JP6888239B2 - 腫瘍治療用腫瘍免疫活性促進剤及び腫瘍治療用医薬組成物 - Google Patents
腫瘍治療用腫瘍免疫活性促進剤及び腫瘍治療用医薬組成物 Download PDFInfo
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Images
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Description
2−デオキシ−D−グルコースを含有する生体適合性粒子を含み、
前記生体適合性粒子は、
乳酸・グリコール酸共重合体を含む。
抗癌剤と併用される、
こととしてもよい。
抗癌剤を含み、
上記本発明の第1の観点に係る腫瘍治療用腫瘍免疫活性促進剤と併用される。
ソラフェニブ、ドキソルビシン又はシスプラチンである、
こととしてもよい。
50〜170nmである、
こととしてもよい。
肝細胞癌、腎臓癌、大腸癌又は膵臓癌の治療に使用される、
こととしてもよい。
本発明に係る実施の形態について説明する。本実施の形態に係る医薬組成物は、糖誘導体を含有する生体適合性粒子を含む。例えば、糖誘導体は、D−グルコースの誘導体であって、解糖系を阻害するものである。
(a)対照群:PBSを腹腔内に200μL連日投与した。
(b)2DG低用量群:2DGをPBSに溶解した100mg/mLの2DG溶液を100mg/kg/日で腹腔内に連日投与した。
(c)2DG高用量群:100mg/mLの2DG溶液を1000mg/kg/日で腹腔内に連日投与した。
(d)ソラフェニブ群:ソラフェニブ(サンタクルーズバイオテクノロジー社製)溶液を5mg/kg/日でゾンデを用いて連日経口投与し、かつ200μLのPBSを腹腔内に連日投与した。なお、ソラフェニブ溶液は、原末をDMSO全量で溶解し、さらにその溶液をオリーブ油で1/20に希釈したものである(最終的には5%DMSO溶液)。
(e)ソラフェニブ+2DG低用量群:ソラフェニブ溶液を5mg/kg/日でゾンデを用いて連日経口投与し、かつ2DG溶液を100mg/kg/日で腹腔内に連日投与した。
(f)ソラフェニブ+2DG高用量群:ソラフェニブ溶液を5mg/kg/日でゾンデを用いて連日経口投与し、2DG溶液を1000mg/kg/日で腹腔内に連日投与した。
図1は、各群における投与開始21日後のマウス及び摘出した腫瘍の外観を示す。2DGは、移植された肝癌細胞の腫瘍サイズを減少させた。2DGは、ソラフェニブとの併用によりさらに腫瘍サイズを減少させた。図2は、腫瘍体積の経時変化を示す。2DG低用量群及び2DG高用量投与群において投与量に依存した有意な腫瘍体積の減少が認められた。ソラフェニブ+2DG低用量群及びソラフェニブ+2DG高用量群では、2DGとソラフェニブとの併用により投与量に依存した有意な腫瘍体積のさらなる減少が認められた。
ULREA SS−11(エム・テクニック社製)を使用して、以下のように2DGナノ粒子(2DG−PLGA)を作製した。まず、A液をA液タンクに充填し、タンクを0.3MPaに加圧した。その後、設定値43℃でA液を167mL/分で送液し、次いで設定値41℃(実測値約29℃)でB液を100mL/分で送液した。A液は0.5%PVAを含む水溶液である。また、B液は、PLGA:2DG:アセトン:エタノールが重量比で0.65:0.25:66:33の溶液である。回転数を1000rpmとし、背圧を0.02MPaとした。吐出液400.5mLを回収し、吐出液からエバポレーターで80分間、溶媒を留去した。なお、B液におけるPLGAとして、PLGA−7520(乳酸:グリコール酸=75:25、平均重量分子量20,000、和光純薬社製)を用いた。得られた2DG−PLGA水性分散液224mLを凍結乾燥し、2.16gの2DG−PLGAを得た。
