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Patients with brain metastases of triple negative breast cancer (TNBC) have a poor prognosis owing to the lack of targeted therapies, the aggressive nature of TNBC, and the presence of the blood-brain barrier (BBB) that blocks penetration of most drugs. Additionally, infiltration of tumor-associated macrophages (TAMs) promotes tumor progression. Here, a terpolymer-lipid hybrid nanoparticle (TPLN) system is designed with multiple targeting moieties to first undergo synchronized BBB crossing and then actively target TNBC cells and TAMs in microlesions of brain metastases. In vitro and in vivo studies demonstrate that covalently bound polysorbate 80 in the terpolymer enables the low-density lipoprotein receptor-mediated BBB crossing and TAM-targetability of the TPLN. Conjugation of cyclic internalizing peptide (iRGD) enhances cellular uptake, cytotoxicity, and drug delivery to brain metastases of integrin-overexpressing TNBC cells. iRGD-TPLN with coloaded doxorubicin (DOX) and mitomycin C (MMC) (iRGD-DMTPLN) exhibits higher efficacy in reducing metastatic burden and TAMs than nontargeted DMTPLN or a free DOX/MMC combination. iRGD-DMTPLN treatment reduces metastatic burden by 6-fold and 19-fold and increases host median survival by 1.3-fold and 1.6-fold compared to DMTPLN or free DOX/MMC treatments, respectively. These findings suggest that iRGD-DMTPLN is a promising multitargeted drug delivery system for the treatment of integrin-overexpressing brain metastases of TNBC., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Therapeutic antibodies (e.g., trastuzumab, TRA) against human epidermal growth factor receptor 2 (HER2)-positive breast cancers have shown benefits in controlling primary tumors, yet are ineffective against brain metastases due to their inability to cross the blood-brain barrier (BBB). A novel hybrid nanoconstruct system is designed to deliver trastuzumab to brain metastasis of HER2-positive breast cancer via a two-step sequential targeting approach. Self-assembly of a polysorbate 80 (PS 80)-containing polymer, lipid, and polymer-conjugated TRA forms hybrid nanoconstructs (TRA-terpolymer nanoparticles (TPN)) with high encapsulation efficiency and bioactivity. The PS 80 moiety enables the first-step targeting and receptor-mediated trancytosis across BBB is demonstrated in vitro with a 3D human BBB model in healthy and brain tumor-bearing mice. The subsequent partial dissociation of the nanoconstructs exposes the encapsulated TRA for the second-step targeting to HER2-positive cancer cells in the brain. Intravenously injected TRA- TPN delivers 50-fold TRA compared to free TRA to the brain metastasis of HER2-positive breast cancer. Treatment with TRA-TPN increases tumor cell apoptosis by 4-fold, inhibits tumor growth by 43-fold, and prolongs median survival by >1.3-fold compared to free TRA, without causing noticeable organ toxicity. These findings suggest the two-step targeted nanoconstruct system is promising for shuttling therapeutic antibodies to treat central nervous system diseases. [ABSTRACT FROM AUTHOR]

We demonstrate a role of the vitamin D receptor (VDR) in reducing cerebral soluble and insoluble amyloid-β (Aβ) peptides. Short-term treatment of two human amyloid precursor protein-expressing models, Tg2576 and TgCRND8 mice, with 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], the endogenous active ligand of VDR, resulted in higher brain P-glycoprotein (P-gp) and lower soluble Aβ levels, effects negated with coadministration of elacridar, a P-gp inhibitor. Long-term treatment of TgCRND8 mice with 1,25(OH)2D3 during the period of plaque formation reduced soluble and insoluble plaque-associated Aβ, particularly in the hippocampus in which theVDRis abundant and P-gp induction is greatest after 1,25(OH)2D3 treatment, and this led to improved conditioned fear memory. In mice fed a vitamin D-deficient diet, lower cerebral P-gp expression was observed, but levels were restored on replenishment with VDR ligands. The composite data suggest that the VDR is an important therapeutic target in the prevention and treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

• A novel multifunctional and bioreactive nanoconstruct (NC) system is designed and synthesized by self-assembly in one-pot. • The NCs efficiently cross the blood-brain barrier and target amyloid-β and oxidative stress-affected AD brain regions. • The NCs enhance MRI contrast enabling non-invasive early detection of CSF pathology with high sensitivity and accuracy. • The NCs facilitate oxygenation, reduce oxidative stress and pro-inflammatory cytokines, and increase neuron survival. Lack of sensitive detection of early onset and progression of Alzheimer's disease (AD) by non-invasive methods limits the development and implementation of therapeutic interventions. Given that cerebral oxidative stress and inflammation occur before diagnosable clinical symptoms, a multifunctional theranostic nanoconstruct (NC) system has been developed. It gains entry to the brain by a targeting moiety, binds selectively with soluble amyloid-β (Aβ) and Aβ plagues via a conjugated anti-Aβ antibody. The NC is activated by endogenous reactive oxygen species (ROS), enhancing magnetic resonance (MR) contrast signals in disease-affected areas. It exhibits superior performance in detecting cerebrospinal fluid (CSF) pathology in an AD mouse model by MR imaging. Intravenously injected NCs significantly amplify T1-weighted MR signals in the CSF by 1.51–2.24 fold, nearly proportional to cerebral concentrations of ROS and pro-inflammatory cytokine interleukin-1β (IL-1β). The NC-enhanced CSF MR signals demonstrate high detection sensitivity (88.9 %) and specificity (100 %) even at early-stage AD. Moreover, the NCs protected primary cortical neurons from oxidative stress in vitro and reduce cerebral ROS and IL-1β levels in AD mice by 36 %–83 %. This multifunctional NC-based technology may allow for early detection and treatment of AD prior to cognitive decline when therapies may prove more beneficial. [ABSTRACT FROM AUTHOR]

Brain metastasis is a fatal disease with limited treatment options and very short survival. Although systemic chemotherapy has some effect on peripheral metastases of breast cancer, it is ineffective in treating brain metastasis due largely to the blood-brain barrier (BBB). Here we developed a BBB-penetrating amphiphilic polymer-lipid nanoparticle (NP) system that efficiently delivered anti-mitotic drug docetaxel (DTX) for the treatment of brain metastasis of triple negative breast cancer (TNBC). We evaluated the biodistribution, brain accumulation, pharmacokinetics and efficacy of DTX-NP in a mouse model of brain metastasis of TNBC. Confocal fluorescence microscopy revealed extravasation of dye-loaded NPs from intact brain microvessels in healthy mice. DTX-NP also extravasated from brain microvessels and accumulated in micrometastasis lesions in the brain. Intravenously injected DTX-NPs increased the blood circulation time of DTX by 5.5-fold and the AUC 0–24 h in tumor-bearing brain by 5-fold compared to the clinically used DTX formulation Taxotere® . The kinetics of NPs in the brain, determined by ex vivo fluorescence imaging, showed synchronization with DTX kinetics in the brain measured by LC-MS/MS. This result confirmed successful delivery of DTX by the NPs into the brain and suggested that ex vivo fluorescence imaging of NP could be an effective and quick means for probing drug disposition in the brain. Treatment with the DTX-NP formulation delayed tumor growth by 11-fold and prolonged median survival of tumor-bearing mice by 94% compared to an equivalent dose of Taxotere®, without inducing histological changes in the major organs. [ABSTRACT FROM AUTHOR]