JP7076104B2 - グルタミントランスポーターと多価結合することができるリガンド、及び当該リガンドを含む組成物 - Google Patents
グルタミントランスポーターと多価結合することができるリガンド、及び当該リガンドを含む組成物 Download PDFInfo
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- JP7076104B2 JP7076104B2 JP2018535630A JP2018535630A JP7076104B2 JP 7076104 B2 JP7076104 B2 JP 7076104B2 JP 2018535630 A JP2018535630 A JP 2018535630A JP 2018535630 A JP2018535630 A JP 2018535630A JP 7076104 B2 JP7076104 B2 JP 7076104B2
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- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 1
- 229910001416 lithium ion Inorganic materials 0.000 description 1
- KNJDBYZZKAZQNG-UHFFFAOYSA-N lucigenin Chemical compound [O-][N+]([O-])=O.[O-][N+]([O-])=O.C12=CC=CC=C2[N+](C)=C(C=CC=C2)C2=C1C1=C(C=CC=C2)C2=[N+](C)C2=CC=CC=C12 KNJDBYZZKAZQNG-UHFFFAOYSA-N 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- QVGXLLKOCUKJST-BJUDXGSMSA-N oxygen-15 atom Chemical compound [15O] QVGXLLKOCUKJST-BJUDXGSMSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
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- 239000004417 polycarbonate Substances 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 108010050934 polyleucine Proteins 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 150000004033 porphyrin derivatives Chemical class 0.000 description 1
- 235000020004 porter Nutrition 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
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- 108091092562 ribozyme Proteins 0.000 description 1
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- 150000003384 small molecules Chemical class 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- CIOAGBVUUVVLOB-OUBTZVSYSA-N strontium-89 Chemical compound [89Sr] CIOAGBVUUVVLOB-OUBTZVSYSA-N 0.000 description 1
- 229940006509 strontium-89 Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940056501 technetium 99m Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- BKVIYDNLLOSFOA-OIOBTWANSA-N thallium-201 Chemical compound [201Tl] BKVIYDNLLOSFOA-OIOBTWANSA-N 0.000 description 1
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- 238000001931 thermography Methods 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
