 3.Whereas the contraction effect stated above might be ableto prevent diffusion of large particles, this model approachcould be responsible for the detection of very small particlesin the receptor medium erroneously interpreted as penetra-tion. For all human in vivo studies reported in the review ofLabouta and Schneider [46], no penetration or permeationcould be detected. As animal models, mostly porcine skin,mouse or rat skin was utilized. For the in vitro approacheson animal skin, similar concerns as for human in vitroapproaches arise. In total, 16% of the studies were performedin vivo on either porcine skin or mouse skin. Only few ofthese studies reported a penetration for very small particles.Huang et al. [54] hypothesized that the gold nanoparticles(11.6 nm) used in their study might interact hydrophobicallywith the skin lipids leading to a disruption of the lipid layerstructure which consequently leads to increased skin porosityand permeability.

In summary, the behavior of particle with respect to the skinbarrier is still in question, with several conflicting resultsreported. However, there are clear indications that particleslarger than 100 nm are unable to penetrate or permeate inter-cellularly or transfollicularly into deeper skin layers, if theexperiments are performed in vivo on intact skin. For smallerparticles, also with regard to risk assessment, further researchis necessary to determine a clear threshold below which trans-follicular and intercellular penetration becomes feasible. In thiscontext, it seems to be of highest priority to define suitablemethods and models to investigate particle penetration cor-rectly without the risk of underestimation and overestimationas may occur when skin penetration of particles is investigatedwith dermatomed skin of thickness 200 -- 400 µm as recom-mended by the Organisation for Economic Co-operationand Development [55].

4.2 Activity status of the hair follicles and

regional differencesPenetration properties vary not only with the physicochemicalcharacteristics of the applied substance but also with hairfollicle morphology, density and functional status of the hairfollicle. Each hair follicle undergoes continuous cycling,which includes the complete remodeling of its non-perma-nent portion. During each cycle, the hair follicle experiencessubstantial changes in the immune and gene expression status,as well as in its vascular supply, all of which must be consid-ered for the design of drug delivery systems [56]. In a previousstudy, it was shown that it has to be distinguished betweenopen and closed hair follicles. Hair follicles were receptive

~ 3500 µm

Receptor

~ 500 µm

Substance

Figure 3. For diffusion cell experiments mostly skin

discarded from subcutaneous fat tissue or even derma-

tomed skin is utilized meaning that the inferior part of the

hair follicle is cut off and the substance topically applied can

just diffuse into the receptor medium. This effect seems to

be minimized by the contraction of the elastic fibers

surrounding the hair follicle which contract automatically

when the skin is excised.



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for topical application and penetration, provided sebum flowand/or hair growth were active, whereas inactive hair folliclesshowed neither sebum flow nor hair growth [57]. A cover con-sisting of dry sebum, desquamated corneocytes and other celldetritus was detected on the inactive follicles blocking thepenetration. In the region of the upper forearm, only 74%of the hair follicles were receptive for penetration [57].Moreover, density and size vary extremely depending on the

body site. As early as in 1967, it was detected by Feldmannand Maibach [58] that higher absorption rates occur in skinareas with higher follicular density. Otberg et al. [10] analyzedthe volume and surface areas and reservoir capacity in differentbody regions and found significant differences of more than afactor of 10 for different skin sites which should be taken intoconsideration when interpreting penetration studies.

4.3 Hair follicle: a copious long-term reservoirWhereas effective transfollicular penetration seems to bereality rather for small molecular substances as for particulatesubstances, the question arises what happens to substancesonce penetrated into the hair follicle without the opportunityto permeate transfollicularly due to their size. The reservoir ofthe stratum corneum seems to be rather fugacious as most oftopically applied substances are located on the skin surfaceand in the upper cell layers being vulnerable to textile contact,washing and the physiologically occurring desquamationprocess eliminating one skin layer of the stratum corneum perday. By contrast, the hair follicle represents a well-protected

physiological reservoir in the skin which can be onlydepleted -- in addition to absorption -- by such slow processesas sebum flow or hair growth. In this context, it could be dem-onstrated that a particle-containing formulation could be storedup to 10 days within the hair follicles, whereas the stratum cor-neum reservoir was already nearly completely depleted after1 day [6]. This reservoir effect promises new therapeutic optionsas in this way, particles could be applied to release active sub-stances over a period of several days, making frequentlyrepeated applications unnecessary and concurrently increasingthe compliance of patients and the therapeutic outcome.

