Localized delivery of curcumin into brain with polysorbate 80-modified cerasomes by ultrasound-targeted microbubble destruction for improved Parkinson's disease therapy.

Rationale: Treatment for Parkinson's disease (PD) is challenged by the presence of the blood-brain barrier (BBB) that significantly limits the effective drug concentration in a patient's brain for therapeutic response throughout various stages of PD. Curcumin holds the potential for α-synuclein clearance to treat PD; however, its applications are still limited due to its low bioavailability and poor permeability through the BBB in a free form. Methods: Herein, this paper fabricated curcumin-loaded polysorbate 80-modified cerasome (CPC) nanoparticles (NPs) with a mean diameter of ~110 nm for enhancing the localized curcumin delivery into the targeted brain nuclei via effective BBB opening in combination with ultrasound-targeted microbubble destruction (UTMD). Results: The liposomal nanohybrid cerasome exhibited superior stability towards PS 80 surfactant solubilization and longer circulation lifetime (t1/2 = 6.22 h), much longer than free curcumin (t1/2 = 0.76 h). The permeation was found to be 1.7-fold higher than that of CPC treatment only at 6 h after the systemic administration of CPC NPs. Notably, motor behaviors, dopamine (DA) level and tyrosine hydroxylase (TH) expression all returned to normal, thanks to α-synuclein (AS) removal mediated by efficient curcumin delivery to the striatum. Most importantly, the animal experiment demonstrated that the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice had notably improved behavior disorder and dopamine depletion during two-week post-observation after treatment with CPC NPs (15 mg curcumin/kg) coupled with UTMD. Conclusion: This novel CPC-UTMD formulation approach could be an effective, safe and amenable choice with higher therapeutic relevance and fewer unwanted complications than conventional chemotherapeutics delivery systems for PD treatment in the near future.

Cerasomal Lovastatin Nanohybrids for Efficient Inhibition of Triple-Negative Breast Cancer Stem Cells To Improve Therapeutic Efficacy.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a higher risk in younger women and a poorer prognosis and without targeted therapies available currently. Cancer stem cells (CSCs) are increasingly recognized as the main cause of treatment failure and tumor recurrence. The present paper reports the encapsulation of lovastatin (LV) into cerasomes. Compared with free LV, cerasome-encapsulated LV (C-LV) nanohybrids showed cytotoxicity to MDA-MB-231 CSCs in a dose- and time-dependent manner. Furthermore, intravenous injection of C-LV nanohybrids resulted in a significant tumor size reduction in a dose-dependent manner in xenograft tumors derived from subcutaneous inoculation of MDA-MB-231 cells. Furthermore, histopathological and/or immunohistochemical analysis revealed that C-LV nanohybrids significantly induced mammary gland formation and apoptosis and inhibited angiogenesis, the CSC phenotype, and the epithelial-to-mesenchymal transition in xenograft tumors. Most importantly, C-LV nanohybrids were found to be more effective than free LV in inhibiting the growth of breast cancer xenografts and the stemness properties in vivo. To the best of our knowledge, ours is the first demonstration of nanohybrids for efficient inhibition of CSCs derived from TNBC, offering a new option for the TNBC treatment.

Monitoring the intracellular transformation process of surface-cleavable PLGA particles containing disulfide bonds by fluorescence resonance energy transfer.

A great number of stimuli-responsive particles have been developed and used for biomedical applications such as intracellular drug delivery. It is of paramount importance to study the intracellular responsive process of these particles, offering insight into the understanding of their structure variation and design criteria for better performance. In this study polyethyleneimine (PEI)-coated poly(lactide-co-glycolide) (PLGA) particles with a diameter of 430 nm were prepared via a one-step emulsion method. The amino groups in the PEI molecules allowed further covalent linking of fluorescein isothiocyanate (FITC), bifunctional coupling agents 3,3'-dithiobispropionimidate, amino-ended polyethylene glycol (NH2-PEG-NH2) and tetramethylrhodamine isothiocyanate (TRITC), resulting in fluorescence resonance energy transfer (FRET) pairs on the particles. The particles exhibited glutathione-responsive ability, and lost the FRET effect due to the separation of FITC/TRITC pairs from the particle surface as a result of the cleavage of disulfide bonds. The particles showed different FRET change rates in A549 cells and HEK293 cells depending on the intracellular GSH concentration. Moreover, a much slower degradation rate was found inside cells than in simulated buffer with a similar GSH concentration. The results suggest that the responsive behaviors of the particles obtained in simulated buffer may not match fully/correctly with the real situation in a complicated intracellular environment.

Influence of surface coatings of poly(d,l-lactide-co-glycolide) particles on HepG2 cell behavior and particle fate.

This study is focused on the intracellular fate of poly(d,l-lactide-co-glycolide) (PLGA) particles with different surface coatings after cellular uptake, and their influence on the functions of human liver cancer cells (HepG2 cells). The PLGA particles coated with polyethyleneimine (PEI) and bovine serum albumin (BSA) with a similar diameter of ∼400 nm but different surface chemistry were prepared. The intracellular distribution of the PLGA particles was also largely dependent on their surface coatings. The PLGA-PEI particles were removed from cells by exocytosis with a slower rate compared to the PLGA-BSA particles. In general, uptake of both types of the PLGA particles did not cause apparent impedance on cell viability and cell cycle, but uptake of the PLGA-PEI particles did have certain influence on cell functions such as intracellular level of reactive oxygen species, cytoskeleton organization, cell migration, and secretion levels of triglyceride.