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- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940106670 xenon-133 Drugs 0.000 description 1
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Description
近年、癌疾病は重大な問題となっている。WHOからの報告によると2012年には、820万人が癌疾病で亡くなっており、これは死因の13.2%を占める。癌の治療法の一つとして、化学療法がある。化学療法とは、体中に抗癌剤を行き渡らせることにより、癌細胞を殺傷する治療法である。化学療法は低侵襲であるという利点がある一方、副作用による患者の身体への負担が大きく、投与方法においても様々な制約が存在する。そのため副作用を抑制しつつ、癌を殺傷出来、患者への負担が減らし、Quality of life(QOL)を向上させつつ、治療が行える抗癌剤の開発が求められている。
細胞は癌化することによって、解糖系が促進され、グルコースを大量に消費する。そのため、癌細胞にはグルコースを取り込むグルコーストランスポーターが細胞表面に過剰に発現しており、グルコースの過剰な取り込みがなされる。癌細胞におけるグルコースの取り込みの亢進を利用して、グルコースの水素の一部を18Fに変えた18F-フルオロデオキシグルコース-ポジトロン断層法(18F-fluorodeoxyglucose-positron emission tomography) ([18F]FDG-PET)が、がん診断に実用化されている(非特許文献4)。
[1]正常細胞と比較して過剰に発現している癌細胞のグルタミントランスポーターと多価結合することができるリガンドであって、複数の、以下の式(1):
で表される基を含む、リガンド。
[2]
10個以上の前記式(1)の基が直接的に又はリンカーを介して連結している、ポリマー主鎖を含む、[1]に記載のリガンド。
[3]
数平均分子量が5,000Da以上である、[2]に記載のリガンド。
[4]
前記ポリマー主鎖が、ポリエステル、ポリエーテル、ポリアクリレート、ポリペプチド及びそれらの共重合体から成る群から選択される、[2]又は[3]に記載のリガンド。
[5]
前記ポリマー主鎖がポリペプチドである、[2]~[4]のいずれか1つに記載のリガンド。
[6]
前記ポリペプチド中の10個以上のアミノ酸の側鎖に、以下の式(2):
矢印は、前記側鎖への連結を示し、
Xは、-NH-、-O-、-NH-CO-、-C(O)O-、-C(O)S-、-S-及び-S-S-から成る群から選択される基であるか、又は存在せず、
Wは、C1-6アルキレン基、ポリオキシアルキレン基及びポリアミノアルキレン基から成る群から選択されるリンカーであるか、又は存在しない]
で表される基が連結している、[5]に記載のリガンド。
[7]
前記ポリペプチドがα-ポリリシンである、[5]又は[6]に記載のリガンド。
[8]
前記α-ポリリシン中の10個以上のリシンの側鎖アミノ基に、以下の式(3):
で表される基が連結している、[7]に記載のリガンド。
[9]
複数の式(1)で表される基のうち、一部の基の末端の一級アミノ基が低pH環境で脱離する保護基によりキャッピングされている、[1]~[8]のいずれか1つに記載のリガンド。
[10]
前記低pH環境で脱離する保護基が、フタロイル基、マレオイル基、2-カルボキシ-ベンゾイル基及び(2Z)-3-カルボキシ-2-プロペノイル基から成る群から選択される、[9]に記載のリガンド。
[11]
少なくとも1つの検出可能な標識又は抗癌剤を含む、[1]~[10]のいずれか1つに記載のリガンド。
[12]
前記検出可能な標識が、蛍光標識、発光標識、造影剤、金属原子、1種または2種以上の金属原子を含む化合物、放射性同位体、1種または2種以上の放射性同位体を含む化合物、ナノ粒子、またはリポソームである、[11]に記載のリガンド。
[13]
以下の式(4)
で表される化合物又はその薬学的に許容される塩である、[1]に記載のリガンド。
[14]
[1]~[13]のいずれか1つに記載のリガンドを含む、組成物。
[15]
それを必要とする対象に、有効量の[11]又は[12]に記載のリガンドを投与することを含む、癌の診断又は検出方法であって、前記リガンドは少なくとも1つの検出可能な標識を含む、方法。
[16]
癌を診断又は検出するための、[11]又は[12]に記載のリガンドであって、少なくとも1つの検出可能な標識を含む、リガンド。
[17]
癌を診断又は検出するための医薬の製造における、[11]又は[12]に記載のリガンドの使用であって、前記リガンドは少なくとも1つの検出可能な標識を含む、使用。
[18]
それを必要とする対象に、有効量の[11]に記載のリガンドを投与することを含む、癌の治療方法であって、前記前記リガンドは少なくとも1つの抗癌剤を含む、方法。
