JP2020169146A - 高分子型抗がん剤の抗腫瘍効果の増強剤 - Google Patents
高分子型抗がん剤の抗腫瘍効果の増強剤 Download PDFInfo
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Abstract
Description
項1. 高分子型抗がん剤の抗腫瘍効果を増強させるために使用される増強剤であって、
高分子型抗がん剤を含んでいない炭酸アパタイトを含む、前記増強剤。
項2. 前記高分子型抗がん剤がポリマー結合抗がん剤である、項1に記載の増強剤。
項3. 更にアルブミンを含有する、項1又は2に記載の増強剤。
項4. 高分子型抗がん剤を含んでいない炭酸アパタイトを含有する第1剤と、高分子型抗がん剤を含有する第2剤とを含む、2剤タイプのがん治療剤。
項5. 前記高分子型抗がん剤がポリマー結合抗がん剤である、項4に記載の2剤タイプのがん治療剤。
項6. 前記第1剤が更にアルブミンを含有する、項4又は5に記載の2剤タイプのがん治療剤。
項7. 高分子型抗がん剤を含んでいない炭酸アパタイトの、高分子型抗がん剤の抗腫瘍効果を増強させるために使用される増強剤の製造のための使用。
項8. 前記高分子型抗がん剤がポリマー結合抗がん剤である、項7に記載の使用。
項9. 更にアルブミンを含有する、項7又は8に記載の使用。
項10. 高分子型抗がん剤を含んでいない炭酸アパタイトを含有する第1剤と、高分子型抗がん剤を含有する第2剤の、2剤タイプのがん治療剤の製造のための使用。
項11. 前記高分子型抗がん剤がポリマー結合抗がん剤である、項11に記載の使用。
項12. 前記第1剤が更にアルブミンを含有する、項11又は12に記載の使用。
本発明の増強剤は、高分子型抗がん剤の抗腫瘍効果を増強させる目的で使用されるものであって、高分子型抗がん剤を含んでいない炭酸アパタイトを有効成分とすることを特徴とする。以下、本発明の増強剤について詳述する。
本発明では、高分子型抗がん剤を含んでいない炭酸アパタイトを使用する。「高分子型抗がん剤を含んでいない炭酸アパタイト」とは、粒子内部に高分子型抗がん剤を含んでいない炭酸アパタイトである。後述する炭酸アパタイトの調製方法において、炭酸アパタイトの製造原料を含む水溶液中に高分子型抗がん剤を含有させると、高分子型抗がん剤を含む炭酸アパタイトが生成するので、本発明では、調製工程において高分子型抗がん剤を添加することなく得られた炭酸アパタイトを使用する。
水槽の温度:例えば5〜45℃、好ましくは10〜35℃、更に好ましくは20〜30℃
高周波出力:例えば10〜500W、好ましくは20〜400W、更に好ましくは30〜300W、より好ましくは40〜100W。
発振周波数:例えば10〜60Hz、好ましくは20〜50Hz、更に好ましくは30〜40Hz。
処理時間:例えば、30秒〜30分、好ましくは1〜20分、更に好ましくは3〜10分。
本発明の増強剤は、高分子型抗がん剤の抗腫瘍効果を増強させる目的で使用される。
本発明のがん治療剤は、前記増強剤を含む第1剤と、高分子型抗がん剤を含む第剤とを含む、2剤タイプのがん治療剤である。本発明において、2剤タイプのがん治療剤とは、前記第1剤と前記第2剤が、それぞれ異なる製剤として含まれ、2つの製剤からなるがん治療薬である。
1−1.細胞培養
以下に示す実験では、HCT116及びHT29の2種のヒト大腸がん細胞株を用いた。HCT116の培養には、DMEM(Dulbecco's Modified Eagle Medium)(Thermo Fisher Scientific, Waltham, Massachusetts, USA)を使用し、HT29の培養にはRPMI1640(Roswell Park Memorial Institute Medium)(Thermo Fisher Scientific)を使用した。両培地に、10% FBS(Fetal Bovine Serum)(BIO-WEST, San Marcos, Texas, USA)を加え、5%CO2、37℃のインキュベータで培養した。
0.37gのNaHCO3、90μLのNaH2PO4・2H2O(1M)、及び180μlのCaCl2(1M)を100mlの蒸留水に加え、完全に溶解させ、1NのHClにてpH 7.5に調整し、バッファーを調整した。得られたバッファーを直径0.2μmのフィルターでろ過して滅菌し、25mlずつ分注した。次いで、バッファー25ml当たり100μlのCaCl2(1M)を加え、ボルテックスで3秒間撹拌後、37℃で30分間インキュベートした。その後、4℃、12,000rpmで3分間遠心分離し、上清を捨て、バッファー50ml分のペレットを生理食塩水(200〜400μl)で回収した。次いで、液量に対して0.5%となるようにアルブミンを添加し、軽く撹拌して、炭酸アパタイト粒子(以下、iNaD(inorganic nanoparticle drug)と表記する。)の分散液を作製した。尾静脈注射を行う前には、超音波基にて10分間超音波処理(38kHz、80W)し、10分以内に尾静脈注射を行った。
担がんマウスは、7週齢・メスのBALB/cAJcl nudeマウス(CLEA Japan, Osaka, Japan)の背部2カ所にHT29及びHCT116を各3×106個皮下注射し、作製した。
インフルラン(Pfizer, New York, USA)による麻酔下で、IVIS Spectrum CT instrument (Perkin Elmer, Waltham, Massachusetts, USA)を用いて画像撮影を行った。撮影は、蛍光モードで、励起波長P-THP 500nmで行った。Relative fluorescent unitは、ROI(Region of Interest)を設定し得られたROI値をBack groundのROI値で差し引くことにより算出した。
