Chang Hao, Wen Xueyu, Li Zhiming, Ling Zhixin, Zheng Yanting, Xu Chenjie
The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences Hangzhou Zhejiang China.
Department of Biomedical Engineering City University of Hong Kong Hong Kong China.
Bioeng Transl Med. 2022 Nov 27;8(5):e10457. doi: 10.1002/btm2.10457. eCollection 2023 Sep.
Combinational immunotherapy of dendritic cell (DC) vaccines and anti-programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor-specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co-delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co-deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre-suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co-delivery of ovalbumin (OVA)-pulsed DCs (OVA-DCs) and aPD1 via cryoMNs induced higher antigen-specific cellular immune responses compared with the mono-delivery of OVA-DCs or aPD1. Finally, administration with cryoMNs co-encapsulated with OVA-DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti-tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA-DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co-delivery system of therapeutic cells and biomacromolecules for combinational therapies.
树突状细胞（DC）疫苗与抗程序性细胞死亡蛋白1抗体（aPD1）的联合免疫疗法被视为一种很有前景的癌症治疗策略，因为它不仅能诱导肿瘤特异性T细胞免疫反应，还能通过肿瘤的免疫抑制环境防止T细胞功能衰竭。微针已成为高效经皮免疫疗法的创新平台。然而，由于传统微针平台不适用于如活细胞和抗体等脆弱的治疗剂，通过微针联合递送DC疫苗和aPD1尚未得到研究。本研究采用我们新发明的低温微针（cryoMNs）来联合递送DC疫苗和aPD1进行联合免疫治疗。低温微针是通过对含有预先悬浮的DC和aPD1的低温介质进行逐步低温微成型制造的，然后进一步与自制手柄集成以便于应用。低温微针中DC的活力保持在85%以上。低温微针机械强度足够，可以插入猪和小鼠皮肤，融化后成功地在皮肤组织内释放DC和aPD1。与单独递送卵清蛋白（OVA）脉冲DC（OVA-DC）或aPD1相比，通过低温微针联合递送OVA-DC和aPD1诱导了更高的抗原特异性细胞免疫反应。最后，用包裹有OVA-DC和aPD1的低温微针给药增加了效应T细胞在肿瘤中的浸润，与用负载OVA-DC或aPD1的低温微针给药相比，在预防性和治疗性黑色素瘤模型中均产生了更强的抗肿瘤治疗效果。本研究证明了低温微针作为治疗细胞和生物大分子联合递送系统用于联合治疗的巨大潜力。