5. Drug delivery via hair follicle: currentapplications

Reflecting on the actually available results with regard to drugdelivery via hair follicles it can be summarized that the hairfollicle represents an interesting target site as well as a potentand fast access into the deeper viable skin layers by bypassingthe complex intercellular penetration pathway. Yet, thedisadvantage -- or advantage in terms of risk assessment -- is,that particulate substances which are still propagated to bepowerful cutaneous drug delivery systems were reliably shownto penetrate into the living tissue neither intercellularly nortransfolliculary so far. Only for deep follicular penetrationinto the hair follicle dependable data exist. Nevertheless, theobvious advantage of particulate substances is the possibilityof sustained release, resulting in extended activity or enhanced

860 nm230 nm 643 nm470 nm300 nm122 nm0 µm

200 µm

400 µm

600 µm

800 µm

1000 µm

1200 µm

1400 µm

0 µm

200 µm

400 µm

600 µm

800 µm

1000 µm

1200 µm

1400 µm

1 2 3

THF VHF

1 2 3

~ 3500 µm

Figure 4. Illustration of the different penetration depths reached with varying particle sizes ranging from 122 to 860 nm

(data from Patzelt et al. [13]) in correlation with the target sites within the hair follicles (morphometrical data of hair follicles

obtained from [9]). Smaller and larger particles only penetrated into the infundibular region, whereas the 643 nm particles

even reached the bulge region of the terminal hair follicle (THF). Morphometrical data for the vellus hair follicles (VHF) are

depicted for comparison at the right. (1) Length of the hair follicle, (2) length of the infundibulum, (3) position of the

bulge region.



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uptake and the possible reduction of adverse effects. Further-more, the encapsulated active substances are shielded fromdegradation in the particles [59].

Therefore, three different approaches to take advantage ofthe selective follicular penetration of particulate substanceshave currently emerged and are schematically illustratedin Figure 5: i) particles can be utilized to deliver therapeuticsubstances into the hair follicles and more specifically to thepre-determined target sites within the follicle by selecting spe-cific particle sizes or ii) particles can be utilized to translocatetherapeutic substances to the viable skin after skin barrier dis-ruption or iii) -- which might be a more elegant way withoutviolation of the skin -- particles equipped with a specificrelease mechanism are applied to deliver therapeutic substan-ces deeply into the hair follicles where they are releasedactively and subsequently translocated independently to theviable skin.

While the latter approach including the development ofappropriate release mechanisms still needs further efforts, prac-tical examples already exist for the first approach. Recently, itwas demonstrated that a nanoparticle-emulsion containingpolyhexanide was able to achieve a better and long-lastingantisepsis of the human skin than the same drug in non-partic-ulate form [60]. Background of the concept was that 25% of theresident bacterial flora of the human skin resides within the hairfollicles [61], however, conventional antiseptics are not able topenetrate deeply enough to effectively eradicate the bacteriafrom the hair follicles, so that a fast re-colonization occurs.

The nanoparticle emulsion containing polyhexanide, however,was demonstrated to block the endogenous recontaminationpathway. Also for chlorhexidine-loaded nanoparticles a pro-longed effect was demonstrated which was argued to be dueto the sustained release from the particle core which seems tohave an additional prolonging effect [62,63]. Also hair-growingingredients in PLGA particles were shown to increase their per-meation into the hair follicles 2- to 2.5-fold more than in thecase of the aqueous solutions used as control [64]. Hinokitiolencapsulated into particles enhanced the transition of hairfollicles from the telogen to the anagen phase [65]. Also theencapsulation of other hair growth therapeutics such as minox-idil [66] or finasteride [67] improved its permeation within thehair follicle region. Specific targeting of the sebaceous glandadditionally seems to be a promising therapeutic option forthe therapy of sebaceous gland disorders such as acne orrosacea [20]. Taglietti et al. [68] carved out in their recent reviewthat a diversity of nanoproducts has been demonstrated toincrease follicular penetration of acne therapeutics and toachieve higher local drug concentrations and optimized thera-peutic effects. Some products are already commerciallyavailable [64].