[19]
癌を治療するための[11]に記載のリガンドであって、少なくとも1つの抗癌剤を含む、リガンド。
[20]
癌を治療するための医薬の製造における、[11]に記載のリガンドの使用であって、前記前記リガンドは少なくとも1つの抗癌剤を含む、使用。
で表される基を含む、リガンドに関する。以下で「本発明のリガンド」とも呼ぶ。
矢印は、前記側鎖への連結を示し、
Xは、-NH-、-O-、-NH-CO-、-C(O)O-、-C(O)S-、-S-及び-S-S-から成る群から選択される基であるか、又は存在せず、
Wは、C1-6アルキレン基、ポリオキシアルキレン基及びポリアミノアルキレン基から成る群から選択されるリンカーであるか、又は存在しない]
で表される基が連結している。この場合、リガンド中の式(2)の基の数については、上記の式(1)の基の数が同様に適用される。好ましくは、前記ポリペプチド中の10個以上のアミノ酸の側鎖に、上記式(2)で表される基が連結している。X及びWの組み合わせとしては、Xが-NH-又は-NH-CO-であってWがリンカーである場合、あるいはX及びWが共に存在しない場合が好ましい。
で表される基が連結している。この場合、リガンド中の式(3)の基の数については、上記の式(1)の基の数が同様に適用される。好ましくは、前記ポリペプチド中の10個以上のリシンの側鎖アミノ基に、上記式(3)で表される基が連結している。より好ましくは、前記ポリペプチド中の全てのリシンの側鎖アミノ基に、上記式(3)で表される基が連結している。
で表される基が連結している。
で表される化合物又はその薬学的に許容される塩である。nは重合度であり、その下限は10であるが、好ましくは、15、20、25、30、35、40、45、50、60、70、80、90、又は100である。nの上限は、特に限定されないが、例えば、200、300、400、500、600、700、800、900、1000、3000又は5000である。nは、例えば10~5000の整数であり、好ましくは10~500の整数であり、より好ましくは20~200の整数である。上記重合度は、1H-NMRスペクトルの積分値に基づく末端基定量法により算出することができる。
R1はアミノ基の保護基(例えばBoc基)であり、R2はカルボン酸の保護基(例えばベンジル基)である]
で表される化合物を、公知の縮合条件にて縮合し、その後保護基を除去することにより製造されてもよい。適切な保護基及びその脱保護条件は、例えば、T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999に記載されたものを使用できる。また、例えば本発明のリガンドが、親水性ポリマーセグメントと疎水性ポリマーセグメントとを含むブロックコポリマーを含んで成るポリマーミセルであって、親水性ポリマーセグメント中にカルボン酸と縮合可能な1級又は2級アミノ基が存在する場合には、上記と同様の方法を適用して式(1)の基を親水性ポリマーセグメントに導入することができる。
N-ε-トリフルオロアセチル-L-リシン-N-カルボキシ無水物(Lys(TFA)-NCA)・・・中央化成
11-アジド-3,6,9-トリオキサウンデカン-1-アミン・・・Sigma Aldrich
ジメチルスルホキシド(DMSO)・・・関東化学
Boc-Glu-OBzl・・・Sigma Aldrich
Boc-Glu(OBzl)-OH・・・Sigma Aldrich
4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(DMT-MM)・・・fluorochem
トリエチルアミン(TEA)・・・関東化学
5N HCl・・・和光純薬
メタノール・・・関東化学
5N NaOH・・・和光純薬
酢酸 (AcOH)・・・和光純薬
Cy5-DBCO・・・Click Chemistry Tools
NaHCO3・・・和光純薬
NaCl・・・VETEC
N-メチルピロリドン (NMP)・・・関東化学
臭化リチウム(LiBr)・・・Sigma Aldrich
D-PBS(-)(PBS)・・・和光純薬
トリプシン-EDTA溶液(Trp)・・・Sigma Aldrich
ダルベッコ変法イーグル培地(DMEM)
ロズウェルパーク記念研究所培地(RPMI)
ウシ胎児血清(Fetal bovine serum:FBS)・・・Thermo Scientific
ペニシリン-ストレプトマイシン(PS)・・・Sigma Aldrich
EGM(商標)-2BulletKit(商標)・・・Lonza
O-ベンジル-L-セリン(Bzl-Ser)・・・東京化成工業
L-グルタミン(Gln)・・・和光純薬
抗ASCT2抗体(H-52)・・・Santa Cruz
ヤギ抗ウサギIgG H&L(DyLight(登録商標)488)・・・abcam
ウシ血清アルブミン(Bovine serum albumin: BSA)
Hoechst33342・・・Thermo Scientific
