Presentation Information
[P01-112]Synergistic Chemo-Photodynamic Microneedle Patch for Post-Surgical Melanoma Recurrence Inhibition
○Taejung Kim1, Jae-Young Lee1 (1. Seoul National University (Korea))
Keywords:
Melanoma,Vemurafenib,microneedle,Chlorin e6,Photodynamic therapy
[Purpose] Melanoma has a high recurrence risk even after surgical resection. Vemurafenib, a BRAF V600E-targeted therapy, is limited by food-dependent bioavailability, systemic toxicities, and acquired resistance within 6–7 months. We developed dissolving microneedles (dMNs) loaded with PLGA microspheres (MSs) co-encapsulating vemurafenib and Chlorin e6 (Ce6) to achieve synergistic antitumor efficacy through combined targeted therapy and photodynamic therapy (PDT), while leveraging sustained drug release from MSs to prevent post-surgical melanoma recurrence.
[Method] PLGA MSs were fabricated via O/W emulsion-solvent evaporation at 10,000 rpm (~5 µm). Drug loading was quantified by HPLC (vemurafenib) and UV-Vis (Ce6). MSs were dispersed in PVA matrix and loaded into PVDF molds under pressurized drying to fabricate dMNs. Mechanical strength and morphology were evaluated by UTM and SEM. In vitro studies included drug release profiling (pH 5.0/6.5/7.4), cellular uptake (FACS), and cytotoxicity (CCK-8) using A375/M2 macrophage TAM models. In vivo, A375 xenografts in BALB/c nude mice were ~80% surgically resected, and four groups (Blank MN, Ce6@MS-MN+laser, Vem@MS-MN, Vem+Ce6@MS-MN+laser; n=3) were monitored for 21 days with Ki67 IHC, TUNEL, CBC, and serum biochemistry analyses.
[Results] MSs showed excellent colloidal stability over 3 days. Sustained drug release from MSs was confirmed in vitro. MS-encapsulated drug uptake was 5.34-fold (1 h) and 5.88-fold (4 h) higher than free drug solution. dMNs maintained sufficient mechanical strength post-MS loading. In vivo, the Vem+Ce6@MS-MN+laser group exhibited the greatest tumor suppression, with tumor weight reduced by ~60% vs. Blank MN and ~38% vs. Vem@MS-MN at day 21. While all groups showed comparable suppression until day 17 via sustained release, only the Vem+Ce6@MS-MN+laser group maintained prolonged inhibition thereafter, demonstrating synergistic chemo-PDT efficacy. Ki67 reduction and increased TUNEL positivity confirmed antiproliferative and pro-apoptotic effects. No significant systemic toxicity was observed.
[Consideration] PLGA MS-based sustained release enables gradual drug delivery, potentially mitigating resistance development. The combination of targeted therapy and PDT produced synergistic effects, overcoming monotherapy limitations due to tumor heterogeneity. Transdermal dMN delivery enhances local efficacy while reducing systemic toxicity and improving patient compliance by eliminating the burden of daily oral dosing. Challenges include ensuring uniform MS distribution within MNs and minimizing drug loss during production. Incorporating oxygen carriers such as hemoglobin could further enhance PDT efficacy.
[Conclusion] The dMN system co-delivering vemurafenib and Ce6 via PLGA MSs effectively prevented post-surgical melanoma recurrence through sustained release and synergistic chemo-photodynamic therapy with no significant systemic toxicity, presenting a promising transdermal combinatorial platform for advanced melanoma treatment.
[Method] PLGA MSs were fabricated via O/W emulsion-solvent evaporation at 10,000 rpm (~5 µm). Drug loading was quantified by HPLC (vemurafenib) and UV-Vis (Ce6). MSs were dispersed in PVA matrix and loaded into PVDF molds under pressurized drying to fabricate dMNs. Mechanical strength and morphology were evaluated by UTM and SEM. In vitro studies included drug release profiling (pH 5.0/6.5/7.4), cellular uptake (FACS), and cytotoxicity (CCK-8) using A375/M2 macrophage TAM models. In vivo, A375 xenografts in BALB/c nude mice were ~80% surgically resected, and four groups (Blank MN, Ce6@MS-MN+laser, Vem@MS-MN, Vem+Ce6@MS-MN+laser; n=3) were monitored for 21 days with Ki67 IHC, TUNEL, CBC, and serum biochemistry analyses.
[Results] MSs showed excellent colloidal stability over 3 days. Sustained drug release from MSs was confirmed in vitro. MS-encapsulated drug uptake was 5.34-fold (1 h) and 5.88-fold (4 h) higher than free drug solution. dMNs maintained sufficient mechanical strength post-MS loading. In vivo, the Vem+Ce6@MS-MN+laser group exhibited the greatest tumor suppression, with tumor weight reduced by ~60% vs. Blank MN and ~38% vs. Vem@MS-MN at day 21. While all groups showed comparable suppression until day 17 via sustained release, only the Vem+Ce6@MS-MN+laser group maintained prolonged inhibition thereafter, demonstrating synergistic chemo-PDT efficacy. Ki67 reduction and increased TUNEL positivity confirmed antiproliferative and pro-apoptotic effects. No significant systemic toxicity was observed.
[Consideration] PLGA MS-based sustained release enables gradual drug delivery, potentially mitigating resistance development. The combination of targeted therapy and PDT produced synergistic effects, overcoming monotherapy limitations due to tumor heterogeneity. Transdermal dMN delivery enhances local efficacy while reducing systemic toxicity and improving patient compliance by eliminating the burden of daily oral dosing. Challenges include ensuring uniform MS distribution within MNs and minimizing drug loss during production. Incorporating oxygen carriers such as hemoglobin could further enhance PDT efficacy.
[Conclusion] The dMN system co-delivering vemurafenib and Ce6 via PLGA MSs effectively prevented post-surgical melanoma recurrence through sustained release and synergistic chemo-photodynamic therapy with no significant systemic toxicity, presenting a promising transdermal combinatorial platform for advanced melanoma treatment.
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