Hyaluronic acid modified pH-sensitive liposomes for targeted intracellular delivery of doxorubicin

脂质体 阿霉素 细胞毒性 透明质酸 化学 药物输送 药理学 靶向给药 细胞内 IC50型 CD44细胞 体外 盐酸阿霉素 生物化学 生物物理学 生物 化疗 有机化学 遗传学
作者
Shivani Rai Paliwal,Rishi Paliwal,Govind P. Agrawal,Suresh P. Vyas
出处
期刊:Journal of Liposome Research [Informa]
卷期号:26 (4): 276-287 被引量:68
标识
DOI:10.3109/08982104.2015.1117489
摘要

AbstractContext: Surface-modified pH-sensitive liposomal system may be useful for intracellular delivery of chemotherapeutics.Objective: Achieving site-specific targeting with over-expressed hyaluronic acid (HA) receptors along with using pH sensitive liposome carrier for intracellular drug delivery was the aim of this study.Materials and methods: Stealth HA-targeted pH-sensitive liposomes (SL-pH-HA) were developed and evaluated to achieve effective intracellular delivery of doxorubicin (DOX) vis–a-vis enhanced antitumor activity.Results: The in vitro release studies demonstrated that the release of DOX from SL-pH-HA was pH-dependent, i.e. faster at mildly acidic pH ∼5, compared to physiological pH ∼7.4. SLpH-HA was evaluated for their cytotoxicity potential on CD44 receptor expressing MCF-7 cells. The half maximal inhibitory concentration (IC50) of SL-pH-HA and SL-HA were about 1.9 and 2.5 μM, respectively, after 48 h of incubation. The quantitative uptake study revealed higher localization of targeted liposomes in the receptor positive cells, which was further confirmed by fluorescent microscopy. The antitumor efficacy of the DOX-loaded HA-targeted pH-sensitive liposomes was also verified in a tumor xenograft mouse model.Discussion: DOX was efficiently delivered to the tumor site by active targeting via HA and CD44 receptor interaction. The major side-effect of conventional DOX formulation, i.e. cardiotoxicity was also estimated by measuring serum enzyme levels of LDH and CPK and found to be minimized with developed formulation. Overall, HA targeted pH-sensitive liposomes were significantly more potent than the non-targeted liposomes in cells expressing high levels of CD44.Conclusion: Results strongly implies the promise of such liposomal system as an intracellular drug delivery carrier developed for potential anticancer treatment.Keywords: Breast cancerCD44 receptorsdoxorubicinhyaluronic acidtargeting AcknowledgementsThe authors are thankful to Sun Pharma, Vadodara, India, for gift sample of doxorubicin. Authors are also thankful to SAIF-AIIMS (New Delhi, India), for performing transmission electron microscopy (TEM) studies and SAIF-CDRI (Lucknow, India) for providing the IR and NMR facility.Declaration of interestThe author SRP expresses her sincere thanks to UGC New Delhi, India, for providing financial assistance.
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