p-ホルムアルデヒド・・・和光純薬
トリス緩衝生理食塩水(TBS)・・・Sigma
Tween20・・・BETHYL
VECTASHIELD封入剤(VECTASHIELD)・・・VECTOR
アセタール-PEG-NH2(Mw:10kDa)・・・日油
無水酢酸・・・和光純薬
Cy5-NH2・・・Thermo Fisher Scientific
N,N-ジメチルホルムアミド(DMF)・・・関東化学
2-ピコリンボラン(Pic-BH3)・・・和光純薬
passive lysis buffer・・・Promega
ヘパリン・・・和光純薬
Bx-PC3細胞(ヒト膵臓癌細胞株)
HepG2細胞(ヒト肝臓癌細胞株)
HUVEC細胞(ヒト臍帯静脈内皮細胞株)
BALB/c-nu/nu ヌードマウス(雌)・・・オリエンタル酵母
NMR・・・Bruker 400MHz
ゲル浸透クロマトグラフィー(GPC)・・・Jasco(カラム:Superdex200 increase、検出器:UV220nm)
蛍光分光光度計(FP8300)・・・Jasco
guava easy Cyte6-2L・・・MERCK,励起波長:642nm,吸収波長:661nm
共焦点レーザー走査型顕微鏡(LSM710)・・・ZEISS
蛍光分光光度計(FP8300)・・・Jasco
IVIS Imaging System・・・PerkinElmer、励起波長:640nm、測定吸収波長:700nm
ZEN2012・・・ZEISS
IMALIS・・・ZEISS
以下の式(4)で表される化合物を、以下で「Cy5-P[Lys(Gln)]n」とも呼ぶ。ポリリシンの側鎖のアミノ基がグルタミン酸のγ位カルボキシル基と縮合した構造をしている。また、ポリリシンの末端に、リンカーを介して蛍光色素であるCy5が連結している。
Cy5-P[Lys(Gln)]n(n=25、46、106)の合成
(1)化合物(b)(n=25、46、106)の合成
Cy5-P[Lys(α-Glu)](n=46、106)の合成
(1)化合物(f)(n=46、106)の合成
化合物(f)(n=46、106)を用いて、実施例1(5)と同様の方法により調製した。得られた化合物の蛍光スペクトルを図19に示す。
Cy5-PEG-Acの合成
アセタール-PEG-NH2(Mw:10kDa)をDMF中で無水酢酸と反応させ、アミノ基をアセチル基で保護した。その後、0.1N HCl中でアセタール基を脱保護し、アルデヒド基とした。その後、このポリマーとCy5-NH2および還元剤Pic-BH3をMeOH/酢酸(10/1(vol))中で反応させ、Cy5を還元的アミノ化により導入することでCy5-PEG-Acを調製した。
リガンドと所定時間接触させた際の細胞内取り込み量の変化
実施例1で合成した化合物がリガンド機能を示すか否かを評価するため、グルタミントランスポーターであるASCT2が過剰発現している癌細胞種(BxPC-3細胞)と実施例1、比較例1及び2の化合物を所定時間接触させた際の取り込み量の変化を、フローサイトメトリーによって細胞内の蛍光強度から評価を行った。
異なる細胞種に対する細胞内取り込み量の評価
Cy5-P[Lys(Gln)]nの標的であるASCT2は、種々の癌細胞に過剰発現しており、特に膵臓癌細胞と肝臓癌細胞での過剰発現が報告されている。Cy5-P[Lys(Gln)]nの膵臓癌細胞(Bx-PC3)におけるリガンド能評価は、実施例2で確認されたが、肝臓癌細胞においても同様にリガンド能を示すのかを確認するため、及び正常細胞と比較して取り込み量に差異が生じるかを確認するため、Bx-PC3(膵臓癌細胞)、HepG2(肝臓癌細胞)、HUVEC細胞(正常細胞)を用いて、リガンドの取り込み量の評価を行った。
阻害剤を添加した場合における、高分子リガンドの細胞内取り込み量の変化
本実験では、ASCT2を含むシステムASCトランスポーターの阻害剤として用いられるBzl-Ser、システムNのトランスポーターの阻害剤として用いられているグルタミン(Gln)の2種類を阻害剤として用いて、高分子リガンドの取り込み量の評価を行った。
抗ASCT2抗体(H-52)による高分子リガンドの取り込み阻害実験
Bx-PC3細胞をRPMI培地に懸濁させ、1.25×105cells/mlの細胞懸濁液を調製した。この細胞懸濁液400μlを24ウェルプレートに播き(1ウェル当たり5.0×104cells)、37℃で24時間インキュベートした。培地を除去後、PBSで1回洗浄した後、PBSで1/25倍に抗ASCT2抗体を希釈させた抗体溶液およびPBSを160μl各ウェルに播き、37℃、80分インキュベートした。インキュベート後、Cy5-P[Lys(Gln)]n(n=46、106)、Cy5-P[Lys(α-Glu)]n(n=46、106)及びCy-PEGをそれぞれ、各溶液に0.3mg/ml、80μl加え、37℃で1時間インキュベートした。所定時間のインキュベート後、溶液を除去してPBSで洗浄を2回行い、Trpを150μl加え、37℃、7分間インキュベートした後、PBS+10%FBSを150μl加えてセルストレーナーを通し、フローサイトメーター(FCM)で測定した。結果を図7に示す。