本実験では、高分子型抗がん剤としてP-THPを使用した。P-THPは、水溶性ポリマーであるポリヒドロキシプロピルメタクリルアミド(Poly(N-(2-hydroxypropyl)methacrylamide: PHPMA)がヒドラゾンを介して低分子量抗がん剤ピラルビシン(pirarubicin: THP)が共有結合で連結している高分子型抗がん剤(平均分子量39,000)である。
HT29担がんマウスのHT29腫瘍体積が約80 mm3に達した時点で、無治療群(n=7)、P-THP(i.v.)群(n=5)、及びiNaD(i.v.)+P-THP(i.v.)群(n=3)の3群に分けた。P-THP(i.v.)群、及びiNaD(i.v.)+P-THP(i.v.)群では、0日目にP-THP 10mg/kg、5及び13日目にP-THP 20mg/kgを尾静脈注射した。また、iNaD(i.v.)+P-THP(i.v.)群では、0、5、13日目にiNaDを炭酸アパタイト量で120 mg/kgとなる用量で尾静脈注射した。0、5、13、16、及び21日目に腫瘍径を測定した。腫瘍体積は、計算式[腫瘍体積(mm3)=a×b2/2(a:長径mm、b:短径mm)]により算出した。
本実験では、低分子型抗がん剤としてオキサリプラチン(Oxaliplatin: L-OHP、分子量397)(Yakult,Tokyo, Japan)を使用した。HCT116担がんマウスを、L-OHPを尾静脈注射するL-OHP(i.v.)群、iNaDの尾静脈注射1時間後にL-OHPを尾静脈注射するiNaD(i.v.)+L-OHP(i.v.)群の2群に分けた。L-OHPは0.15 mg/kgを尾静脈注射した。iNaDは、炭酸アパタイト量で120 mg/kgを尾静脈注射した。P-THP投与から1及び4時間後に、マウスを安楽死させ、腫瘍(n=4〜6)と肝臓(n=3)を採取し、誘導結合プラズマ質量分析(ICP-MS)にて、プラチナ量を測定した。ICP-MSの手順については、以下の通りである。
HCT116担がんマウスのHCT116腫瘍体積が約80 mm3に達した時点で、無治療群(n=6)、L-OHP(i.v.)群(n=6)、及びiNaD(i.v.)+L-OHP(i.v.)群(n=6)の3群に分けた。L-OHP(i.v.)群、及びiNaD(i.v.)+L-OHP(i.v.)群では、0、4、8、12、15、19、及び22日目にL-OHP 0.15mg/kgを尾静脈注射し、同日に腫瘍径を測定した。また、iNaD(i.v.)+L-OHP(i.v.)群では、0、4、8、12、15、19、及び22日目にiNaDを炭酸アパタイト量で120 mg/kgとなる用量で尾静脈注射した。
HCT116担がんマウスを無治療群(n=3)及びiNaD(i.v.)群(n=3)にそれぞれ分け、iNaD(i.v.)群には、iNaDを炭酸アパタイト量で120 mg/kgとなる用量で尾静脈注射した。4時間後、両群にイメージング試薬としてOTN Ceramic probe Y(Katayama Chemical Industries, Osaka, Japan)を尾静脈注射し、in vivo蛍光イメージングシステム(SAI-1000, Shimadzu, Kyoto, Japan)を用いて腫瘍内の血管造影を行った。また、血管造影画像における蛍光強度を用いて比較した。
HT29担がんマウスを無治療群(n=3)及びiNaD(i.v.)群(n=3)にそれぞれ分け、iNaD(i.v.)群にはiNaDを炭酸アパタイト量で120 mg/kgとなる用量で尾静脈注射し、4時間後に安楽死させた。両群から腫瘍を切除し、RNA later(Thermo Fisher Scientific)に浸漬させ、-80℃で保存した。そして、マイクロアレイ解析とIPAを行った。Z-scoreが2以上又は2以下である遺伝子を有意差ある遺伝子として判定した。
統計学的数値は、平均±標準偏差で表した。統計学的評価には、Student-T検定を行い、P<0.05であれば有意と判定した。
2−1.iNaD併用によるP-THPの抗腫瘍効果の検討
動物実験において、iNaD併用による抗腫瘍効果の増強を検討した。本実験では、高分子型抗がん剤(P-THP)を用いて、IVISによるP-THP集積量の測定と、抗腫瘍効果の検討を行った。
本実験では、低分子型抗がん剤としてオキサリプラチン(L-OHP)を用いて、質量分析法によるL-OHP集積量の測定と、抗腫瘍効果の検討を行った。
本実験では、iNaDによる高分子型抗がん剤と抗腫瘍効果の増強のメカニズムを解明するために、血管造影を行い、iNaDによる腫瘍内の血管透過性の変化を検討した。
血管造影の結果から、iNaD投与で腫瘍内の血管透過性が上昇したことから、iNaDが血管透過性因子の発現量に及ぼす影響について検討を行った。
Claims (6)
- 高分子型抗がん剤の抗腫瘍効果を増強させるために使用される増強剤であって、
高分子型抗がん剤を含んでいない炭酸アパタイトを含む、前記増強剤。 - 前記高分子型抗がん剤がポリマー結合抗がん剤である、請求項1に記載の増強剤。
- 更にアルブミンを含有する、請求項1又は2に記載の増強剤。
- 高分子型抗がん剤を含んでいない炭酸アパタイトを含有する第1剤と、高分子型抗がん剤を含有する第2剤とを含む、2剤タイプのがん治療剤。
- 前記高分子型抗がん剤がポリマー結合抗がん剤である、請求項4に記載の2剤タイプのがん治療剤。
- 前記第1剤が更にアルブミンを含有する、請求項4又は5に記載の2剤タイプのがん治療剤。
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