Dissolvable Microneedle Administration Combined with Ultrasonic Cavitation Promotes Melanoma Penetrating Capability of Ce6

Binrui Shi,1– 5,* Mingjie Li,1– 5,* Renjie Feng,1– 5 Guihua Wang,6 Liyong Deng,6 Yueyong Li,6 Kezhen Wang,1– 3,7 Meng Du,1– 3,5 Zhiyi Chen1– 3,5 1Key Laboratory of Medical Imaging Precision Theranostics and Radiation Protection, College of Hunan Province, the Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, 410004, People’s Republic of China; 2Institute of Medical Imaging, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China; 3Department of Medical Imaging, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, 410004, People’s Republic of China; 4The Seventh Affiliated Hospital, Hunan Veterans Administration Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, 410118, People’s Republic of China; 5Institute for Future Sciences, University of South China, Changsha, Hunan, 410008, People’s Republic of China; 6Department of Oncology, the Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, 410004, People’s Republic of China; 7College of Mechanical Engineering, University of South China, Changsha, Hunan, 410004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Meng Du; Zhiyi Chen, Key Laboratory of Medical Imaging Precision Theranostics and Radiation Protection, College of Hunan Province, the Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, 410004, People’s Republic of China, Email [email protected]; [email protected]: Melanoma, a highly aggressive superficial malignancy with rising incidence and mortality, faces limited sonodynamic therapy (SDT) efficacy due to poor sonosensitizer accumulation and penetration. To overcome this, we employed chlorin e6 (Ce6), a high-ROS-yield sonosensitizer, and enhanced its tumor delivery using a synergistic microneedle (MN) and ultrasound (US) strategy.Methods: Using melanoma as an application scenario, a “stepwise drug delivery” system was developed. It consisted of dissolving MN encapsulating US-responsive nanoparticles (Ce6-PFP@PLGA, CPP) and termed CPP@MN. CPP@MN breaks through the stratum corneum to deliver CPP to tumors, followed by US-triggered cavitation that mediates perfluoropentane (PFP) phase transition to enhance the tumor-penetrating capability of chlorin e6 (Ce6). Delivery efficacy was validated using three experimental models: an in vitro agarose skin phantom, ex vivo pig skin, and in vivo tumors. Furthermore, the anti-tumor efficacy of US-combined CPP@MN was evaluated at the cellular level and in tumor-bearing mice.Results: According to the results, CPP@MN showed excellent transdermal performance, including rapid dissolution of sonosensitizer and sufficient mechanical strength. MN combined with US increased the tumor penetration depth of loading drug by 2.5– 4 times across all experimental models. Ultrasonic cavitation promotes nanoparticle-derived Ce6 release and deeper tumor diffusion, resulting in specific anti-tumor efficacy.Conclusion: This innovative “stepwise drug delivery” system addresses persistent challenges in superficial tumor SDT, including inadequate sonosensitizer aggregation and poor tissue penetration, while establishing a multifunctional platform for spatiotemporally controlled drug release that sequentially overcomes the skin biological barriers.Keywords: transdermal drug delivery, microneedle, ultrasonic cavitation, superficial tumors, sonodynamic therapy