低温中における細胞内取り込み量の変化
Cy5-P[Lys(Gln)]nは比較的大きな分子のため、細胞膜上のASCT2と結合した後、主にエンドサイトーシスによって細胞内に取り込まれると推察される。それを確かめるべく、エンドサイトーシスが抑制される低温中(4℃)における高分子リガンドの取り込み量を、エンドサイトーシスが働く37℃での取り込み量と比較した。
重合度の異なるリガンドを用いた場合における細胞内取り込み量の評価
本実験では、重合度の異なるリガンドを用いた場合における細胞への取り込み能を評価するため、Cy5-P[Lys(Gln)]25、Cy5-P[Lys(Gln)]46及びCy5-P[Lys(Gln)]106を用いて評価を行った。
共焦点レーザー顕微鏡(Confocal Laser Scanning Microscope: CLSM)を用いた細胞内取り込み評価
インキュベーション温度を変えた際の高分子リガンドの細胞への取り込みを、CLSMを用いて評価した。Bx-PC3細胞をRPMI培地に懸濁させ、1.25×106cells/mlの細胞懸濁液を調製した。この細胞懸濁液200μlを8ウェルグラスディッシュに播き(1ウェル当たり1.0×104cells)、37℃で24時間インキュベートした。培地を除去後、PBSで1回洗浄した後、Cy5-P[Lys(Gln)]106を1μMの濃度で200μl加え、37℃および4℃で1時間インキュベートした。なお、4℃でインキュベートを行うディッシュは培地除去前、4℃で10分間静置した。所定時間インキュベート後、溶液を除去し、PBSで2回洗浄した後、4%p-ホルムアルデヒドを加え、3分静置後、除去し、PBSで1回洗浄した。TBSTで3回洗浄した後、5%BSA溶液を加え、10分静置して、ブロッキングをした。ブロッキング後、PBSで1回洗浄を行った。その後、1%BSAで50倍に希釈した抗ASCT2抗体溶液を各ウェルに70μl加え、常温で2時間静置した。溶液を除去後、PBSで3回洗浄を経て、PBSで800倍に希釈したDyLight(登録商標)488溶液を100μl加え、常温で1時間静置した。溶液を除去後、PBSで3回洗浄を経て、PBSで1000倍に希釈したHoechst溶液を加え、3分常温で静置した。Hoechst溶液を除去後、PBSで1回洗浄を経てPBS200μl、VECTASHIELDを1滴加えCLSMで観察した。CLSM測定は63倍レンズを用い、検出は405nm(Diode CW/Pulse)、488nm(Arレーザー)、640nm(HeNeレーザー)を用いた。そのCLSM画像を解析ソフトIMALISで3Dモデル化した。結果を図11~14に示す。
高分子リガンドの腫瘍滞留率の評価
ヌードマウスにBxPC3細胞とHepG2細胞の懸濁液それぞれを皮下移植した。細胞懸濁液の条件は1.0×108cells/ml、50μlである。HepG2およびBxPC3皮下移植マウスの腫瘍の大きさが200mm3に成長した後に、腫瘍部分に、Cy5-P[Lys(Gln)]n(n=46、106)及びCy5-P[Lys(α-Glu)]n(n=46、106)、40μM(Cy5-P[Lys(Gln)]106及びCy5-P[Lys(α-Glu)]106は1.2mg/ml、Cy5-P[Lys(Gln)]46及びCy5-P[Lys(α-Glu)]46は0.6mg/ml)をそれぞれ20μl投与した。投与してから30分後を0時間として、0、8、24、48時間後にIVISで腫瘍部分の蛍光強度を測定した。蛍光強度は腫瘍部分の面積当たりのRadiant Efficiencyから算出した(励起波長:640nm、吸収波長:700nm)。結果を図15及び16に示す。
Claims (11)
- 数平均分子量が5,000Da以上である、請求項1に記載のリガンド。
- 前記ポリペプチドがα-ポリリシンである、請求項1~3のいずれか1項に記載のリガンド。
- 複数の式(1)で表される基のうち、一部の基の末端の一級アミノ基が低pH環境で脱離する保護基によりキャッピングされている、請求項1~5のいずれか1項に記載のリガンド。
- 前記低pH環境で脱離する保護基が、フタロイル基、マレオイル基、2-カルボキシ-ベンゾイル基及び(2Z)-3-カルボキシ-2-プロペノイル基から成る群から選択される、請求項6に記載のリガンド。
- 少なくとも1つの検出可能な標識又は抗癌剤を含む、請求項1~7のいずれか1項に記載のリガンド。
- 前記検出可能な標識が、蛍光標識、発光標識、造影剤、金属原子、1種または2種以上の金属原子を含む化合物、放射性同位体、1種または2種以上の放射性同位体を含む化合物、ナノ粒子、またはリポソームである、請求項8に記載のリガンド。
- 請求項1~10のいずれか1項に記載のリガンドを含む、組成物。
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