機器:Shimadzu 10A series(島津製作所社製)
検出:Shimadzu ELSD−LT
ゲイン:8
ドリフト温度:40℃
ガス圧力:350kPa(実測358kPa)
ネブライザーガス:N2
カラム:Shodex Asahipak NH2P−504D(150mm×4.6mm)
カラム温度:40℃
移動相:A:水、B:アセトニトリル
B.濃度 75%→69%(8分)69%→75%(8分→16分)
流量:1.0mL/分
カラム温度:40℃
注入量:20μL
測定時間:16分
2DG−PLGAにおける2DGの含有率は、8.1±0.4%であった。図6に示すように、2DG−PLGAの粒度分布はシングルピークで、D50が166nm±5.4nm、スパン値は1.52±0.15であった。
実施例1と同様にHuh−7を皮下移植することで作製した皮下移植ヌードマウスを以下の6群に群分けした。
(g)対照群:200μLのPBSを週1回、頚静脈投与した。
(h)PLGA群:PLGAを週1回、頚静脈投与した。
(i)2DG群:100mg/mLの2DG溶液を100mg/kg/日で週1回、頚静脈投与した。
(j)2DG−PLGA群:2DG−PLGAを週1回、頚静脈投与した。
(k)2DG腹腔内注射群:上記2DG溶液を100mg/kg/日で腹腔内に連日投与した。
(l)ソラフェニブ+PLGA群:ソラフェニブ溶液を5mg/kg/日でゾンデを用いて連日経口投与し、かつPLGAを週1回、頚静脈投与した。
(m)ソラフェニブ+2DG−PLGA群:ソラフェニブ溶液を5mg/kg/日でゾンデを用いて連日経口投与し、かつ2DG−PLGAを週1回、頚静脈投与した。
投与開始21日後の腫瘍の外観を図7に示す。2DG−PLGAは、移植された肝癌細胞の腫瘍サイズを減少させた。さらに、2DG−PLGAは、ソラフェニブとの併用によりさらに腫瘍サイズを減少させた。図8は、腫瘍体積の経時変化を示す。2DG−PLGA群では、対照群、PLGA群及び2DG静注群に対して有意な腫瘍体積の減少が認められた。ソラフェニブを併用したソラフェニブ+2DG−PLGA群でも有意な腫瘍体積の減少が認められた。
上記実施例1と同様にHuh−7を皮下移植したマウスを、以下の4群に群分けてソラフェニブと異なる抗癌剤との併用による抗腫瘍効果及び安全性を検討した。
ドキソルビシン+PLGA群:ドキソルビシン(SIGMA社製)溶液を4mg/kgで1日おきに腹腔内投与し、かつPLGAを週1回、頚静脈投与した。
ドキソルビシン+2DG−PLGA群:ドキソルビシン溶液を4mg/kgで1日おきに腹腔内投与し、かつ2DG−PLGAを週1回、頚静脈投与した。
シスプラチン+PLGA群:シスプラチン(SIGMA社製)溶液を3mg/kgで週1回、腹腔内に投与し、かつPLGAを週1回、頚静脈投与した。
シスプラチン+2DG−PLGA群:シスプラチン溶液を3mg/kgで週1回、腹腔内に投与し、かつ2DG−PLGAを週1回、頚静脈投与した。
図12に示すように、2DG−PLGA群及びドキソルビシン+2DG−PLGA群では、対照群に対して腫瘍体積の有意な減少が認められた。また、ドキソルビシン+2DG−PLGA群では、ドキソルビシン+PLGA群に対して腫瘍体積の有意な減少が認められた。図13に示された投与開始21日後のマウス及び腫瘍の外観から明らかなように、2DG−PLGAの投与は、ドキソルビシンの抗腫瘍効果を増強する。
