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Tumor metastasis is a significant contributor to the mortality of cancer patients. Specifically, current conventional treatments are unable to achieve complete remission of brain metastasis. This is due to the unique pathological environment of brain metastasis, which differs significantly from peripheral metastasis. Brain metastasis is characterized by high tumor mutation rates and a complex microenvironment with immunosuppression. Additionally, the presence of blood-brain barrier (BBB)/blood tumor barrier (BTB) restricts drug leakage into the brain. Therefore, it is crucial to take account of the specific characteristics of brain metastasis when developing new therapeutic strategies. Nanomaterials offer promising opportunities for targeted therapies in treating brain metastasis. They can be tailored and customized based on specific pathological features and incorporate various treatment approaches, which makes them advantageous in advancing therapeutic strategies for brain metastasis. This review provides an overview of current clinical treatment options for patients with brain metastasis. It also explores the roles and changes that different cells within the complex microenvironment play during tumor spread. Furthermore, it highlights the use of nanomaterials in current brain treatment approaches. [Display omitted] • The unique pathological environment of brain metastases limits clinical outcomes. • Different cell types play different roles and change during the progression of BM. • NMs can be customized to specific pathological features and thus offer significant advantages in BM treatment. [ABSTRACT FROM AUTHOR]

Immunotherapy is regarded as one of the most promising approaches for treating tumors, with a multitude of immunotherapeutic thoughts currently under consideration for the lethal glioblastoma (GBM). However, issues with immunotherapeutic agents, such as limited in vivo stability, poor blood-brain barrier (BBB) penetration, insufficient GBM targeting, and represented monotherapy, have hindered the success of immunotherapeutic interventions. Moreover, even with the aid of conventional drug delivery systems, outcomes remain suboptimal. Biomimetic strategies seek to overcome these formidable drug delivery challenges by emulating nature's intelligent structures and functions. Leveraging the variety of biological structures and functions, biomimetic drug delivery systems afford a versatile platform with enhanced biocompatibility for the co-delivery of diverse immunotherapeutic agents. Moreover, their inherent capacity to traverse the BBB and home in on GBM holds promise for augmenting the efficacy of GBM immunotherapy. Thus, this review begins by revisiting the various thoughts and agents on immunotherapy for GBM. Then, the barriers to successful GBM immunotherapy are analyzed, and the corresponding biomimetic strategies are explored from the perspective of function and structure. Finally, the clinical translation's current state and prospects of biomimetic strategy are addressed. This review aspires to provide fresh perspectives on the advancement of immunotherapy for GBM. [Display omitted] • Immunotherapeutic thoughts and agents for glioblastoma are revisited comprehensively. • Obstacles encountered during the process of achieving immunotherapy for GBM are analyzed. • Biomimetic strategies to overcome all barriers are summarized from the perspective of function and structure. • The future direction of biomimetic strategies in the immunotherapy of glioblastoma are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Combination of gene therapy and chemotherapy is a promising approach for glioma therapy. In this study, a co-delivery system of plasmid encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF-hTRAIL, Trail) and doxorubicin (DOX) has been simply constructed in two steps. Firstly, DOX was intercalated into Trail to form a stable complex. Secondly, DOX-Trail complex was condensed by Dendrigraft poly-l-lysine (DGL) to form a nanoscaled co-delivery system. Choline transporters are both expressed on blood–brain barrier (BBB) and glioma, Herein, a choline derivate with high choline transporter affinity was chosen as BBB and glioma dual targeting ligand. Choline-derivate modified co-delivery system showed higher cellular uptake efficiency and cytotoxicity than unmodified co-delivery system in U87 MG cells. In comparison with single medication or unmodified delivery system, Choline-derivate modified co-delivery system induced more apoptosis both in vitro and in vivo. The therapeutic efficacy on U87 MG bearing xenografts further confirmed the predominance of this dual targeting and co-delivery system. [Copyright &y& Elsevier]