The second approach to translocate therapeutic substancesto the viable skin is to disrupt the skin barrier prior to topicalapplication of substances. Therefore, various techniques suchas cyanoacrylate skin surface stripping, chemical enhancers,microneedles, electroporation and ultrasound have beendeveloped [16,69]. Vogt et al., for example, used cyanoacrylateskin surface stripping to enhance the uptake of transcutaneousanti-influenza vaccines [16]. The dense network of antigen-presenting cells being especially accessible in the lowerinfundibulum of the hair follicle renders the hair follicle apromising target for vaccination, which is the topic of severalrecent investigations. Diverse nanomaterials such as liposomes,non-degradable and biodegradable particles are currently beingtested, promising new challenging results in the emerging fieldof particle-based transcutaneous vaccination [64].

The third approach is to equip particles with specificrelease mechanism. In this case, the particles are only respon-sible to deliver the therapeutic substances deeply into thehair follicles where they are released actively and sub-sequently translocated independently to the viable skin.Applying this carrier concept, it is essential to quickly releasethe drug from the particles onto the specific target structure,at the appropriate time [70]. Compared with the sustained-release system, the stimuli-responsive controlled-release sys-tem can achieve a site-selective, controlled-release pattern,which can improve therapeutic efficacy [71]. In this context,the utilization of porous particles seems to be inappropriatesince release would occur continuously and already at thebeginning of fabrication [72]. Recently, it was demonstratedby Mak et al. [70] that the release of a model drug from par-ticles composed of bovine serum albumin could be realizedby the interaction of a protease. In the first series of theirinvestigations they applied the drug-containing particles

1 2 3

Figure 5. Illustration of current approaches to utilize

particulate substances as drug delivery systems. (1) Particles

are utilized to deliver therapeutic substances into the hair

follicles and more specifically to pre-determined target sites

within the hair follicle by selecting specific particle sizes

without translocating to the viable tissue. (2) Particles are

utilized to translocate therapeutic substances to the viable

tissue after skin barrier disruption (crosshatched areas on the

skin surface and infundibulum). (3) Particles are equipped

with specific release mechanisms. After penetrating into the

hair follicle, external or internal stimuli lead to an active

release of the drugs from the particles. Subsequently, the

drugs can translocate independently to the viable skin or

other desired target sites.



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prior to the application of a protease formulation. Therelease of the model drug was analyzed by the time-dependent fluorescent properties of the dye. Whereas theparticles were shown to penetrate down to the sebaceousgland, the protease only penetrated into the upper third ofthe follicular infundibulum, where the release exclusivelyoccurred, accordingly. In their subsequent series of experi-ments [72], they therefore used the protease likewise in partic-ulate form being able to penetrate to similar depths withinthe hair follicle as the drug-carrying particles. Here, therelease also occurred at significant depths within the hair fol-licle. Even an uptake of the model drug in the sebaceousgland was observed.Moreover, further mechanisms for controlled drug release

are under investigation. External stimulation factors includ-ing radiofrequency [73], ultrasound [74], light [75] as well aspH control [71] have already been used to control drug release.Zhu et al. [71] studied pH stimuli-response controlled drugrelease from hollow silica spheres by coating multilayer poly-electrolyte possessed pH-sensitive properties. Lai et al. [76]

reported the stimuli-responsive controlled drug release ofwater-soluble drugs from mesoporous silica particles by usingchemically CdS nanoparticles as caps for mesoporous chan-nels and disulfide bond-reducing molecules as release triggers.Mal et al. realized photo-controlled reversible release of drugmolecules from coumarin-modified mesoporous silicaparticles [77]. Also magnetic-sensitive drug release from silicananospheres was proposed by controlled bursting to atherapeutically effective concentration by a high-frequencymagnetic field [78]. Additionally, gold nanoparticles are prom-ising agents for drug delivery as they can be easily preparedand do not show significant toxicity in vitro or in vivo [79].Gold nanorods have an absorption band in the near-infraredregion, convert absorbed light energy into heat and can there-fore act as a controller of a drug-release system capable ofresponding to the near-infrared light irradiation.Whereas the application of protease-triggered drug release

has already been shown to be successful in the follicular situ-ation, corresponding evidence is still missing for the otherpromising concepts which will be certainly the topic offuture investigations.

