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Tumor-specific delivery of doxorubicin through conjugation of pH-responsive peptide for overcoming drug resistance in cancer. | LitMetric

AI Article Synopsis

  • The study addresses challenges with doxorubicin (Dox) chemotherapy, particularly drug resistance and toxicity to healthy cells, by developing a tumor-targeting peptide-Dox conjugate called SAPSP-Dox.
  • The SAPSP-Dox prodrug features a pH-sensitive peptide that enhances Dox's selective accumulation in cancer cells, showing significantly lower toxicity to non-cancerous cells.
  • In vivo tests indicated that SAPSP-Dox not only effectively targets both drug-sensitive and drug-resistant tumors but also has a longer half-life and reduced side effects, suggesting it could be a promising treatment for resistant cancers.

Article Abstract

The major obstacles opposed to doxorubicin (Dox) based chemotherapy are the induction of drug resistance, together with non-specific toxicities for healthy cells. In this study, we prepared a peptide-Dox conjugate aimed at offering Dox molecules a tumor-specific functionality and improving the therapeutic effects of Dox against resistant tumor cells. A slightly acidic pH-sensitive peptide (SAPSP) with high selectivity for cancer cells was attached to Dox to obtain SAPSP-Dox prodrug. The structures and properties of this prodrug were characterized, confirming several merits, including desirable pH-sensitive property, good serum stability and favorable release behavior. Cellular uptake studies demonstrated that SAPSP-Dox was preferably accumulated in cancer cells (Dox-sensitive MCF-7 and Dox-resistant MCF-7/ADR), followed by displaying 26-fold less toxic toward noncancerous MCF-10A cells than free Dox do. The conjugated peptides enabled Dox to escape the efflux effect of P-glycoprotein mediated pump via endocytotic pathway, giving rise to remarkable cytotoxicity and apoptotic effect on MCF-7/ADR cells. Moreover, the superior inhibition efficacy of SAPSP-Dox in vivo was more evident in the both drug-sensitive and drug-resistant xenograft tumor animal models, which enabled Dox to primarily accumulated in tumor. The conjugates also demonstrated a longer half-life in plasma and a lower side effect, for example, reduced cardiac toxicity. Evidence of this study suggests that SAPSP-Dox has the potential to be a potent prodrug for treating drug resistant cancers.

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Source
http://dx.doi.org/10.1016/j.ijpharm.2017.06.022DOI Listing

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