Purpose: To prepare an angiopep-conjugated dendrigraft poly-L-lysine (DGL)-based gene delivery system and evaluate the neuroprotective effects in the rotenone-induced chronic model of Parkinson's disease (PD). Methods: Angiopep was applied as a ligand specifically binding to low-density lipoprotein receptor-related protein (LRP) which is overexpressed on blood-brain barrier (BBB), and conjugated to biodegradable DGL via hydrophilic polyethyleneglycol (PEG), yielding DGL-PEG-angiopep (DPA). In vitro characterization was carried out. The neuroprotective effects were evaluated in a chronic parkinsonian model induced by rotenone using a regimen of multiple dosing intravenous administrations. Results: The successful synthesis of DPA was demonstrated via H-NMR. After encapsulating the therapeutic gene encoding human glial cell line-derived neurotrophic factor ( hGDNF), DPA/ hGDNF NPs showed a sphere-like shape with the size of 119 ± 12 nm and zeta potential of 8.2 ± 0.7 mV. Angiopep-conjugated NPs exhibited higher cellular uptake and gene expression in brain cells compared to unmodified counterpart. The pharmacodynamic results showed that rats in the group with five injections of DPA/ hGDNF NPs obtained best improved locomotor activity and apparent recovery of dopaminergic neurons compared to those in other groups. Conclusion: This work provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Abstract: The activation of caspase-3 mediated neuron death is a common process in neurodegenerative diseases. Efficient activated caspase-3 imaging in brain would be helpful to monitor the potential lesion and intervene promptly. However, the blood–brain barrier (BBB) is the major obstacle that hinders the delivery of diagnostic agents into the brain. Herein, the fluorescence resonance energy transfer (FRET) was successfully applied to detect in vivo activated caspase-3 in apoptotic neuron with a brain-targeted nano-device, which was based on dendrigraft poly-l-lysines (DGLs) and linked with a brain-targeted peptide RVG29 as well as the caspase-3 cleavable peptide linker (DEVD). This nano-device could detect the level of caspase-3 activation in accordance with the degree of apoptosis in rat brain; meanwhile normal rat showed no fluorescence signal. The location of fluorescence signal was confirmed to accumulate more in caspase-3 activated neurons. Taken together, our nano-device would help to image activated caspase-3 in vivo and hold great promise in early diagnosis of neurodegenerative diseases. [Copyright &y& Elsevier]

Abstract: One of the most common life-threatening infections in immunosuppressive patients, like AIDs patients, is cryptococcal meningitis or meningoencephalitis. Current therapeutic options are mostly ineffective and mortality rates remain high. Hydrophobic antifungal drug Amphotericin B (AmB), has become a golden standard in severe systemic fungal infection therapy. However, most AmB commercial formulations, including deoxycholate AmB and lipid formulations of AmB, show poor penetration into the CNS and difficulty to reach the therapeutic levels. To improve the CNS permeability of AmB, we have successfully developed an effective brain-targeting polymeric micellar system with angiopep-2 modified, named Angiopep-PEG-PE/AmB polymeric micelles. An immunosuppressive murine model with Cryptococcus neoformans meningoencephalitis (CNME) was established to evaluate the CNS penetration efficiency and antifungal treatment efficacy of the AmB-incorporated brain-vectored polymeric micellar formulation, compared with the AmB commercial formulations. After three consecutive days of i.v. administration, the results showed that the group treated with Angiopep-PEG-PE/AmB achieved the greatest treatment efficacy, which reached the highest AmB level in brain, reduced the brain fungal burden significantly, decreased histopathological severity and prolonged the median survival time. The increased treatment efficacy could be attributed to the brain-targeting delivery system promoted AmB crossing the BBB and penetrating into the brain to reach the therapeutic concentration. The underlying mechanism was also explored in this work. Therefore, the brain-targeting delivery system could have potential and promising implications for treatment of intracerebral fungal infection. [Copyright &y& Elsevier]

