앱타머는 그 자체의 3차원 구조를 통하여 표적에 특이적으로 결합하고 상호작용할 수 있는 단일 가닥 핵산으로 높은 특이성 및 친화성을 갖는다. 이에 따라 암 바이오 마커를 표적으로 하는 수많은 앱타머가 개발되었으며, 일부는 특이적 약물 전달 및 항암 요법을 위한 표적화 재료로서 이용된다. 본 연구에서는 ...
앱타머는 그 자체의 3차원 구조를 통하여 표적에 특이적으로 결합하고 상호작용할 수 있는 단일 가닥 핵산으로 높은 특이성 및 친화성을 갖는다. 이에 따라 암 바이오 마커를 표적으로 하는 수많은 앱타머가 개발되었으며, 일부는 특이적 약물 전달 및 항암 요법을 위한 표적화 재료로서 이용된다. 본 연구에서는 암 줄기세포에 의한 암의 전이, 재발, 약재 내성 등을 최소화하기 위해 유방암 세포와 유방암 줄기세포의 막 항원 (이하 MUC1, CD44)에 특이적으로 결합하는 앱타머를 부착시킨 리포좀 (이하 dual-Aptamosome)을 제조하였으며, 이에 항암제 독소루비신을 포집시켜 이용하였다. Dual-Aptamosome은 앱타머가 결여된 리포좀과 비교하였을 때, MUC1, CD44 발현 유방암 세포 주에 특이적 결합과 약물 전달이 크게 효과적이었으며 높은 세포 독성이 확인되었다. 또한, 실제 종양과 유사한 특성을 지니는 3D-배양 유방암 세포주에서도 효과적인 약물 전달과 높은 세포 독성이 나타났다. In vivo 상에서도, 암 줄기세포와 암세포를 주입한 쥐에 뒤이어 dual-Aptamosome을 주입하였을 때 암 줄기세포와 암세포에 의한 종양 전이를 효과적으로 억제함을 관찰하였다. 그러므로 본 연구에서는 항암제를 담지하고 있는 dual-Aptamosome이 임상에서 암 줄기세포에 의해 나타나는 암 치료의 문제점들을 극복하고 우수한 암 치료 효과를 나타낼 것이라고 제안한다. 또한, 이러한 항암제 및 나노입자 접합과 같은 광범위한 앱타머 응용 방안들은 앱타머 기반 암 치료제의 발전을 선도할 것이라고 기대되어진다.
앱타머는 그 자체의 3차원 구조를 통하여 표적에 특이적으로 결합하고 상호작용할 수 있는 단일 가닥 핵산으로 높은 특이성 및 친화성을 갖는다. 이에 따라 암 바이오 마커를 표적으로 하는 수많은 앱타머가 개발되었으며, 일부는 특이적 약물 전달 및 항암 요법을 위한 표적화 재료로서 이용된다. 본 연구에서는 암 줄기세포에 의한 암의 전이, 재발, 약재 내성 등을 최소화하기 위해 유방암 세포와 유방암 줄기세포의 막 항원 (이하 MUC1, CD44)에 특이적으로 결합하는 앱타머를 부착시킨 리포좀 (이하 dual-Aptamosome)을 제조하였으며, 이에 항암제 독소루비신을 포집시켜 이용하였다. Dual-Aptamosome은 앱타머가 결여된 리포좀과 비교하였을 때, MUC1, CD44 발현 유방암 세포 주에 특이적 결합과 약물 전달이 크게 효과적이었으며 높은 세포 독성이 확인되었다. 또한, 실제 종양과 유사한 특성을 지니는 3D-배양 유방암 세포주에서도 효과적인 약물 전달과 높은 세포 독성이 나타났다. In vivo 상에서도, 암 줄기세포와 암세포를 주입한 쥐에 뒤이어 dual-Aptamosome을 주입하였을 때 암 줄기세포와 암세포에 의한 종양 전이를 효과적으로 억제함을 관찰하였다. 그러므로 본 연구에서는 항암제를 담지하고 있는 dual-Aptamosome이 임상에서 암 줄기세포에 의해 나타나는 암 치료의 문제점들을 극복하고 우수한 암 치료 효과를 나타낼 것이라고 제안한다. 또한, 이러한 항암제 및 나노입자 접합과 같은 광범위한 앱타머 응용 방안들은 앱타머 기반 암 치료제의 발전을 선도할 것이라고 기대되어진다.
Chapter 1 Aptamers are single-stranded oligonucleotides that specifically bind and interact with their corresponding targets, including proteins and cells, through unique three-dimensional structures. Numerous aptamers have been developed to target cancer biomarkers with high specificity and aff...