6. Conclusion

Due to the complex structure of the hair follicle, the optimi-zation of drug delivery to and via this specific target site isbecoming increasingly important. Current aspects of optimi-zation include the utilization of particulate substances whichhave been shown to penetrate preferably into the hair folliclesor of controlled drug release systems. In this case, the par-ticles are utilized only as transporters to a desired depthwithin the hair follicle, where the active drug is then releasedand can translocate independently to the deeper viable skinlayers surrounding the hair follicles. The latter possibilityrepresents a promising concept to utilize the advantageous

delivering attributes of particles also for transfollicularpenetration intentions.

7. Expert opinion

The research in the area of drug delivery to the hair follicleshas intensified significantly during the last years and stilloffers further potential. A variety of facts possibly influencingthe process of follicular penetration has not yet been fullyexplained and needs further investigation. It seems, however,that the size of the applied substance -- next to otherfactors -- predominantly influences how deep a substance isdelivered into the hair follicle and if the substance is allowedto permeate into the deeper skin layers through the follicularbarrier. Although there is clear evidence that particulate sub-stances larger than 100 nm are not able to penetrate or perme-ate in deeper skin layers of intact skin, a clear threshold belowwhich transfollicular and intercellular penetration becomesfeasible has not been determined, yet, and should be in thefocus of future research activities. First of all, it seems to beof highest priority to define suitable models and methods toinvestigate follicular particle penetration correctly, as the crit-ical consideration of previously applied models and methods(such as the utilization of dermatomed skin and diffusioncells) may have led to overestimations with regard to particu-late penetration due to the violation of the distal hair follicleallowing simple diffusion through the cut off distal hair folli-cle. On the other hand, of course, an underestimation has tobe avoided, too. If in vivo studies in humans are not possibledue to, for example, ethical reasons, porcine ear skin has beendemonstrated to be a helpful skin model as skin and folliclestructure in humans and pigs are similar. A clear advantageof porcine ear skin is, however, that the skin can remain fixedon the underlying cartilage during the experiments inhibitingany violation and contraction of the hair follicle.

Although transfollicular penetration of at least larger par-ticulate substances could be excluded due to size reasons,particles still remain ideal transporter systems. Particulatedelivery still provides several advantages such as high sur-face-to-volume ratio, deep intrafollicular penetration, selectivetargeted delivery to specific sites of interest within the hair fol-licle by choosing the corresponding particle sizes, sustainedrelease resulting in extended activity or enhanced uptake andtherewith the possible reduction of adverse effects. Therefore,different approaches to take advantage of these positive attrib-utes have been proposed. Next to targeted delivery of substan-ces directly to the site of action within the hair follicle,particles can be equipped with specific release mechanismsto release drugs actively from the particles from whereuponthey can translocate independently into the viable skin orother desired targets. Currently, promising drug-releaseconcepts are the utilization of protease particles leading to adegradation of the particles and thereby releasing the drugand the application of gold particles in combination withnear-infrared irradiation leading to a heat-controlled release.



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Although further research is still necessary to convert thisknowledge into clinical applications, the controlled drugrelease with external or internal stimuli represents an auspi-cious concept also in terms of risk assessment as the controver-sially discussed particulate substances are not getting intocontact with the viable tissue on this path. Future investiga-tions should therefore focus on the optimization of controlleddrug release within the hair follicle with all possible modi-fications such as retarded release, continuous release orintermittent release.

Acknowledgements

The authors would like to thank the Foundation ‘Skin Phys-iology’ of the Donor Association for German Science andHumanities for financial support.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.

BibliographyPapers of special note have been highlighted as

either of interest (�) or of considerable interest(��) to readers.

1. Helmstadter A. Endermatic, epidermatic,

enepidermatic-the early history of

penetration enhancers. Int J Pharm

2011;416:12-15

2. Patzelt A, Antoniou C, Sterry W,

Lademann J. Skin penetration from the

inside to the outside: a review.

