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Nanostructure-based targeted drug delivery and photothermal therapy
나노구조체 기반 약물 표적 전달 및 광열치료

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Authors
박주연
Advisor
오유경
Major
약학대학 약학과
Issue Date
2017-02
Publisher
서울대학교 대학원
Keywords
Targeted drug deliveryphotothermal therapyrolling circle amplificationreduced graphene oxideboron nitride nanosheettannic acid–Fe coatinggold nanocluster
Description
학위논문 (박사)-- 서울대학교 대학원 : 약학과, 2017. 2. 오유경.
Abstract
표적 약물 전달은 항암제의 치료효과를 증진시키는 유망한 전략 중의 하나로 여겨져 왔다. Protein tyrosine kinase 7 (PTK7)에 특이적으로 결합하는 것으로 알려진 DNA aptamer의 반복서열인 polyaptamer nanothread가 rolling circle amplification (RCA) 기술을 통하여 합성되었고, 환원 그래핀 나노시트 (rGO)에 polyaptamer nanothread를 수식하여 PTK7 과발현 세포주에 항암제 전달 효율을 증진시켰다. 또한 polyaptamer nanothread가 수식된 rGO (PNT/rGO)는 PTK7 과발현 암종이 이식된 쥐에 정맥주사를 통해 항암제인 doxorubicin을 효과적으로 전달하여 암의 성장을 억제하였다. RCA 기법을 통해 antisense oligonucleotide (ASO)에 상보적인 서열을 갖는 DNA nanoball을 제조하였다. Dz13과 OGX-427이 DNA nanoball에 탑재되었고, Mu peptide와 히알루론산(HA)으로 수식되어 CD44를 과발현하는 암세포에 전달하였다. Dz13과 OGX-427을 탑재한 DNA nanoball은 효과적으로 타겟 mRNA와 단백질의 발현을 억제하였고, 세포 수준과 암이식 쥐 모델에서 뛰어난 항암효과를 보였다. 광열치료는 강력하고, 상대적으로 비침습적인 암치료법으로 연구되고 있다. 본 연구에서는 탄닌산 (TA)과 철의 킬레이트 화합물에 의해 표면이 개질된 boron nitride nanosheets (BNNSs)를 안전하고 새로운 광열 치료 물질로 제시하였다. TA-Fe/BNNS는 근적외선 레이저 조사에 의해 온도가 올라가는 광감응성을 보였고, TA-Fe/BNNS의 광열효과는 암세포주의 세포사멸을 유도하였고, 암이 이식된 쥐 모델에 국소 투여 되었을 때 암조직을 완전히 제거하였다. 마지막으로, 금 나노클러스터가 봉입된 DNA nanoball (AuDNB)을 RCA 기술을 통하여 제조하였고, AuDNB는 근적외선 조사에 의한 광열 효과를 나타내었다. 또한 AuDNB를 암세포주에 처리하고, 근적외선을 조사함으로써 AuDNB의 광열 효과에 의한 암세포 사멸효과를 확인하였다.
Targeted drug delivery has been considered as a promising strategy to improve therapeutic effects of anticancer agents including chemicals and biomolecules. First, DNA polyaptamer nanothreads against protein tyrosine kinase 7 (PTK7) receptor anchored onto redcued graphene oxide (rGO) nanosheets (PNTrGO) were prepared for targeted delivery. The polyaptamer was produced by rolling circle amplicifation (RCA) and introduced onto rGO nanosheets via high affinity between oligo-T sequence and rGO nanosheets. PNTrGO improved cellular uptake to PTK7 overexpressed cancer and enhanced tumor accumulation in tumor xenografted mice. Moreover, doxorubicin (Dox)-loaded PNTrGO enhanced the inhibition effect of tumor growth in PTK7-positive tumor bearing mice. Secondly, DNA nanoballs which are able to carry antisense oligonucleotide (ASO) and target to CD44 overexpressed cancer were developed. Two types of ASOs, Dz13 and OGX-427, were loaded to RCA product in complementary manner via hybridization. Furthermore, Mu peptide derived from adenovirus was condensed the ASO-loaded RCA product. Hyaluronic acid (HA) coating enhanced the cellular uptake of both Dz13 and OGX-427 to CD44-positive cancer cells, and reduced their target mRNA and proteins effectively. Photothermal therapy (PTT) has been investigated as potent and less invasive cancer treatment method. Boron nitride nanosheets (BNNSs) coated with tannic acid (TA) and iron film (TA-Fe/BNNSs) were prepared as novel and safe PTT agent. TA-Fe/BNNSs showed photothermal activity followed by NIR laser irradiation, and the photothermal effect of TA-Fe/BNNS was enough to eradicate tumor tissues after local administration to tumor-bearing mice. Lastly, gold nanocluster (AuNC)-loaded DNA nanoballs (AuDNBs) were designed as biocompatible PTT agent. AuNCs were synthesized with long single stranded DNA (ssDNA) produced by RCA and incorporated into the RCA product. The assembly of AuNCs located in DNA nanoballs generated heat after NIR laser irradiation, and the anticancer effect was achieved by AuDNB treatment followed by NIR laser irradiation in cancer cells.
Language
English
URI
https://hdl.handle.net/10371/120155
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Theses (Ph.D. / Sc.D._약학과)
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