728*90상단 와이드 상단2

본 블로그는 윈도우비스타, 윈도우7 / 맑은고딕, 나눔고딕 / 1,280 * 1,024 이상에서 최적화됩니다.

전립선 암을 특이적으로 공격하는 초정밀 유도탄 Inven.Discov.Tech.

Prostate Cancer 'Homing Device' Created For Drug Delivery

미국의 경우 전립선 암은 남성의 암으로 인한 사망원인 중 2위를 차지하고 있으며, 올해에는 192,280명의 남성이 전립선 암으로 진단을 받아 그 중 27,360명이 사망할 것으로 추산된다. 현재 전립선 암 만을 특이적으로 지향하는 약물은 개발되어 있지 않다. 이는 전립선암 치료제가 인체의 모든 부분에 퍼져 건강한 세포에 독성을 미칠 수 있다는 것을 의미한다. 이와 관련하여, 미국 퍼듀 대학교의 연구진은 전립선 암을 찾아 침투해 들어가는 분자를 합성하였으며, 이 분자에 치료제와 조영제를 결합시켜 전립선 암을 진단·치료하는 방법을 개발하였다고 발표하였다.


연구진이 개발한 분자는 전립선 암 특이적 막항원(PSMA: prostate-specific membrane antigen)에 결합한다고 한다. "PSMA는 전립선 암의 90% 이상에서 발견되는 막단백질이지만, 대부분의 고형 암의 혈관에서도 발견된다. 따라서 PSMA를 표적으로 하면, 전립선 암 자체를 파괴할 수 있을 뿐만 아니라, 전립선 암에 혈액을 공급하는 혈관구조까지도 파괴할 수 있어, 일석이조의 효과를 거둘 수 있다는 장점이 있다."고 연구진은 말했다.


1995년 연구진은 엽산(folate)에 항암제를 결합하여 암을 치료하는 방법을 개발한 바 있다. 암세포는 엽산을 많이 필요로 하기 때문에, 엽산에 항암제를 결합하면 암세포가 엽산을 흡수하면서 항암제까지도 함께 흡수하게 할 수 있다. 이러한 트로이목마식 접근방법은 대형분자를 암세포 안으로 침투시킬 수 있는 좋은 방법이다. 연구진은 이 방법을 전립선 암의 치료에 적용하는 아이디어를 생각해 냈지만, 전립선 암은 엽산을 선호하지 않기 때문에 엽산을 대체하는 새로운 화합물을 탐색하는 데 초점을 맞추어 왔다. 연구진은 천연화합물을 탐색한 끝에 PSMA에 강하게 결합하는 DUPA라는 화합물을 찾아내었다. 연구진은 DUPA의 화학구조를 여러 차례 변형시켜 다양한 화물(조영제나 치료제)을 탑재할 수 있는 연결고리를 부착하고, 이 화물들로 인하여 DUPA가 PSMA에 결합하는 것이 방해되지 않도록 연장선(spacer)을 달았다.(이 연장선은 다른 한편으로 DUPA의 표적지향성을 강화시키는 역할을 하기도 한다.)


연구진은 DUPA에 결합된 조영제(DUPA?99mTc)가 나노몰 수준의 친화력(KD = 14 nM)으로 전립선암세포에 결합하는 것을 확인하였다(첨부그림 1 참조). 이미징 및 생체분포분석을 통하여 확인한 결과, DUPA?99mTc은 종양과 근육에 75:1의 비율로 분포하는 것으로 나타났다. 다른 두 개의 광학조영제(DUPA?FITC, DUPA?rhodamine B)도 전립선 암 세포를 지향하며 세포 내의 엔도좀(endosome)으로 운반되는 것으로 밝혀졌다. 한편 DUPA에 결합된 화학요법제(DUPA?TubH)는 in vitro에서 전립선 암 세포를 효과적으로 살해하였으며(IC50 = 3 nM), 마우스에 이식된 전립선 암 세포를 체중감소 없이 제거하는 것으로 나타났다.