Drug Discov Today 2008;5:229-35

3. Schaefer H. Skin barrier: principles of

percutaneous absorption. Karger, Basel;

1996

4. Bos JD, Meinardi MM. The 500 Dalton

rule for the skin penetration of chemical

compounds and drugs. Exp Dermatol

2000;9:165-9

5. Luther N, Darvin ME, Sterry W, et al.

Ethnic differences in skin physiology,

hair follicle morphology and follicular

penetration. Skin Pharmacol Physiol

2012;25:182-91

6. Lademann J, Richter H, Schaefer UF,

et al. Hair follicles - a long-term reservoir

for drug delivery.

Skin Pharmacol Physiol 2006;19:232-6. An important study demonstrating that

the hair follicles serves as long-term

reservoirs for topically

applied substances.

7. Rogers GE. Hair follicle differentiation

and regulation. Int J Dev Biol

2004;48:163-70

8. Krause K, Foitzik K. Biology of the hair

follicle: the basics. Semin Cutan

Med Surg 2006;25:2-10

9. Vogt A, Hadam S, Heiderhoff M, et al.

Morphometry of human terminal and

vellus hair follicles. Exp Dermatol

2007;16:946-50

10. Otberg N, Richter H, Schaefer H, et al.

Variations of hair follicle size and

distribution in different body sites.

J Invest Dermatol 2004;122:14-19

11. Meidan VM, Bonner MC, Michniak BB.

Transfollicular drug delivery -- is it a

reality? Int J Pharm 2005;306:1-14

12. Blume-Peytavi U, Vogt A. Human hair

follicle: reservoir function and selective

targeting. Br J Dermatol

2011;165(Suppl 2):13-17

13. Patzelt A, Richter H, Knorr F, et al.

Selective follicular targeting by

modification of the particle sizes.

J Control Release 2011;150:45-8.. A landmark study showing that

follicular targeting is mainly dependent

on the size of the applied substances.

14. Blume-Peytavi U, Massoudy L, Patzelt A,

et al. Follicular and percutaneous

penetration pathways of topically applied

minoxidil foam. Eur J Pharm Biopharm

2010;76:450-3

15. Otberg N, Patzelt A, Rasulev U, et al.

The role of hair follicles in the

percutaneous absorption of caffeine. Br J

Clin Pharmacol 2008;65:488-92

16. Vogt A, Mahe B, Costagliola D, et al.

Transcutaneous anti-influenza vaccination

promotes both CD4 and CD8 T cell

immune responses in humans.

J Immunol 2008;180:1482-9

17. Meinke MC, Patzelt A, Richter H, et al.

Prevention of follicular penetration:

barrier-enhancing formulations against

the penetration of pollen allergens into

hair follicles. Skin Pharmacol Physiol

2011;24:144-50

18. Ohyama M. Hair follicle bulge:

a fascinating reservoir of epithelial stem

cells. J Dermatol Sci 2007;46:81-9

19. Grachtchouk M, Pero J, Yang SH, et al.

Basal cell carcinomas in mice arise from

hair follicle stem cells and multiple

epithelial progenitor populations.

J Clin Invest 2011;121:1768-81

20. Rolland A, Wagner N, Chatelus A, et al.

Site-specific drug delivery to

pilosebaceous structures using polymeric

microspheres. Pharm Res

1993;10:1738-44

21. Morgan AJ, Lewis G,

Van den Hoven WE, et al. The effect of

zinc in the form of erythromycin-zinc

complex (Zineryt lotion) and zinc acetate

on metallothionein expression and

distribution in hamster skin.

Br J Dermatol 1993;129:563-70

22. Ridolfi DM, Marcato PD, Justo GZ,

et al. Chitosan-solid lipid nanoparticles

as carriers for topical delivery of

tretinoin. Colloids Surf B Biointerfaces

2012;93:36-40

23. Ohyama M, Vogel JC. Gene delivery to

the hair follicle. J Investig Dermatol

Symp Proc 2003;8:204-6

24. Li L, Lishko V, Hoffman RM. Liposome

targeting of high molecular weight

DNA to the hair follicles of histocultured

skin: a model for gene therapy of the

hair growth processes. In Vitro Cell Dev

Biol Anim 1993;29A:258-60

25. Meidan VM. Methods for quantifying

intrafollicular drug delivery: a critical

appraisal. Expert Opin Drug Deliv

2010;7:1095-108.. This is an important review on the

methods available to investigate and

quantify hair follicle delivery.

