Development of hyaluronic acid-based molecular imaging and chemo / photodynamic dual therapeutic agents

Abstract

항암제를 사용하는 chemotherapy는 실제 암 치료 법으로 널리 사용되는 방법이다. 그러나 항암제는 강한 독성효과 때문에 정상세포에서도 심각한 독성효과를 나타내고 여러 부작용 때문에 반복적인 치료가 불가능 하다. 광증감제를 사용하는 photodynamic therapy는 빛을 조사하지 않으면 형광도 없고 세포 독성도 거의 없다가 특정 파장의 빛을 조사할 때에만 형광 및 반응성 산소종을 생성하여 세포 독성을 나타낸다. 그러므로 선택적으로 빛을 조사한 부분에서만 독성을 나타낼 수 있고 이로 인해 부작용도 줄어들며 반복적인 치료가 가능하여 많은 부분에서 치료 가능하다. 이와 같이 photodynamic therapy가 chemotherapy의 부작용 및 암 치료 이후의 후유증 문제를 해결 할 수 있다는 장점을 가지므로 chemotherapy와 photodynamic therapy를 병행하여 부작용을 줄이면서 보다 높은 치료 효과를 얻을 수 있는 방법을 선택하였다. 히알루론산을 기반으로 한 광증감제와 항암제의 복합적인 치료제는 생물학적으로 활성화 될 수 있는 근적외선 형광이미징과 동시에 암 치료를 위해 많이 개발되고 있다. 이를 이용하여 본 연구에서는, 광증감제인 chlorin e6가 결합 된 히알루론산 나노입자가 항암제인 camptothecin을 둘러 쌓아 운반하는 전달체 구조로 HPACe6-CPT 나노 입자를 개발하였다. 이 나노입자는 세포 안에서 hyaluronidase에 의해 분해되어 광증감제와 항암제가 드러나게 되며, 특정 파장의 빛을 조사하여 형광 및 세포 독성을 나타 낼 수 있게 된다. 그러므로 부작용이 거의 없는 광역학 치료를 항암제 치료와 병행하면 항암제 복용량을 낮추어 부작용을 줄임과 동시에 암의 위치를 확인하면서 보다 효과적인 치료가 가능하기에 앞으로의 생체 및 임상 응용 분야에서 보다 광범위하게 적용될 것으로 예상된다.| Chemotherapy using an anticancer drug is widely used in actual therapy method. However, this therapy has strong toxicity on normal cells and repeated treatment is difficult. Photodynamic therapy (PDT) using a photosensitizer is non-fluorescence and non-phototoxicity in nonirradiated state. However, when irradiated with specific wavelength light, the photosensitizers become high fluorescence and phototoxicity. Therefore, the treatment area can choose and repeated treatment also possible. Thus, photodynamic therapy can be a solution to the side effects of chemotherapy by dual treatment. Photosensitizers and anticancer drug conjugated therapeutic agents with hyaluronic acid were produced for biologically activatable near-infrared (NIR) fluorescence imaging and therapy. In this study, using these points, the nanoparticles prepared from PEGylated hyaluronic acid nanoparticles (HPA NPs) were developed as carriers for Chlorin e6 (Ce6) of photosensitizer and camptothecin (CPT) of anticancer drug. The nanoparticles become highly fluorescent and toxic with decompose by a hyaluronidase (HAdase) inside cancer cells. Therefore, these nanoparticles showed the potential not only chemotherapy with CPT but also Photodynamic imaging and therapy with Ce6. We anticipate the potential advantage for future in vivo and clinical application.; Chemotherapy using an anticancer drug is widely used in actual therapy method. However, this therapy has strong toxicity on normal cells and repeated treatment is difficult. Photodynamic therapy (PDT) using a photosensitizer is non-fluorescence and non-phototoxicity in nonirradiated state. However, when irradiated with specific wavelength light, the photosensitizers become high fluorescence and phototoxicity. Therefore, the treatment area can choose and repeated treatment also possible. Thus, photodynamic therapy can be a solution to the side effects of chemotherapy by dual treatment. Photosensitizers and anticancer drug conjugated therapeutic agents with hyaluronic acid were produced for biologically activatable near-infrared (NIR) fluorescence imaging and therapy. In this study, using these points, the nanoparticles prepared from PEGylated hyaluronic acid nanoparticles (HPA NPs) were developed as carriers for Chlorin e6 (Ce6) of photosensitizer and camptothecin (CPT) of anticancer drug. The nanoparticles become highly fluorescent and toxic with decompose by a hyaluronidase (HAdase) inside cancer cells. Therefore, these nanoparticles showed the potential not only chemotherapy with CPT but also Photodynamic imaging and therapy with Ce6. We anticipate the potential advantage for future in vivo and clinical application.