Chapter 1 Aptamers are single-stranded oligonucleotides that specifically bind and interact with their corresponding targets, including proteins and cells, through unique three-dimensional structures. Numerous aptamers have been developed to target cancer biomarkers with high specificity and affinity, and some are employed as versatile guiding ligands for cancer-specific drug delivery and anti-cancer therapeutics. In this review, I list the aptamers that target tumor surface biomarkers and summarize the representative applications of aptamers as agonists and antagonists that activate anti-cancer and inactivate pro-cancer biomarkers, respectively. In addition, I describe applications of aptamer-drug or aptamer-oligonucleotide conjugates that can deliver therapeutic agents, including small interfering RNAs, micro RNAs, short hairpin RNAs, and chemotherapeutic molecules, to cancer cells. Moreover, I provide examples of aptamer- conjugated nano-vehicles, in which cancer-targeting oligonucleotide aptamers are conjugated with nano-vehicles such as liposomes, micelles, polymeric nanoparticles, and quantum dots. Conjugation of aptamers with anti-cancer drugs and nano-vehicles will facilitate innovative applications of aptamer-based cancer therapeutics.
Chapter 2. Cancer stem cells (CSCs) are believed to be a major source for tumor initiation and maintenance. Their ability of unlimited self-renewal and differentiation into cancer cells are enhancing the risk of drug resistance, tumor recurrence, and metastasis after treatment. Thus, anti-cancer drug delivery targeting CSCs as well as cancer cells are highly desirable for effective anticancer chemotherapy. To this end, I designed a drug-encapsulating liposome conjugated with dual-DNA aptamers specific to surface markers of CSCs and cancer cells; cell surface glycoprotein CD44 antigen (CD44) and transmembrane glycoprotein mucin 1 antigen (MUC1), respectively. Dual aptamer-conjugated liposomes, named as “dual-aptamosomes” were prepared according to our previously published method for RNA aptamer-conjugated aptamosomes with slight modification. I have investigated properties of dual-aptamosomes for delivering of doxorubicin (Dox) specifically to the 3D-cultured breast CSCs and cancer cells. Dox was readily delivered into the cancer cells via ligand-mediated cellular uptake of dual-aptamosome. Cell viability assay showed that dual-aptamosomes harboring Dox (dual-Apt-Dox) are significantly more cytotoxic to the CSCs and cancer cells than liposomes lacking the aptamers. Furthermore, I demonstrated in vivo inhibitory efficacy of dual-Apt-Dox on metastasis of breast CSCs and cancer cells in athymic nude mice. Based these results, I suggest that dual-aptamer conjugated liposomal system can be a useful drug delivery carrier for treatment of breast cancer due to its efficient targeting efficacy toward cancer cells as well as CSCs.
Chapter 1 Aptamers are single-stranded oligonucleotides that specifically bind and interact with their corresponding targets, including proteins and cells, through unique three-dimensional structures. Numerous aptamers have been developed to target cancer biomarkers with high specificity and affinity, and some are employed as versatile guiding ligands for cancer-specific drug delivery and anti-cancer therapeutics. In this review, I list the aptamers that target tumor surface biomarkers and summarize the representative applications of aptamers as agonists and antagonists that activate anti-cancer and inactivate pro-cancer biomarkers, respectively. In addition, I describe applications of aptamer-drug or aptamer-oligonucleotide conjugates that can deliver therapeutic agents, including small interfering RNAs, micro RNAs, short hairpin RNAs, and chemotherapeutic molecules, to cancer cells. Moreover, I provide examples of aptamer- conjugated nano-vehicles, in which cancer-targeting oligonucleotide aptamers are conjugated with nano-vehicles such as liposomes, micelles, polymeric nanoparticles, and quantum dots. Conjugation of aptamers with anti-cancer drugs and nano-vehicles will facilitate innovative applications of aptamer-based cancer therapeutics.
Chapter 2. Cancer stem cells (CSCs) are believed to be a major source for tumor initiation and maintenance. Their ability of unlimited self-renewal and differentiation into cancer cells are enhancing the risk of drug resistance, tumor recurrence, and metastasis after treatment. Thus, anti-cancer drug delivery targeting CSCs as well as cancer cells are highly desirable for effective anticancer chemotherapy. To this end, I designed a drug-encapsulating liposome conjugated with dual-DNA aptamers specific to surface markers of CSCs and cancer cells; cell surface glycoprotein CD44 antigen (CD44) and transmembrane glycoprotein mucin 1 antigen (MUC1), respectively. Dual aptamer-conjugated liposomes, named as “dual-aptamosomes” were prepared according to our previously published method for RNA aptamer-conjugated aptamosomes with slight modification. I have investigated properties of dual-aptamosomes for delivering of doxorubicin (Dox) specifically to the 3D-cultured breast CSCs and cancer cells. Dox was readily delivered into the cancer cells via ligand-mediated cellular uptake of dual-aptamosome. Cell viability assay showed that dual-aptamosomes harboring Dox (dual-Apt-Dox) are significantly more cytotoxic to the CSCs and cancer cells than liposomes lacking the aptamers. Furthermore, I demonstrated in vivo inhibitory efficacy of dual-Apt-Dox on metastasis of breast CSCs and cancer cells in athymic nude mice. Based these results, I suggest that dual-aptamer conjugated liposomal system can be a useful drug delivery carrier for treatment of breast cancer due to its efficient targeting efficacy toward cancer cells as well as CSCs.
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