腎癌細胞株OS−RC−2(理化学研究所より取得)は、5%CO2インキュベーターを用いて37℃で培養した。OS−RC−2の培地には、10%ウシ胎児血清を含むRPMIを用いた。
対照群:200μLのPBSを週1回、頚静脈投与した。
2DG群:100mg/mLの2DG溶液を100mg/kg/日で腹腔内に連日投与した。
2DG−PLGA群:2DG−PLGAを週1回、頚静脈投与した。
図16は、腫瘍体積の経時変化を示す。2DG−PLGA群では、対照群及び2DG群に対して腫瘍体積の有意な減少が認められた。投与開始14日後のマウス及び腫瘍の外観を図17に示す。2DG群と比較して、2DG−PLGA群の腫瘍サイズは明らかに小さかった。2DG−PLGAは、腎癌細胞株OS−RC−2皮下移植ヌードマウスにおいても抗腫瘍効果を示した。
大腸癌細胞株HT−29は、5%CO2インキュベーターを用いて37℃で培養した。HT−29の培地には、10%ウシ胎児血清を含むMcCoy’s5Aを用いた。OS−RC−2の代わりにHT−29をマウスに移植する点及びマウスを投与開始14日後ではなく21日後に安楽死させる点を除いて、上記実施例5と同様に2DG−PLGAによる抗腫瘍効果を評価した。
図18は、腫瘍体積の経時変化を示す。2DG−PLGA群では、対照群及び2DG群に対して腫瘍体積の有意な減少が認められた。投与開始21日後のマウス及び腫瘍の外観を図19に示す。2DG群と比較して、2DG−PLGA群の腫瘍サイズは明らかに小さかった。2DG−PLGAは、大腸癌細胞株HT−29皮下移植ヌードマウスにおいても抗腫瘍効果を示した。
膵癌細胞株Bx−PC−3は、5%CO2インキュベーターを用いて37℃で培養した。Bx−PC−3の培地には、10%ウシ胎児血清を含むRPMIを用いた。上記実施例6と同様に2DG−PLGAによる抗腫瘍効果を評価した。
図20は、腫瘍体積の経時変化を示す。2DG−PLGA群では、対照群及び2DG群に対して腫瘍体積の有意な減少が認められた。投与開始21日後のマウス及び腫瘍の外観を図21に示す。2DG群と比較して、2DG−PLGA群の腫瘍サイズは明らかに小さかった。2DG−PLGAは、膵癌細胞株Bx−PC−3皮下移植ヌードマウスにおいても抗腫瘍効果を示した。
ULREA SS−11(エム・テクニック社製)を使用して、インドシアニングリーン(以下「ICG」とする、第一三共社製)を内包するPLGA粒子を作製した。実施例2と同様の方法で調製した0.5%PVAを含む水溶液(A液)と、PLGA:ICG:アセトン:エタノールが重量比で0.65:0.1:66:33の溶液(B液)と、から得られたICG−PLGA水性分散液を凍結乾燥し、0.61gのICG−PLGAを得た。
図22及び図23はIVISでの解析結果を示す。図22に示すように、ICG−PLGAの投与直後より、IVISにて全身にICGの分布が確認されたが、ICG−PLGAは投与直後から腫瘍へ集積した。投与7日後も腫瘍部にICGが集積していたが、その他の生体組織へのICGの集積は認めなかった。なお、ICG−PLGA投与7日後、腫瘍組織及び各臓器を採取し、IVISにて撮像したところ、図23に示すように、腫瘍組織のみにICGの強い集積が認められ、それ以外の各臓器への明らかな集積は認められなかった。
6週齢のヌードマウス(BALBc−nu/nu、雄)に1×107個のHuh−7を皮下移植した。腫瘍サイズをノギスで計測し、腫瘍の体積が100〜150mm3程度になった時点で、マウスを次の3群に群分けした。
対照群:200μLのPBSを週1回、頚静脈投与した。
