Abstract
Simple SummaryBleomycin, a chemotherapy drug, is currently injected into patients, but this can damage healthy tissues. Ideally, we would like to apply bleomycin directly onto a skin tumour but bleomycin is a big molecule and cannot pass through the skin or directly enter into cancer cells to kill them. Therefore, we need to find new ways of packaging the drug to get it inside cancer cells. Liposomes are small artificial bubbles made of from the same building blocks as our skin and cell membranes that can be filled with pharmaceutical drugs. In this study we propose that liposomes can assist with the delivery of bleomycin by improving penetration through the skin. We are using a new compound called Bleosome, which contains liposomes packed with bleomycin. We found that Bleosome penetrated more through the healthy skin of dogs and horses than bleomycin. These are promising results, indicating that Bleosome may be an effective treatment, with easy application and limited side-effects, to treat skin cancer.Bleomycin is a chemotherapy agent that, when administered systemically, can cause severe pulmonary toxicity. Bleosome is a novel formulation of bleomycin encapsulated in ultra-deformable (UD) liposomes that may be applicable as a topical chemotherapy for diseases such as non-melanoma skin cancer. To date, the ability of Bleosome to effectively penetrate through the skin has not been evaluated. In this study, we investigated the ability of Bleosome to penetrate through ex vivo skin explants from dogs and horses. We visualized the penetration of UD liposomes through the skin by transmission electron microscopy. However, to effectively image the drug itself we fluorescently labeled bleomycin prior to encapsulation within liposomes and utilized multiphoton microscopy. We showed that UD liposomes do not penetrate beyond the stratum corneum, whereas bleomycin is released from UD liposomes and can penetrate to the deeper layers of the epidermis. This is the first study to show that Bleosome can effectively penetrate through the skin. We speculate that UD liposomes are penetration enhancers in that UD liposomes carry bleomycin through the outer skin to the stratum corneum and then release the drug, allowing diffusion into the deeper layers. Our results are comparative in dogs and horses and warrant further studies on the efficacy of Bleosome as topical treatment.
Highlights
In both veterinary and human medicine there is an unmet clinical need for effective anti-cancer drugs that can be applied topically
We found that UD liposomes act as penetration enhancers: liposomes are visible throughout stratum corneum but not beyond, whereas the fluorescently labeled drug is seen within the stratum corneum as dense spots as the drug is enclosed with the liposome, but in the deeper layers of the epidermis the drug is more diffuse, indicating that it has been released from the UD liposome
Bleosome is a novel formulation of bleomycin that has potential as a topical chemotherapy to treat non-melanoma skin cancers (NMSC) and negate the adverse side-effects of pulmonary toxicity when administered systemically
Summary
In both veterinary and human medicine there is an unmet clinical need for effective anti-cancer drugs that can be applied topically. The standard treatment of non-melanoma skin cancers (NMSC), including basal cell carcinoma and squamous cell carcinoma, are surgical modalities that can cause severe pain, inflammation, and scarring [1,2] These side-effects can be significant given that the tumors may be spread over large areas of the body, anti-cancer drugs that can be applied topically would be therapeutically and cosmetically valuable by reducing surgical costs and by avoiding undesirable scarring. In the case of NMSCs, topical application of bleomycin may avoid these systemic side-effects, but because bleomycin itself is a large hydrophilic molecule with a polar charge, it is unable to penetrate lipophilic skin barriers and efficiently diffuse across the plasma membrane to reach its site of action [4,10] To overcome these issues, bleomycin has been administered by electrochemotherapy, which uses short electric impulses to transiently permeabilize the cell membrane allowing delivery of non-permeant drugs to the interior of the cell. Patients generally undergo a general or local anesthetic, which, especially in veterinary patients, can be distressing for patients and owners
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