PROTAC Degraders of Androgen Receptor‐Integrated Dissolving Microneedles for Androgenetic Alopecia and Recrudescence Treatment via Single Topical Administration

Abstract

Androgenetic alopecia (AGA) is a transracial and cross‐gender disease worldwide with a youth‐oriented tendency, but it lacks effective treatment. The binding of androgen receptor (AR) and androgen plays an essential role in the occurrence and progression of AGA. Herein, novel proteolysis targeting chimera degrader of AR (AR‐PROTAC) is synthesized and integrated with dissolving microneedles (PROTAC‐MNs) to achieve AR destruction in hair follicles for AGA treatment. The PROTAC‐MNs possess adequate mechanical capabilities for precise AR‐PROTAC delivery into the hair follicle‐residing regions for AR degradation. After applying only once topically, the PROTAC‐MNs achieve an accelerated onset of hair regeneration as compared to the daily application of the first‐line topical drug minoxidil. Intriguingly, PROTAC‐MNs via single administration still realize superior hair regeneration in AGA recrudescence, which is the major drawback of minoxidil in clinical practice. With the degradation of AR, the PROTAC‐MNs successfully regulate the signaling cascade related to hair growth and activate hair follicle stem cells. Furthermore, the PROTAC‐MNs do not cause systemic toxicity or androgen deficiency‐related chaos in vivo. Collectively, these AR‐degrading dissolving microneedles with long‐lasting efficacy, one‐step administration, and high biocompatibility provide a great therapeutic potential for AGA treatment.

Observing the clinical efficacy of combined serum microneedle therapy for moderate to severe androgenetic alopecia in scalp repair

“…In hair regrowth treatments, densely arranged fine needles physically puncture the scalp, causing temporary, water‐filled cavities. This enhances the transdermal absorption of large molecules and/or hydrophilic molecules by creating micrometer‐sized delivery channels 10 . The potential mechanisms of microneedle therapy for hair loss include the following: (1) inducing the overexpression of hair growth‐related genes such as Wnt3a, Wnt10b, VEGF, and so on, thereby regulating the hair growth cycle, stimulating the dermal papilla, and promoting hair growth; (2) disrupting the integrity of the scalp skin barrier, causing the formation and expansion of neoangiogenesis, and the migration of keratinocytes, thereby promoting the growth of new hair; (3) inducing mechanical changes in the keratin barrier, forming micrometer‐level channels in the skin, and delivering various effective ingredients, including protein molecules and plant extracts, improving the efficiency of drug delivery.…”

Nano-PROTACs: state of the art and perspectives

“…Microneedle patches are powerful transdermal drug delivery systems that enable direct delivery of encapsulated drugs to the epidermis and dermis layers by physically overcoming the stratum corneum. With a minimally invasive approach, microneedle patch-assisted drug delivery systems have attracted soaring attention in several multifunctional therapies, such as cancers, [84][85][86] hair follicle regeneration, 87,88 wound healing, 89 and rheumatoid arthritis. 90 In January 2023, Wang et al 87 reported an androgen receptor-degrading PROTAC loaded dissolving microneedle patch for androgenetic alopecia and recrudescence treatment via single topical administration.…”

“…With a minimally invasive approach, microneedle patch-assisted drug delivery systems have attracted soaring attention in several multifunctional therapies, such as cancers, [84][85][86] hair follicle regeneration, 87,88 wound healing, 89 and rheumatoid arthritis. 90 In January 2023, Wang et al 87 reported an androgen receptor-degrading PROTAC loaded dissolving microneedle patch for androgenetic alopecia and recrudescence treatment via single topical administration. This work first demonstrated the PROTAC drug delivery potential of a microneedle patch.…”

PROTACs: A novel strategy for cancer drug discovery and development

“…At the present, more than 10 PROTAC degraders have entered clinical Phase I‐II trials with ARV‐471 and ARV‐110 from Arvinas, Inc as the most advanced ones for the treatment of recurrent breast cancer and prostate cancer, respectively 46–49 . However, PROTAC still faces many challenges 50–65 . A typical PROTAC degrader consists of three components: the target‐binding small molecule ligand (protein of interest, POI), the E3 ligase ligand and the appropriate linker that connects the two components (Figure 1).…”

“… 46 , 47 , 48 , 49 However, PROTAC still faces many challenges. 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 A typical PROTAC degrader consists of three components: the target‐binding small molecule ligand (protein of interest, POI), the E3 ligase ligand and the appropriate linker that connects the two components (Figure 1 ). 50 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 E3 ligases and the corresponding ligands are important as the driving force of protein degradation.…”