26. Hueber F, Besnard M, Schaefer H, et al.

Percutaneous absorption of estradiol and

progesterone in normal and

appendage-free skin of the hairless rat:

lack of importance of nutritional blood

flow. Skin Pharmacol 1994;7:245-56

27. Tenjarla SN, Kasina R, Puranajoti P,

et al. Synthesis and evaluation of

N-acetylprolinate esters - novel skin

penetration enhancers. Int J Pharm

1999;192:147-58



Exp

ert O

pin.

Dru

g D

eliv

. Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Yal

e D

erm

atol

ogic

Sur

gery

on

04/0

9/13

For

pers

onal

use

onl

y.

28. Barry BW. Drug delivery routes in skin:

a novel approach. Adv Drug Deliv Rev

2002;54(Suppl 1):S31-40

29. Teichmann A, Otberg N, Jacobi U, et al.

Follicular penetration: development of a

method to block the follicles selectively

against the penetration of topically

applied substances.

Skin Pharmacol Physiol 2006;19:216-23

30. Teichmann A, Jacobi U, Ossadnik M,

et al. Differential stripping:

determination of the amount of topically

applied substances penetrated into the

hair follicles. J Invest Dermatol

2005;125:264-9

31. Fabin B, Touitou E. Localization of

lipophilic molecules penetrating rat skin

in vivo by quantitative autoradiography.

Int J Pharm 1991;74:59-65

32. Lademann J, Richter H, Meinke M,

et al. Which skin model is the most

appropriate for the investigation of

topically applied substances into the hair

follicles? Skin Pharmacol Physiol

2010;23:47-52

33. Caspers PJ, Lucassen GW, Puppels GJ.

Combined in vivo confocal Raman

spectroscopy and confocal microscopy of

human skin. Biophys J 2003;85:572-80

34. Patzelt A, Richter H, Buettemeyer R,

et al. Differential stripping demonstrates

a significant reduction of the hair follicle

reservoir in vitro compared to in vivo.

Eur J Pharm Biopharm 2008;70:234-8.. This study is of importance as it

elucidates that the correct choice of

models and methodologies plays an

important role when investigating

follicular penetration.

35. Senzui M, Tamura T, Miura K, et al.

Study on penetration of titanium dioxide

(TiO(2)) nanoparticles into intact and

damaged skin in vitro. J Toxicol Sci

2010;35:107-13

36. Illel B. Formulation for transfollicular

drug administration: some recent

advances. Crit Rev Ther Drug

Carrier Syst 1997;14:207-19

37. Motwani MR, Rhein LD, Zatz JL.

Deposition of salicylic acid into hamster

sebaceous. J Cosmet Sci 2004;55:519-31

38. Patzelt A, Richter H, Daehne L, et al.

Influence of the vehicle on the

penetration of particles into hair follicles.

Pharmaceutics 2011;3:307-14

39. Mura S, Pirot F, Manconi M, et al.

Liposomes and niosomes as potential

carriers for dermal delivery of minoxidil.

J Drug Target 2007;15:101-8

40. Hoffman RM. Topical liposome

targeting of dyes, melanins, genes, and

proteins selectively to hair follicles.

J Drug Target 1998;5:67-74

41. El Maghraby GM, Williams AC,

Barry BW. Can drug-bearing liposomes

penetrate intact skin? J Pharm Pharmacol

2006;58:415-29

42. Lademann J, Richter H, Teichmann A,

et al. Nanoparticles--an efficient carrier

for drug delivery into the hair follicles.

Eur J Pharm Biopharm 2007;66:159-64

43. Schaefer H, Lademann J. The role of

follicular penetration. A differential view.

Skin Pharmacol Appl Skin Physiol

2001;14(Suppl 1):23-7

44. Toll R, Jacobi U, Richter H, et al.

Penetration profile of microspheres in

follicular targeting of terminal hair

follicles. J Invest Dermatol

2004;123:168-76

45. Lademann J, Patzelt A, Richter H, et al.

Determination of the cuticula thickness

of human and porcine hairs and their

potential influence on the penetration of

nanoparticles into the hair follicles.