"DUPA 분자는 전립선 암을 추적하는 미사일과 같다. PSMA는 전립선 암세포와 암세포의 혈관에 존재하며, 미사일을 유도하는 신호로 작용한다. 이 미사일에 핵탄두(약물)를 적재하면 건강한 세포는 그대로 두고 암세포만을 찾아 핵탄두를 전달할 수 있다. 일단 이 미사일이 전립선 암 세포에 도달하면, PSMA에 결합한 다음 세포 내 이입(endocytosis)을 통하여 핵탄두와 함께 세포 내부로 들여간다. 암세포 내부로 들어간 핵탄두는 미사일에서 분리되어 암세포를 파괴한다."고 연구진은 말했다.


이번 연구의 의의는 DUPA를 이용하여 PSMA를 발현하는 암세포를 진단하거나 치료하는 새로운 방법을 제시하였다는 데 있다. 더욱이 DUPA에 항암제와 조영제를 함께 결합시킬 경우 암세포의 진단과 치료를 동시에 행할 수 있다는 장점도 있다. DUPA를 이용한 방사성 촬영장치(radioimaging application)는 올 가을에 임상시험에 들어갈 예정이며, 혈액 샘플 속의 전립선 암 세포를 찾아내는 광학적 촬영장치(optical imaging application)는 현재 임상시험에 계류 중이다.


Reference: Kularatne et al. Prostate-Specific Membrane Antigen Targeted Imaging and Therapy of Prostate Cancer Using a PSMA Inhibitor as a Homing Ligand. Molecular Pharmaceutics, 2009; 6 (3): 780 DOI: 10.1021/mp900069d

 

http://www.sciencedaily.com/releases/2009/07/090706161306.htm

 

 


  

Prostate Cancer 'Homing Device' Created For Drug Delivery

ScienceDaily (July 7, 2009) — A new prostate cancer "homing device" could improve detection and allow for the first targeted treatment of the disease.

enlarge

This image depicts transporter molecules carrying therapeutic drugs to PSMA targets on a prostate cancer cell. A Purdue research team designed a molecule that finds and penetrates prostate cancer cells and can transport drugs or imaging agents into the cell. (Credit: Image courtesy of Low laboratory)

A team of Purdue University researchers has synthesized a molecule that finds and penetrates prostate cancer cells and has created imaging agents and therapeutic drugs that can link to the molecule and be carried with it as cargo.

A radioimaging application used for body scans is expected to enter clinical trials this fall, and an optical imaging application used to measure prostate cancer cells in blood samples is already in clinical trials.

Philip Low, the Ralph C. Corley Distinguished Professor of Biochemistry who led the team, said a targeted treatment could be much more effective in treating cancer and would greatly reduce the harmful side effects associated with current treatments.

"Currently none of the drugs available to treat prostate cancer are targeted, which means they go everywhere in the body as opposed to only the tumor, and so are quite toxic for the patient," said Low, who is a member of the Purdue Cancer Center. "By being able to target only the cancer cells, we could eliminate toxic side effects of treatments. In addition, the ability to target only the cancer cells can greatly improve imaging of the cancer to diagnose the disease, determine if it has spread or is responding to treatment."

Prostate cancer is the most common cancer, other than skin cancers, and is the second leading cause of cancer death in American men, according to the American Cancer Society. It is estimated that about 192,280 new cases will be diagnosed and 27,360 men will die of prostate cancer in the United States this year.

The molecule Low's team created attaches to prostate-specific membrane antigen, or PSMA, a protein that is found on the membrane of more than 90 percent of all prostate cancers. It also is found on the blood vessels of most solid tumors and could provide a way to cut off the tumor blood supply, Low said.

"A lot of new drugs are being designed to destroy the vasculature of solid tumors, and, if they could be linked to this new targeting molecule, we could have a two-pronged attack for prostate cancer," he said. "We could not only kill the prostate cancer cells directly, we could also destroy the vasculature that feeds the tumors."

There also is potential for the targeting molecule to be used to attack the vasculature of solid tumors of other types of cancers, Low said.

Two papers detailing the work of the Purdue team were published in the June 1 issue of Molecular Pharmaceutics. Endocyte Inc. funded the work.

The team's animal study data shows an ability to eliminate human prostate cancer cells in mice with no evidence of collateral toxicity in normal tissue.

Sumith Kularatne, a graduate student in Purdue's chemistry department and first author of both papers, compared the targeting molecule to a homing device.

"The molecule acts like a homing device for prostate cancer," he said. "PSMA, which is found only on prostate cancer cells and tumor blood vessels, acts as the homing signal that the molecule targets. The molecule and its cargo go only to cancerous tissue, leaving healthy tissue unharmed."

