(B-49) A Hydrogel-Based Approach for the Delivery of Vasoconstricting Drugs as a Promising Chemotherapy-Induced Alopecia Therapy

Introduction:: Chemotherapy drugs like anthracyclines and alkylating agents can cause hair loss as a side effect by harming the hair follicle, known as chemotherapy-induced alopecia (CIA)¹. This can be undesirable for social, business, and family reasons. Patients undergoing chemotherapy currently only have the option of using scalp hypothermia treatments, 'cold caps', to reduce hair loss. These treatments work by constricting blood vessels to reduce the delivery of drugs to the hair follicles, but they are costly and painful, causing cold sensations, headaches, and dizziness. They are also logistically challenging for patients and providers, and not routinely covered by insurance in the United States. Moreover, they leave the scalp unprotected once the infusion has ceased, and chemotherapy drugs continue to circulate in the body. To address these issues, a novel bioengineered hydrogel-based solution has been developed to treat the scalps of chemotherapy patients. This gel-based 'shampoo' employs a similar mechanism of action as hypothermic caps but without the adverse effects and challenges. In this regard, Poly (vinyl Alcohol) (PVA) containing two vasoconstricting drugs, Lidocaine (LID) and Adrenalone (ADR) have been developed. The physical and chemical characteristics of LID- and ADR-based hydrogels, including their rheology, have been examined, and their primary mechanism-of-action has been verified in in vivo models, showing vasoconstriction function.


Materials and Methods:: Polyvinyl alcohol (PVA, hydrolized), Lidocaine Hydrochloride (LID, powder), and Adrenalone Hydrochloride (ADR) were used to prepare hydrogels. PVA hydrogel (PVA blank), LID-loaded PVA hydrogel (PVA-LID), and ADR-loaded PVA hydrogel (PVA-ADR) were prepared by dissolving the 10 wt% of PVA in deionized water, followed by loading drugs (10 wt% LID or 1 wt% ADR) into the aqueous solution. The hydrogel surface morphology after lyophilization was analyzed using scanning electron microscopy (SEM). A custom-made setup using a 25 mm membrane was designed to study in vitro drug release from hydrogels. A spectrophotometer (Nanodrop ONE, ThermoScientific) was used to evaluate the release of drugs at 260 nm and 320 nm for LID and ADR from 0 to 495 minutes, respectively. Freshly euthanized Flemish giant rabbits were utilized as animal models for blood vessel shrinkage tests. The rheological analysis of the hydrogels was carried out using a Discovery HR-2 hybrid rheometer (AR-1500, USA) equipped with a parallel plate cell geometry (40 mm diameter) operating at a gap of 1000 μm. Gelation of the PVA hydrogels was determined by temperature sweep test at the oscillatory frequency of 1 Hz from 0 to 45 °C at 1°C/min rate. Furthermore, the frequency sweep test was around the gelation temperature as well as temperatures of 2, 12, 23, and 37°C at oscillatory mode over the frequency range of 0.1 to 200 rad/s. Utilizing the frequency sweep results, complex viscosity was evaluated as a measure for the total resistance of hydrogels to flow during their application.


Results, Conclusions, and Discussions:: SEM images (Figure 1) represent a homogenous porous structure with the average pore size of 0.300 +/- 0.047 µm, 0.070 +/- 0.046 µm, 0.022 +/- 0.011 µm for PVA blank, PVA-LID, and PVA-ADR, respectively. The average pore size of hydrogels was decreased after loading LID or ADR drugs into the PVA hydrogel. Figure 2 represents the drug release of PVA-LID and PVA-ADR at volumes of 200ul and 400ul (evenly coated on the surface). All hydrogels represented a biphasic drug release, including a pre-plateau regime (burst drug release) followed by a plateau regime (sustained drug release). Pre-plateau time and percentage of drug release for hydrogels with 200ul volume was approximately 65min or 105min and 80% or 86%, while it was 95min or 70min and 70% or 40% for hydrogels with 400ul volume. The non-pressurized blood vessel contraction (BVC) on freshly extracted rabbit ears is represented quantitatively and qualitatively in Figures 3 and 4. BVC for PVA blank, PVA-ADR, and PVA-LID after 45 min were 7.5%, 20%, and 40%, respectively. According to the temperature-sweep test (Figure 5a), PVA blank represents a weak gel structure over 0 to 12℃, while PVA-LID and PVA-ADR represent a gelation point at 32℃ and 45℃, respectively. Both drug-loaded hydrogels below their gelation points represent relatively low viscosity suitable for their application on the skin surface. PVA-LID will represent a gel-like structure at biological temperature (37℃), that can reversibly switch to solution-like state by lowering the temperature below 32℃. Figure 5b-d shows the frequency-sweep tests for the hydrogels at 2, 12, 37, 45℃ as well as two points around their gelation/de-gelation points. Accordingly, PVA blank represent a transition from gel-like state to solution-like state at 12℃. However, PVA-LID and PVA-ADR represent a transition from solution-like state to gel-like state at 30℃ and 50℃, respectively. The complex viscosity of all hydrogels at 23℃ is lower than 40 Pa.s, properties that indicate they can easily be applied on the skin surface. These rheological behaviors are desirable regarding the application of hydrogels as a potential CIA therapy. In the near future, this method could potentially serve as an effective and economical CIA therapeutic option for cancer patients.


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References (Optional): : (1) Santos, T. S.; Hernandéz Galvis, K.; Vañó Galván, S.; Saceda-Corralo, D. Post-chemotherapy alopecia: what the dermatologist needs to know. International Journal of Dermatology 2021, 60 (11), 1313-1317, DOI: https://doi.org/10.1111/ijd.15812.

(2) Marks, D. H.; Okhovat, J.-P.; Hagigeorges, D.; Manatis-Lornell, A. J.; Isakoff, S. J.; Lacouture, M. E.; Senna, M. M. The effect of scalp cooling on CIA-related quality of life in breast cancer patients: a systematic review. Breast Cancer Research and Treatment 2019, 175 (2), 267-276, DOI: 10.1007/s10549-019-05169-0.