2DG−PLGA(D50=49nm)群:D50が49nmの2DG−PLGAを週1回、頚静脈投与した(800mg/kg)。なお、当該2DG−PLGAにおける2DGの含有率は、8.5±0.5%であって、スパン値は0.95であった。
2DG−PLGA(D50=153nm)群:D50が153nmの2DG−PLGAを週1回、頚静脈投与した(800mg/kg)。なお、当該2DG−PLGAにおける2DGの含有率は、7.2±0.2%であって、スパン値は1.3であった。
2DG−PLGA(D50=313nm)群:D50が313nmの2DG−PLGAを週1回、頚静脈投与した(800mg/kg)。なお、当該2DG−PLGAにおける2DGの含有率は、6.6±0.2%であって、スパン値は1.6であった。
図24は、腫瘍体積の経時変化を示す。2DG−PLGA(D50=49nm)群及び2DG−PLGA(D50=153nm)群では、対照群及び2DG−PLGA(D50=313nm)群に対して腫瘍体積の有意な減少が認められた。投与開始21日後のマウス及び腫瘍の外観を図25に示す。対照群と比べ2DG−PLGA(D50=49nm)群及び2DG−PLGA(D50=153nm)群では、同等に移植された肝癌細胞の腫瘍体積を有意に減少させたが、2DG−PLGA(D50=313nm)群では、対照群に対して腫瘍体積を減少させたものの、2DG−PLGA(D50=50nm)群及び2DG−PLGA(D50=153nm)群には及ばなかった。
2DG−PLGAによる抗腫瘍効果における抗腫瘍免疫活性を評価するために、免疫不全ではない肝発癌マウスを用いて実験を行った。
(1)対照群:200μLのPBSを週1回、頚静脈投与した。
(2)2DG群:100mg/mLの2DG溶液を100mg/kg/日で腹腔内に連日投与した。
(3)2DG−PLGA低用量群:2DG−PLGAを週1回、頚静脈投与した。
(4)2DG−PLGA高用量群:(3)の10倍用量の2DG−PLGAを週1回、頚静脈投与した。
投与開始21日後の腫瘍の外観を図26に示す。2DG−PLGAは、高用量群のみならず低用量群においても、腫瘍個数を抑制した。図27に示すように、2DG−PLGAは、高用量群及び低用量群において最大腫瘍径を減少させ、特に高用量群では、最大腫瘍径が対照群に対して有意に減少した。また、図28に示すように、2DG−PLGAは、高用量群のみならず低用量群においても、総腫瘍体積を対照群に対して有意に減少させた。
Claims (6)
- 2−デオキシ−D−グルコースを含有する生体適合性粒子を含み、
前記生体適合性粒子は、
乳酸・グリコール酸共重合体を含む、
腫瘍治療用腫瘍免疫活性促進剤。 - 抗癌剤と併用される、
請求項1に記載の腫瘍治療用腫瘍免疫活性促進剤。 - 抗癌剤を含み、
請求項1に記載の腫瘍治療用腫瘍免疫活性促進剤と併用される、
腫瘍治療用医薬組成物。 - 前記抗癌剤は、
ソラフェニブ、ドキソルビシン又はシスプラチンである、
請求項2に記載の腫瘍治療用腫瘍免疫活性促進剤又は請求項3に記載の腫瘍治療用医薬組成物。 - 前記生体適合性粒子の平均粒径は、
50〜170nmである、
請求項1若しくは2に記載の腫瘍治療用腫瘍免疫活性促進剤、請求項3に記載の腫瘍治療用医薬組成物、又は請求項4に記載の腫瘍治療用腫瘍免疫活性促進剤若しくは腫瘍治療用医薬組成物。 - 肝細胞癌、腎臓癌、大腸癌又は膵臓癌の治療に使用される、
請求項1若しくは2に記載の腫瘍治療用腫瘍免疫活性促進剤、請求項3に記載の腫瘍治療用医薬組成物、又は請求項4若しくは5に記載の腫瘍治療用腫瘍免疫活性促進剤若しくは腫瘍治療用医薬組成物。
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