BackgroundMultidrug resistance is responsible for the poor outcome in breast cancer therapy. Lapa is a novel therapeutic agent that generates ROS through the catalysis of the NAD(P) H:quinone oxidoreductase-1 (NQO1) enzyme which significantly facilitate the intracellular accumulation of the co-delivered DOX to overcome MDR in cancer cells.PurposeHerein, in our study, nanostructured lipid carrier (NLC) co-delivering β-lapachone (Lapa) and doxorubicin (DOX) was developed (LDNLC) with the aim to overcome the multidrug resistance (MDR) in breast cancer therapy.Patients and methodsLapa and DOX were loaded into NLC to prepare LDNLC using melted ultrasonic dispersion method.ResultsThe well designed LDNLC was nanoscaled particles that exhibited preferable stability in physiological environment. In vitro cell experiments on MCF-7 ADR cells showed increased DOX retention as compared to DOX mono-delivery NLC (DNLC). In vivo anti-cancer assays on MCF-7 ADR tumor bearing mice model also revealed significantly enhanced efficacy of LDNLC than mono-delivery NLCs (DNLC and LNLC).ConclusionLDNLC might be a promising platform for effective breast cancer therapy.

Purpose: Opioid tolerance remains a challenging problem, which limits prolonged drug usage in clinics. Previous studies have shown a fundamental role of platelet-derived growth factor receptor β submit (PDGFRβ) in morphine tolerance. The aim of this study was to investigate the mechanisms of spinal PDGFRβ activation in morphine tolerance. Methods: Rats were treated with morphine for 7 days and the effect of drug was evaluated by tail-flick latency test. By using Western blot and real-time PCR, the interaction between μ opioid receptor (MOR) and PDGFRβ in microglia activation, as well as related signaling pathways during morphine tolerance were investigated. Results: Chronic PDGFRβ agonist could induce microglia activation in spinal cord and decrease the analgesic effect of morphine. PDGFRβ inhibitor suppressed microglia activation during the development of morphine tolerance. Furthermore, antagonizing MOR could effectively inhibit the phosphorylations of PDGFRβ and JNK. Blocking PDGFRβ had no influence on JNK signaling, while JNK inhibitor could decrease the phosphorylation of PDGFRβ. Conclusion: These results provide direct evidence that repeatedly activating MOR by morphine could induce the transactivation of PDGFRβ via JNK MAPK in spinal cord, which leads to microglia activation during the development of morphine tolerance.

Morphine is the most potent analgesic in clinical treatment for various painful conditions. Long-term usage of morphine inevitably leads to the development of antinociceptive tolerance, which limits its clinical utilization (Christie, 2008;Wickham, 2017). For several decades, numerous studies have been devoted to illuminating the mechanisms underlying morphine tolerance, including nitric oxide-cyclic 3'-5' guanosine monophosphate signaling pathway, α 2 noradrenergic system cannabinoid system, and hyperexcitability of the central nervous system (Fisher et al., 2019;Gursoy et al., 2011;Ozdemir, 2020;Ozdemir et al., 2011). However, the neurobiological mechanisms of morphine tolerance are multifaceted and only partially understood.Macroautophagy, hereafter autophagy, is a lysosomal-dependent degradation pathway in eukaryotic cells, which is important for the generation of degradation products and intracellular clearance of defective macromolecules and organelles (Mizushima, 2018). Over the