Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment

We have developed multifunctional nanoparticles (NP) for co-delivery of bortezomib (BTZ) and doxorubicin (DOX) to synchronize their pharmacokinetic profiles and synergize their activities in solid tumor treatment, a need still unmet in the clinic. Micellar NP was formed by a spatially segregated, linear-dendritic telodendrimer containing three segments: a hydrophilic polyethylene glycol (PEG), a BTZ-conjugating intermediate, and a dendritic DOX-affinitive interior. BTZ-conjugated telodendrimers, together with DOX, self-assembled into monodispersed micelles (NP(BTZ-DOX)) with small particle sizes (20~30 nm) for dual drug delivery. NP(BTZ-DOX) displayed excellent drug loading capacity and stability, which minimized premature drug leakage and synchronized drug release profiles. BTZ release was accelerated significantly by acidic pH, facilitating drug availability in the acidic tumor microenvironment. Synergistic anticancer effects of combined BTZ and DOX were observed in vitro against both multiple myeloma and ovarian cancer cells. NP(BTZ-DOX) prolonged payload circulation and targeted tumors in vivo efficiently with superior signal ratios of tumor to normal organs. In vitro and in vivo proteasome inhibition analysis and biodistribution studies revealed decreased toxicity and efficient intratumoral BTZ and DOX delivery by nanoformulation. NP(BTZ-DOX) exhibited significantly improved ovarian cancer treatment in SKOV-3 xenograft mouse models in comparison with free drugs and their combinations, including BTZ and Doxil. In summary, tumor-targeted and synchronized delivery system elicits enhanced anticancer effects and merits further development in the clinical setting.

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