HPMA polymers as functional excipients in dermal nanoformulations of imiquimod

Introduction

In dermal drug delivery, effectiveness largely depends on the drug’s ability to traverse the stratum corneum (SC), the skin’s outermost and most significant barrier, and reach the deeper layers where it can exert its therapeutic effect (Gorzelanny et al., 2020; Roger et al., 2019). To overcome the skin barrier, a variety of strategies have been employed, which can be broadly categorized as either passive or active methods. While active methods rely on external energy input, passive methods enhance skin permeability through interactions between formulation components and the skin barrier, as well as within the formulation itself. These interactions result in a temporary increase in skin permeability to active substances (Chaturvedi and Garg, 2021; Vitorino et al., 2014). Several fundamental strategies are currently employed to optimize the penetration of active substances into the skin, primarily by increasing their thermodynamic activity within the formulation or enhancing their solubility in the SC.

A traditional strategy to enhance skin penetration relies on the use of penetration enhancers, which can act through multiple mechanisms. Small molecules, such as alcohols, can improve drug solubility within the vehicle or directly in the lipid matrix of the SC. Amphiphilic compounds, such as Azone or oleic acid, interact with SC lipids, disrupting their ordered structure and increasing membrane fluidity, thereby facilitating drug permeation (Kováčik et al., 2020).

Recently, certain polymers have emerged as promising penetration enhancers due to their diverse mechanisms of action. For example, hyaluronic acid can traverse the SC, promote skin hydration, and improve the delivery of co-administered actives, while poly(amidoamine) (PAMAM) dendrimers have been shown to increase drug flux through the SC (Gökçe et al., 2021; Juhaščik et al., 2022; Venuganti et al., 2011; Zhu et al., 2020). Modern techniques for targeted dermal delivery often integrate these principles, with nanoparticle-based formulations (Kotla et al., 2017; Liu et al., 2023; Patzelt et al., 2017). Encapsulating actives into nanoparticles can enhance their thermodynamic activity, increase adhesion to the skin surface, and even form reservoirs in hair follicles, supporting sustained and localized delivery. (Jain et al., 2011; Kalvodová et al., 2023).

Our research has previously focused on overcoming the limited dermal bioavailability of imiquimod (IMQ), used for, e.g. basal cell carcinoma or actinic keratosis (precancerous skin lesions). IMQ is known to enhance the immune response against infections and abnormal skin cells (Hanna et al., 2016). However, it exhibits poor skin penetration in conventional gels or creams (Al-Mayhay et al., 2019). Advanced nanocarrier systems, including nanocrystals (NC) and an oleic acid-based nanoemulsion (NE), were developed and demonstrated improved targeting of skin tissue (Petrová et al., 2023). Nanocrystals were also successfully integrated into hydrogel microneedle patches, illustrating the potential of combining nanoparticles with hydrophilic polymers for enhanced dermal delivery (Petrová et al., 2025).

Building on these findings, polymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) represent an intriguing yet unexplored class of compounds as potential carriers for dermal penetration. They have shown considerable promise in biomedical applications due to their water solubility, biocompatibility, and lack of toxicity or immunogenicity (Chytil et al., 2018; Kopecek and Kopecková, 2010). When conjugated with drugs, HPMA-based systems can enable controlled release and targeted delivery to specific tissues or cells. Moreover, their structure can be precisely tuned using reversible addition–fragmentation chain-transfer (RAFT) polymerization (Scales et al., 2005) to achieve defined molecular weights and low dispersity. This can make them suitable candidates for skin delivery systems where particle size is a critical factor. Despite their proven advantages in targeted drug delivery (Chytil et al., 2021; Klepac et al., 2025; Lammers et al., 2007), the effect of HPMA polymers on the skin barrier and their potential to modulate its permeability remains unexplored.

The present study represents the first investigation of HPMA polymers (p(HPMA)) in dermal delivery. We synthesize three p(HPMA) polymers of varying molecular weights and evaluate their interaction with the skin barrier and their capacity to penetrate deeper skin layers, using fluorescently labelled variants. Using IMQ as a model active compound, we further assess the ability of p(HPMA) to enhance dermal transport from both conventional suspensions and nanoparticle systems. The aim is not to develop a final IMQ formulation, but rather to map the potential of p(HPMA) as a novel tool for modulating skin permeability and improving topical drug delivery.

Materials

Polymer synthesis: 2,2′-azobisisobutyronitrile (AIBN), 2-cyanopropan-2-yl dithiobenzoate (CTA-DTB), methacryloyl chloride, N,N-diisopropylethylamine (DIPEA), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), and 2-methylpropan-2-ol (t-BuOH) were purchased from Sigma-Aldrich (Czech Republic). The initiator 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) was acquired from Fujifilm Wako Chemicals Europe (Germany), and the fluorescent dye DY-490 amino-derivative from Dyomics (Germany).

Dermal formulation and ex vivo experiments: IMQ was purchased from Cayman Chemical (Michigan, USA). Phospholipid GmbH (Germany) kindly provided Phospholipon® 90 G. Oleic acid, Tween® 80, methanol, acetonitrile, propylene glycol, gentamicin sulfate and phosphate-buffered saline (PBS; 10 mmol phosphate buffer, 2.7 mmol potassium chloride and 137 mmol sodium chloride, pH 7.4, at 25 °C) tablets were obtained from Merck KGaA (Germany). Aldara® (5 wt%) cream was purchased from MEDA AB (Sweden). All the chemicals were of analytical grade and used without further purification. Water was deionized, distilled, and filtered through a Millipore Q purification system.

Eliška Kurfiřtová, Stanislav Chvíla, Nikola Strnádková, Vendula Janoušková, Petr Chytil, Tomáš Etrych, Jarmila Zbytovská, HPMA polymers as functional excipients in dermal nanoformulations of imiquimod,
International Journal of Pharmaceutics: X, 2026, 100486, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2026.100486