J Biomed Opt 2009;14:021014

46. Labouta HI, Schneider M. Interaction of

inorganic nanoparticles with the skin

barrier: current status and critical review.

Nanomedicine 2013;9:39-54.. This review is of great importance as it

reveals that particulate substances of a

certain size are not able to overcome

the intact skin barrier in vivo and that

a distinct size threshold has still to be

determined below which transfollicular

or intercellular penetration and

absorption is feasible.

47. Mortensen LJ, Oberdorster G,

Pentland AP, et al. In vivo skin

penetration of quantum dot nanoparticles

in the murine model: the effect of UVR.

Nano Lett 2008;8:2779-87

48. Upadhyay P. Enhanced

transdermal-immunization with

diptheria-toxoid using local

hyperthermia. Vaccine 2006;24:5593-8

49. Dixit N, Bali V, Baboota S, et al.

Iontophoresis - an approach for

controlled drug delivery: a review.

Curr Drug Deliv 2007;4:1-10

50. Krishnan G, Edwards J, Chen Y, et al.

Enhanced skin permeation of naltrexone

by pulsed electromagnetic fields in

human skin in vitro. J Pharm Sci

2010;99:2724-31

51. Paliwal S, Menon GK, Mitragotri S.

Low-frequency sonophoresis:

ultrastructural basis for stratum corneum

permeability assessed using quantum

dots. J Invest Dermatol

2006;126:1095-101

52. Labouta HI, el-Khordagui LK, Kraus T,

et al. Mechanism and determinants of

nanoparticle penetration through human

skin. Nanoscale 2011;3:4989-99

53. Zhang LW, Monteiro-Riviere NA.

Assessment of quantum dot penetration

into intact, tape-stripped, abraded and

flexed rat skin. Skin Pharmacol Physiol

2008;21:166-80

54. Huang Y, Yu F, Park YS, et al.

Co-administration of protein drugs with

gold nanoparticles to enable percutaneous

delivery. Biomaterials 2010;31:9086-91

55. Development. OfEC-oa. OECD

guidelines for the testing of chemicals,

section 4. Test no. 428: skin absorption:

in vitro method. 2004. Available from:

http://wwwoecd-ilibraryorg/environment/

test-no-428-skin-absorption-in-vitro-

method_9789264071987-en

56. Knorr F, Lademann J, Patzelt A, et al.

Follicular transport route--research

progress and future perspectives. Eur J

Pharm Biopharm 2009;71:173-80

57. Otberg N, Richter H, Knuttel A, et al.

Laser spectroscopic methods for the

characterization of open and closed

follicles. Laser Phys Lett 2004;1:46-9

58. Feldmann RJ, Maibach HI. Regional

variation in percutaneous penetration of

14C cortisol in man. J Invest Dermatol

1967;48:181-3

59. Gupta M, Agrawal U, Vyas SP.

Nanocarrier-based topical drug delivery

for the treatment of skin diseases.

Expert Opin Drug Deliv 2012;9:783-804

60. Ulmer M, Patzelt A, Vergou T, et al. In

vivo investigation of the efficiency of a

nanoparticle-emulsion containing

polihexanide on the human skin. Eur J

Pharm Biopharm 2012.

[Epub ahead of print]

61. Lange-Asschenfeldt B, Marenbach D,

Lang C, et al. Distribution of bacteria in

the epidermal layers and hair follicles of

the human skin. Skin Pharmacol Physiol

2011;24:305-11

62. Lboutounne H, Chaulet JF, Ploton C,

et al. Sustained ex vivo skin antiseptic



Exp

ert O

pin.

Dru

g D

eliv

. Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Yal

e D

erm

atol

ogic

Sur

gery

on

04/0

9/13

For

pers

onal

use

onl

y.

http://wwwoecd-ilibraryorg/environment/test-no-428-skin-absorption-in-vitro-method_9789264071987-en



activity of chlorhexidine in poly(epsilon-

caprolactone) nanocapsule encapsulated

form and as a digluconate.