Once the molecule reaches the PSMA protein, it binds to it. The molecule is designed with a specific shape that fits with the protein like a key to a lock, Kularatne said. The molecule and its cargo are then carried inside the cell with the protein as it goes through its normal cycle.

In 1995 Low developed a similar method to infiltrate cancer cells by attaching treatments to the vitamin folate, which many cancers rapidly consume. This method provided a "Trojan Horse" entry of large treatment molecules that otherwise would not be able to enter cancer cells.

Low was inspired to find a similar way to target prostate cancer, which does not have the same appetite for folate, he said.

A clinical trial of the radioimaging application is expected to begin at the Indiana University Medical Center in the fall through a collaboration between the Purdue Cancer Center and the Indiana University Cancer Center with additional support from Endocyte Inc.

A radioimaging agent linked to the targeting molecule will be injected into prostate cancer patients and pictures will be taken using a special camera that detects radioactivity. The pictures show where the cancer is present to help doctors determine if it has metastasized, or spread, to any other areas of the body. It also will help doctors decide on the best course of treatment, Low said.

There is currently only one radioimaging agent for prostate cancer approved by the Food and Drug Administration.

"The current imaging capabilities available for prostate cancer are very poor," Low said. "The existing imaging agent is limited because of its large size, which is difficult to get into a solid tumor. Also it seeks out a target located inside the cancer cell and is only able to mark injured cells that are falling apart as opposed to actively growing cancer cells."

The targeting molecule and radioimaging agent combination designed by Low's group is more than 150 times smaller than the existing agent and has much easier penetration through a solid tumor to reach all of the cells inside, he said. It also has the advantage of targeting an area of PSMA exposed on the outside of cancer cells.

Already in clinical trials is an optical imaging application that involves attaching a fluorescent dye to the targeting molecule and mixing it with a patient's blood sample. Circulating prostate cancer cells in the sample fluoresce and are easily measured to help in diagnosing patients with prostate cancer. Researchers also are investigating whether this could be used to evaluate a patient's response to therapy, Low said.

Low's research group modeled the targeting molecule after a naturally occurring molecule that strongly binds to PSMA, called DUPA. Several alterations were necessary to create a molecule that fit the needs of a homing device and delivery vehicle, Kularatne said. The team created an area on the molecule that would link to various imaging or therapeutic agents to bring them along as cargo and created a spacer that would stretch the molecule so that its cargo would not keep it from properly fitting into the binding site. The spacer also was designed to improve binding of the targeting molecule to PSMA.

In addition to Low and Kularatne, co-authors of the papers include Endocyte researchers Kevin Wang and Hari-Krishna R. Santhapuram, graduate student in medicinal chemistry Zhigang Zhou, graduate student in chemistry Jun Yang, and professor of medicinal chemistry and molecular pharmacology Carol B. Post.

Low is the chief science officer for Endocyte, a Purdue Research Park-based company that develops receptor-targeted therapeutics for the treatment of cancer and autoimmune diseases. Endocyte holds the license to many of Low's drug-targeting technologies.

Journal reference:

Kularatne et al. Prostate-Specific Membrane Antigen Targeted Imaging and Therapy of Prostate Cancer Using a PSMA Inhibitor as a Homing Ligand. Molecular Pharmaceutics, 2009; 6 (3): 780 DOI: 10.1021/mp900069d

Adapted from materials provided by Purdue University.

Source : KISTI, sciencedaily.com


덧글

  • 2010/03/15 14:06 # 삭제 비공개

    비공개 덧글입니다.
※ 이 포스트는 더 이상 덧글을 남길 수 없습니다.



Fireproofing

Fireproofing(내화피복)

전 품목 시공 상담합니다. (뿜칠. 페인트. UL제품 포함)

석유화학, 해양플랜트 PFP / 일반 건축 및 석유 화학 관련 Fireproofing / Cellulosic Fire, Hydrocarbon Fire, Jet Fire / Oil Refining, Gas Refining, Chemical Process…

061-742-4484 dvesys@gmail.com

구글 번역기

애드센스 160*600 사이드 이미지,텍스트

구글검색

맞춤검색

방문자 국가

free counters

Since 20090714

방문자 지도