pH-sensitive micelles for the intracellular co-delivery of curcumin and Pluronic L61 unimers for synergistic reversal effect of multidrug resistance

Abstract

Pluronic L61 unimers, which are biomacromolecular modulators, and curcumin, a small-molecule modulator, were co-formulated into pH-sensitive micelles to reveal the full synergistic potential of combination drug treatments to reverse multidrug resistance (MDR). Compared to monotherapy, combined therapy significantly improved the cytotoxicity, cellular uptake and apoptotic effects of doxorubicin (DOX) against MCF-7/ADR cells. In mechanistic studies, both L61 and curcumin enhanced the cytotoxic effect by acting on mitochondrial signalling pathways. The compounds selectively accumulated in the mitochondria and disabled the mitochondria by dissipating the mitochondrial membrane potential, decreasing the ATP levels, and releasing cytochrome c, which initiated a cascade of caspase-9 and caspase-3 reactions. Furthermore, both curcumin and L61 down-regulated the expression and function of P-gp in response to drug efflux from the MCF-7/ADR cells. In the MCF-7/ADR tumour-bearing mouse model, intravenous administration of the combined therapy directly targeted the tumour, as revealed by the accumulation of DiR in the tumour site, which led to a significant inhibition of tumour growth without measurable side effects. In conclusion, co-formulation consisting of L61 and curcumin in pH-sensitive micelles induced significant synergistic effects on the reversal of MDR. Therefore, the intracellular co-delivery of various MDR modulators has great potential to reverse MDR in tumours.

Drug resistance reversal in ovarian cancer cells of paclitaxel and borneol combination therapy mediated by PEG-PAMAM nanoparticles

“…The MMP of A2780/PTX cells treated by various PTX formulations was determined using JC-1, which undergoes a reversible transformation from a monomer (green florescence) into an aggregate form (red florescence) when it binds to a membrane with a high MP [ 27 ]. Mitochondrial depolarization (non-functional mitochondria) was indicated by a decrease in the ratio of the red/green fluorescence intensity.…”

Nanoparticle encapsulation of HDACi with HA targeting in endometrial cancer models

“…Pluronic® F-127 (NP) polymer nanoparticles were fabricated using thin-lm hydration [46] and HA conjugated by the introduction of a disulphide pyridyl moiety (SAHA-NP-S-S) followed by HA-thiol treatment to obtain HA-coated F127 NPs (NP-HA) forming a disulphide linkage. SAHA payloads were incorporated into the micelles by co-dissolution prior to thin-lm formation.…”

“…Pluronic® F-127 is a water soluble, triblock copolymer consisting of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) repeats (PEO101-PPO56-PEO101) that possess a low toxicity in vivo, and is FDA approved [41]. F127 nanoparticles have been developed for the controlled release of therapeutic drugs, peptides and proteins [42][43][44] and with carboxylic groups to mediate the addition of tumour targeting moieties such a folate [45,46]. An alternative targeting moiety, HA is a naturally occurring glycosaminoglycan that consists of Nacetyl-d-glucosamine and d-glucuronic acid repeat units and is a ligand for the CD44 receptor.…”

Polymer-Based Nanocarriers for Co-Delivery and Combination of Diverse Therapies against Cancers

“…Although conventional chemotherapy (CHT) performed with small-molecule drugs plays a key role in the combat against cancer, it still shows some limitations, e.g., severe side effects, lack of selectivity (drugs enter healthy cells or tissues, leading to undesirable systematic toxicity and low therapeutic efficacy to tumors), poor water-solubility (hampering distribution in bloodstream and leading to low bioavailability) and multidrug resistance of tumor cells (decreasing therapeutic efficacy) [ 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…Recently, such combined therapies for synergistic effect (the effect of two or more modalities is more than the sum of their individual effects) on tumors have emerged [ 29 , 30 , 31 ]. According to some reports, the synergistic of CHT plus PTT may eradicate in vivo tumors, largely preventing recurrence or metastasis [ 19 , 32 ]. We found that the common factor of the above successful combinational therapy is nanocarriers.…”