Abstract: Clinical diagnosis of cancers using magnetic resonance imaging (MRI) is highly dependent on contrast agents, especially for brain tumors which contain blood–brain barrier (BBB) at the early stage. However, currently mostly used low molecular weight contrast agents such as Gd-DTPA suffer from rapid renal clearance, non-specificity, and low contrast efficiency. The aim of this paper is to investigate the potential of a macromolecular MRI contrast agent based on dendrigraft poly-l-lysines (DGLs), using chlorotoxin (CTX) as a tumor-specific ligand. The contrast agent using CTX-modified conjugate as the main scaffold and Gd-DTPA as the payload was successfully synthesized. The results of fluorescent microscopy showed that the modification of CTX could markedly enhance the cellular uptake in C6 glioma and liver tumor cell lines, but not in normal cell line. Significantly increased accumulation of CTX-modified conjugate within glioma and liver tumor was further demonstrated in tumor-bearing nude mice using in vivo imaging system. The MRI results showed that the signal enhancement of mice treated with CTX-modified contrast reached peak level at 5 min for both glioma and liver tumor, 144.97% ± 19.54% and 158.69% ± 12.41%, respectively, significantly higher than that of unmodified counterpart and commercial control. And most importantly, the signal enhancement of CTX-modified contrast agent maintained much longer compared to that of controls, which might be useful for more exact diagnosis for tumors. CTX-modified dendrimer-based conjugate might be applied as an efficient MRI contrast agent for targeted and accurate tumor diagnosis. This finding is especially important for tumors such as brain glioma which is known hard to be diagnosed due to the presence of BBB. [Copyright &y& Elsevier]

Abstract: The blood–brain barrier is the major obstacle that prevents diagnostic and therapeutic drugs being delivered to the central nervous systems in order to exert their effects. Specific ligand-receptor binding mediated endocytosis is one of the possible strategies to cross this barrier. A 30-amino-acid peptide (leptin30) derived from an endogenic hormone—leptin is exploited as brain-targeting ligand as it is reported to possess the same brain accumulation efficiency after intravenous injection. Dendrigraft poly-l-lysine (DGL) is used as non-viral gene vector in this study. DGL–PEG–Leptin30 was complexed with plasmid DNA yielding nanoparticles (NPs). The cellular uptake characteristic and mechanism were explored in brain capillary endothelial cells (BCECs) which express leptin receptors. Furthermore, brain parenchyma microglia cells such as BV-2 cells expressing leptin receptors could promote ligand-receptor mediated endocytosis leading to enhanced gene transfection ability of DGL–PEG–Leptin30/DNA NPs. The targeted NPs were proved to be transported across in vitro BBB model effectively and accumulate more in brains after i.v. resulting in a relatively high gene transfection efficiency both in vitro and in vivo. Besides, the NPs showed low cytotoxicity after in vitro transfection. Thus, DGL–PEG–Leptin30 provides a safe and noninvasive approach for the delivery of gene across the blood–brain barrier. [Copyright &y& Elsevier]

Abstract: Lactoferrin (Lf)-modified nanoparticles (NPs) have been demonstrated to mediate efficient expression of exogenous genes in the brain via intravenous administration. The brain-targeting properties of Lf-modified NPs were investigated in this study. In vivo imaging results showed that the accumulation of Lf-modified NPs was higher in the brain but lower in the other organs than that of unmodified counterparts. The results of analytical transmission electron microscopy showed that some Lf-modified NPs crossed the blood–brain barrier (BBB) and reached the neural tissues, while some remained within the BBB. Similar results were observed in the distribution of exogenous gene products. All the results demonstrated the successful delivery of Lf-modified NPs into the brain. Lf-modified NPs could be exploited as potential brain-targeting delivery systems for exogenous genes, especially for those encoding secretive proteins. [Copyright &y& Elsevier]

Abstract: Background: Gene therapy is considered one of the most promising approaches to develop an effective treatment for Parkinson''s disease (PD). The existence of blood-brain barrier (BBB) significantly limits its development. In this study, lactoferrin (Lf)-modified nanoparticles (NPs) were used as a potential non-viral gene vector due to its brain-targeting and BBB-crossing ability. Methods and results: The neuroprotective effects were examined in a rotenone-induced chronic rat model of PD after treatment with NPs encapsulating human glial cell line-derived neurotrophic factor gene (hGDNF) via a regimen of multiple dosing intravenous administration. The results showed that multiple injections of Lf-modified NPs obtained higher GDNF expression and this gene expression was maintained for a longer time than the one with a single injection. Multiple dosing intravenous administration of Lf-modified NPs could significantly improve locomotor activity, reduce dopaminergic neuronal loss, and enhance monoamine neurotransmitter levels on rotenone-induced PD rats, which indicates its powerful neuroprotective effects. Conclusion: The findings may have implications for long-term non-invasive gene therapy for neurodegenerative diseases in general. [Copyright &y& Elsevier]