In vivo evaluation of macromolecular antitumor agent, P-THP, in pancreatic cancer

• Project/Area Number: 26860031
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Physical pharmacy
• Research Institution: Sojo University
• Principal Investigator: NAKAMURA Hideaki 崇城大学, 薬学部, 助教 (30435151)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: すい臓がん / ピラルビシン / 高分子ポリマー / HPMA / 高分子化抗がん剤 / 高分子抗がん剤

Outline of Final Research Achievements

Many conjugates of water-soluble polymers with biologically active molecules were developed. However, therapeutic effects of these conjugates do not depend only on the structures and properties of the polymer carriers; they are strongly influenced by properties and mechanisms of action of the attached drugs. Pirarubicin (THP), a tetrahydropyranyl derivative of doxorubicin (DOX), demonstrated more rapid cellular internalization and potent cytotoxicity than DOX. Here, we conjugated the THP or DOX to HPMA polymer via a hydrazone bond. The polymer prodrugs P-THP and P-DOX, respectively, had comparable hydrodynamic sizes and drug loading. Compared with P-DOX, P-THP showed approximately 10 times greater cellular uptake and a cytotoxicity. No significant difference occurred in the tumor drug concentration during 6-24 h after drug administration. Antitumor activity against xenograft human pancreatic tumor (SUIT2) in mice was greater for P-THP than for P-DOX.

Research Products

• [Journal Article] pH-sensitive polymeric cisplatin-ion complex with styrene-maleic acid copolymer exhibits tumor-selective drug delivery and antitumor activity as a result of the enhanced permeability and retention effect. (2016)
  • Author(s): Saisyo A, Nakamura H, Fang J, Tsukigawa K, Greish K, Furukawa H, Maeda H.
  • Journal Title: Colloids Surf B Biointerfaces Volume: 138 Pages: 128-137
  • DOI: 10.1016/j.colsurfb.2015.11.032
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] HPMA Copolymer-Conjugated Pirarubicin in Multimodal Treatment of a Patient with Stage IV Prostate Cancer and Extensive Lung and Bone Metastases. (2016)
  • Author(s): Dozono H, Yanazume S, Nakamura H, Etrych T, Chytil P, Ulbrich K, Fang J, Arimura T, Douchi T, Kobayashi H, Ikoma M, Maeda H.
  • Journal Title: Target Oncol Volume: 11 Issue: 1 Pages: 101-106
  • DOI: 10.1007/s11523-015-0379-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Synthesis and therapeutic effect of styrene-maleic acid copolymer-conjugated pirarubicin. (2015)
  • Author(s): Tsukigawa K, Liao L, Nakamura H, Fang J, Greish K, Otagiri M, Maeda H.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 3 Pages: 270-278
  • DOI: 10.1111/cas.12592
  • Peer Reviewed
• [Journal Article] Effect of different chemical bonds in pegylation of zinc protoporphyrin that affects drug release, intracellular uptake, and therapeutic effect in the tumor. (2015)
  • Author(s): Tsukigawa K, Nakamura H, Fang J, Otagiri M, Maeda H
  • Journal Title: Eur J Pharm Biopharm. Volume: 89 Pages: 259-270
  • DOI: 10.1016/j.ejpb.2014.12.016
  • Peer Reviewed
• [Journal Article] Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice. (2015)
  • Author(s): Nakamura H, Koziolova E, Etrych T, Chytil P, Fang J, Ulbrich K, Maeda H.
  • Journal Title: European journal of pharmaceutics and biopharmaceutics Volume: 90 Pages: 90-96
  • DOI: 10.1016/j.ejpb.2014.10.007
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development of next-generation macromolecular drugs based on the EPR effect: challenges and pitfalls. (2015)
  • Author(s): Nakamura H, Jun F, Maeda H.
  • Journal Title: Expert opinion on drug delivery Volume: 12 Issue: 1 Pages: 53-64
  • DOI: 10.1517/17425247.2014.955011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Enhanced Bacterial Tumor Delivery by Modulating the EPR Effect and Therapeutic Potential of Lactobacillus casei. (2014)
  • Author(s): Fang J, Liao L, Yin H, Nakamura H, Shin T, Maeda H.
  • Journal Title: J Pharm Sci. Volume: 103 Issue: 10 Pages: 3235-43
  • DOI: 10.1002/jps.24083
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Styrene-maleic acid copolymer-encapsulated CORM2, a water-soluble carbon monoxide (CO) donor with a constant CO-releasing property, exhibits therapeutic potential for inflammatory bowel disease. (2014)
  • Author(s): Yin H, Fang J, Liao L, Nakamura H, Maeda H.
  • Journal Title: J Control Release. Volume: 187 Pages: 14-21
  • DOI: 10.1016/j.jconrel.2014.05.018
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 環境応答高分子型抗癌剤（P-THP）の作製と抗癌効果の基礎的検討 (2016)
  • Author(s): 中村 秀明
  • Organizer: 臨床腫瘍薬学会
  • Place of Presentation: 鹿児島市民ホール（鹿児島県、鹿児島市）
  • Year and Date: 2016-03-12
• [Presentation] 高分子結合型アントラサイクリン系抗がん剤の比較 (2015)
  • Author(s): 中村 秀明
  • Organizer: 日本DDS学会
  • Place of Presentation: 京王プラザホテル（東京都、新宿区）
  • Year and Date: 2015-07-02
• [Presentation] がん組織集積性と酸性環境応答性を併せ持つ高分子型抗がん剤の有用性評価 (2014)
  • Author(s): 中村 秀明, Tomas Etrych, 方 軍，Karel Ulbrich, 前田 浩
  • Organizer: 第8回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 熊本大学 （熊本県熊本市）
  • Year and Date: 2014-11-15 – 2014-11-16
  • Invited
• [Presentation] Improved pharmacokinetics and antitumor activity of poly(N-(2-hydroxypropyl)methacrylamide) conjugates of pirarubicin (2014)
  • Author(s): Nakamura H, Koziolova E, Etrych T, Chytil P, Fang J, Ulbrich K, Maeda H.
  • Organizer: 10th International symposium on polymer therapeutics
  • Place of Presentation: Valencia (Spain)
  • Year and Date: 2014-05-19 – 2014-05-21