J Control Release 2002;82:319-34

63. Lboutounne H, Faivre V, Falson F, et al.

Characterization of transport of

chlorhexidine-loaded nanocapsules

through hairless and Wistar rat skin.

Skin Pharmacol Physiol 2004;17:176-82

64. Papakostas D, Rancan F, Sterry W, et al.

Nanoparticles in dermatology.

Arch Dermatol Res 2011;303:533-50

65. Tsujimoto H, Hara K, Tsukada Y, et al.

Evaluation of the permeability of hair

growing ingredient encapsulated

PLGA nanospheres to hair follicles and

their hair growing effects. Bioorg Med

Chem Lett 2007;17:4771-7

66. Shim J, Seok Kang H, Park WS, et al.

Transdermal delivery of mixnoxidil with

block copolymer nanoparticles.

J Control Release 2004;97:477-84

67. Kumar R, Singh B, Bakshi G, et al.

Development of liposomal systems of

finasteride for topical applications:

design, characterization, and in vitro

evaluation. Pharm Dev Technol

2007;12:591-601

68. Taglietti M, Hawkins CN, Rao J. Novel

topical drug delivery systems and their

potential use in acne vulgaris.

Skin Therapy Lett 2008;13:6-8

69. Lawson LB, Freytag LC, Clements JD.

Use of nanocarriers for transdermal

vaccine delivery. Clin Pharmacol Ther

2007;82:641-3

70. Mak WC, Richter H, Patzelt A, et al.

Drug delivery into the skin by

degradable particles. Eur J

Pharm Biopharm 2011;79:23-7

71. Zhu Y, Shi J, Shen W, et al.

Stimuli-responsive controlled drug release

from a hollow mesoporous silica sphere/

polyelectrolyte multilayer core-shell

structure. Angew Chem Int Ed Engl

2005;44:5083-7

72. Mak WC, Patzelt A, Richter H, et al.

Triggering of drug release of particles in

hair follicles. J Control Release

2012;160:509-14. This study describes the mechanisms of

triggered drug release combining the

advantages of deep follicular delivery

due to particles and rapid

transfollicular penetration performed

independently by the released drug.

73. Brazel CS. Magnetothermally-responsive

nanomaterials: combining magnetic

nanostructures and thermally-sensitive

polymers for triggered drug release.

Pharm Res 2009;26:644-56

74. Huang SL. Liposomes in ultrasonic drug

and gene delivery. Adv Drug Deliv Rev

2008;60:1167-76

75. Pissuwan D, Niidome T, Cortie MB.

The forthcoming applications of gold

nanoparticles in drug and gene delivery

systems. J Control Release

2011;149:65-71

76. Lai CY, Trewyn BG, Jeftinija DM, et al.

A mesoporous silica nanosphere-based

carrier system with chemically removable

CdS nanoparticle caps for

stimuli-responsive controlled release of

neurotransmitters and drug molecules.

J Am Chem Soc 2003;125:4451-9

77. Mal NK, Fujiwara M, Tanaka Y.

Photocontrolled reversible release of guest

molecules from coumarin-modified

mesoporous silica. Nature

2003;421:350-3

78. Hu SH, Liu TY, Huang HY, et al.

Magnetic-sensitive silica nanospheres for

controlled drug release. Langmuir

2008;24:239-44

79. Yamashita S, Fukushima H, Niidome Y,

et al. Controlled-release system mediated

by a retro Diels-Alder reaction induced

by the photothermal effect of gold

nanorods. Langmuir 2011;27:14621-6

AffiliationAlexa Patzelt†1 & Juergen Lademann2

†Author for correspondence1Center for Experimental and

Applied Cutaneous Physiology,

Department of Dermatology,

Venerology and Allergology, Charite -

Universitatsmedizin Berlin, Chariteplatz 1,

10117 Berlin, Germany

Tel: +0049 30 450 518 106;

Fax: +0049 30 450 518 918;

E-mail: [email protected],

Center for Experimental and

Applied Cutaneous Physiology,

Department of Dermatology,

Venerology and Allergology,

Charite - Universitatsmedizin Berlin,

Chariteplatz 1, 10117 Berlin, Germany



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Drug delivery to hair follicles