Polymer-lipid hybrid nanoparticles synchronize pharmacokinetics of co-encapsulated doxorubicin-mitomycin C and enable their spatiotemporal co-delivery and local bioavailability in breast tumor

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• 作者：Rui Xue Zhang ; MSc^a ; ^{vicki.zhang@mail.utoronto.ca" class="auth_mail" title="E-mail the corresponding author} ; Ping Cai ; MD^a ; ^{ping.cai@utoronto.ca" class="auth_mail" title="E-mail the corresponding author} ; Tian Zhang ; BSc^a ; ^{tianqq.zhang@mail.utoronto.ca" class="auth_mail" title="E-mail the corresponding author} ; King Chen ; BSc in Pharmacy^a ; Jason Li ; MASc^a ; ^{jason.li@utoronto.ca" class="auth_mail" title="E-mail the corresponding author} ; Ji Cheng ; PhD^a ; K. Sandy Pang ; Prof. PhD^a ; ^{ks.pang@utoronto.ca" class="auth_mail" title="E-mail the corresponding author} ; Hibret A. Adissu ; DVM ; PhD ; DACVP^b ; ^{adissu@lunenfel.ca" class="auth_mail" title="E-mail the corresponding author} ; Andrew M. Rauth ; Prof. PhD^c ; ^{rauth@uhnres.utoronto.ca" class="auth_mail" title="E-mail the corresponding author} ; Xiao Yu Wu ; Prof. PhD^a ; ^{xywu@phm.utoronto.ca" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AKR ; aldo-keto reductase ; AUC ; area under the curve ; CL ; total body clearance ; cTnI ; cardiac troponin I ; DMPLN ; doxorubicin and mitomycin C co-loaded polymer&ndash ; lipid hybrid nanoparticles ; DOX ; doxorubicin ; DOXOL ; doxorubicinol ; EPR ; enhanced permeability and retention ; HPESO ; hydrolyzed polymer of epoxidized soybean oil ; HPLC ; high-pressure liquid chromatography ; ICG ; indocyanine green ; ICG-DMPLN ; indocyanine green coloaded doxorubicin and mitomycin C polymer&ndash ; lipid hybrid nanoparticles
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：12
• 期：5
• 页码：1279-1290
• 全文大小：1914 K

文摘

Effective combination chemotherapy requires the delivery of drugs of synergism to tumor sites while sparing normal tissues. Herein we investigated whether coencapsulation of doxorubicin and mitomycin C within polymer–lipid hybrid nanoparticles (DMPLN) achieved this goal via ratiometric drugs in an orthotopic murine breast tumor model with nanocarrier-modified biodistribution, pharmacokinetics, local bioavailability and toxicity. Fluorescence imaging revealed quickened and extended tumor uptake but reduced cardiac accumulation of DMPLN. Quantitative drug analysis demonstrated prolonged systemic circulation, increased tumor accumulation and sustained synergistic ratios of doxorubicin and mitomycin C delivered by DMPLN over 24 h. Higher levels of tumor cell apoptosis and reduced organ toxicity were obtained with DMPLN compared to free drug cocktails. DMPLN released DOX in tumors more efficiently than that from liposomal doxorubicin, as evidenced by a higher extent of the metabolite, doxorubicinol. These findings substantiate the importance of rational design of nanoparticles for synergistic drug combination therapy.

From the Clinical Editor

The treatment of cancer usually involves using combination chemotherapeutic agents. In adopting a nanomedicine approach, one can in theory design combination therapy consisting of drugs of synergistic activities, with the aim to target tumor specifically while minimizing systemic toxicity. The authors in this study provided evidence for this rational design by co-encapsulation of doxorubicin and mitomycin C within polymer-lipid hybrid nanoparticles (DMPLN) in a breast cancer model.