The structure-dependent toxicity, pharmacokinetics and anti-tumour activity of HPMA copolymer conjugates in the treatment of solid tumours and leukaemia

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• 作者：Barbora Tomalova^a ; ^{barbora.tomalova@biomed.cas.cz" class="auth_mail" title="E-mail the corresponding author} ; Milada Sirova^a ; ^{sirova@biomed.cas.cz" class="auth_mail" title="E-mail the corresponding author} ; Pavel Rossmann^a ; ^{rossmannp@seznam.cz" class="auth_mail" title="E-mail the corresponding author} ; Robert Pola^b ; ^{pola@imc.cas.cz" class="auth_mail" title="E-mail the corresponding author} ; Jiri Strohalm^b ; ^{strohalm@imc.cas.cz" class="auth_mail" title="E-mail the corresponding author} ; Petr Chytil^b ; ^{chytil@imc.cas.cz" class="auth_mail" title="E-mail the corresponding author} ; Viktor Cerny^a ; ^{viktor.cerny@biomed.cas.cz" class="auth_mail" title="E-mail the corresponding author} ; Jakub Tomala^a ; ^{tomala@biomed.cas.cz" class="auth_mail" title="E-mail the corresponding author} ; Martina Kabesova^a ; ^{kabesova@biomed.cas.cz" class="auth_mail" title="E-mail the corresponding author} ; Blanka Rihova^a ; ^{rihova@biomed.cas.cz" class="auth_mail" title="E-mail the corresponding author} ; Karel Ulbrich^b ; ^{ulbrich@imc.cas.cz" class="auth_mail" title="E-mail the corresponding author} ; Tomas Etrych^b ; ^{etrych@imc.cas.cz" class="auth_mail" title="E-mail the corresponding author} ; Marek Kovar^a ; ^{makovar@biomed.cas.cz" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HPMA ; Doxorubicin ; Structure ; Toxicity ; Anti-tumour activity
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：10 February 2016
• 年：2016
• 卷：223
• 期：Complete
• 页码：1-10
• 全文大小：1064 K

文摘

Polymer drug carriers that are based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been widely used in the development and synthesis of high-molecular-weight (HMW) drug delivery systems for cancer therapy. In this study, we compared linear (M_w ~ 27 kDa, R_h ~ 4 nm) and non-degradable star (M_w ~ 250 kDa, R_h ~ 13 nm) HPMA copolymer conjugates bearing anthracycline antibiotic doxorubicin (DOX) bound via pH-sensitive hydrazone bond. We determined the in vitro and in vivo toxicity of both conjugates and their maximum tolerated dose (MTD). We also compared their anti-tumour activity in mouse B-cell leukaemia (BCL1) and a mouse T-cell lymphoma (EL4) model. We found that MTD was higher for the linear conjugate (85 mg DOX/kg) and lower for the star conjugate (22.5 mg DOX/kg). An evaluation of the intestinal barrier integrity using FITC-dextran as a gut permeability tracer proved that no pathology was caused by the MTD of either conjugate. However, free DOX showed some damage to the gut barrier. The therapy of BCL1 leukaemia by both of the polymeric conjugates using the MTD or its fraction (i.e., equitoxic dosage) showed better results in the case of the star conjugate. On the other hand, treatment of EL4 lymphoma seemed to be more efficient when the linear conjugate was used. We suppose that the anti-cancer treatment of solid tumours and leukaemias requires different types of drug conjugates. We hypothesise that the most suitable HPMA copolymer-DOX conjugate for the treatment of solid tumours should have an HMW structure with increased R_h that would be stable for three to four days after the conjugate administration and then rapidly disintegrate in the short polymer chains, which are excretable from the body by glomerular filtration. On the other hand, the treatment of leukaemia requires a drug conjugate with a long circulation half-life. This would provide an active drug, whilst slowly degrading to excretable fragments.