Nanoparticles are of long-standing interest for the treatment of neurological diseases such as glioblastoma. Most past work focused on methods to introduce nanoparticles into the brain, suggesting that reaching the brain interstitium will be sufficient to ensure therapeutic efficacy. However, optimized nanoparticle design for drug delivery to the central nervous system is limited by our understanding of their cellular deposition in the brain. Here, we investigated the cellular fate of poly(lactic acid) nanoparticles presenting different surface chemistries, after administration by convection-enhanced delivery. We demonstrate that nanoparticles with ‘stealth' properties mostly avoid internalization by all cell types, but internalization can be enhanced by functionalization with bio-adhesive end-groups. We also show that association rates measured in cultured cells predict the extent of internalization of nanoparticles in cell populations. Finally, evaluating therapeutic efficacy in an orthotopic model of glioblastoma highlights the need to balance significant uptake without inducing adverse toxicity.
New treatments for glioblastoma multiforme (GBM) are desperately needed, as GBM prognosis remains poor, mainly due to treatment resistance, poor distribution of therapeutics in the tumor tissue, and fast metabolism of chemotherapeutic drugs in the brain extracellular space. Convection-enhanced delivery (CED) of nanoparticles (NPs) has been shown to improve the delivery of chemotherapeutic drugs to the tumor bed, providing sustained release, and enhancing survival of animals with intracranial tumors. Here we administered gemcitabine, a nucleoside analog used as a first line treatment for a wide variety of extracranial solid tumors, within squalene-based NPs using CED, to overcome the above-mentioned challenges of GBM treatment. Small percentages of poly(ethylene) glycol (PEG) dramatically enhanced the distribution of squalene-gemcitabine nanoparticles (SQ-Gem NPs) in healthy animals and tumor-bearing animals after administration by CED. When tested in an orthotopic model of GBM, SQ-Gem-PEG NPs demonstrated significantly improved therapeutic efficacy compared to free gemcitabine, both as a chemotherapeutic drug and as a radiosensitizer. Furthermore, MR contrast agents were incorporated into the SQ-Gem NP formulation, providing a way to non-invasively track the NPs during infusion.
High-grade gliomas such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG) are characterized by an aggressive phenotype with nearly universal local disease progression despite multimodal treatment, which typically includes chemotherapy, radiation therapy (RT), and possibly surgery. Radiosensitizers that have improved the effects of RT for extracranial tumors have been ineffective for the treatment of GBM and DIPG, in part due to poor blood brain barrier penetration and rapid intracranial clearance of small molecules. Here, we demonstrate that nanoparticles can provide sustained drug release and minimal toxicity. When administered locally, these nanoparticles conferred radiosensitization in vitro and improved survival in rats with intracranial gliomas when delivered concurrently with a 5-day course of fractionated RT. Compared to previous work using locally-delivered radiosensitizers and cranial radiation, our approach – based on rational selection of agents and a clinically-relevant radiation dosing schedule – produces the strongest synergistic effects between chemo- and radio-therapy approaches to the treatment of high-grade gliomas.
Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing T lymphocytes that is more likely to involve the peripheral blood in advanced stages. For such patients with advanced disease, there are few available systemic treatment options, and prognosis remains poor. Exome sequencing studies of CTCL have suggested therapeutic targets, including within the JAK/STAT pathway, but JAK inhibition strategies may be limited by patient-specific mutational status. Because our recent research has highlighted the potential roles of single and combination approaches specifically using BCL2, bromodomain and extra-terminal domain (BET), and histone deacetylase (HDAC) inhibition, we aimed to investigate the effects of JAK inhibition on CTCL cells and established CTCL cell lines when paired with these and other targeting agents. Peripheral blood malignant CTCL isolates exhibited differential responses to JAK inhibition, with JAK2 expression levels negatively correlating to 50% inhibitory concentration (IC50) values. Regardless of single-agent sensitivity, JAK inhibition potentiated malignant cell cytotoxicity in combination with BCL2, BET, HDAC, or proteasome inhibition. Combination inhibition of JAK and BCL2 showed the strongest potentiation of CTCL cytotoxicity, driven by both intrinsic and extrinsic apoptosis pathways. JAK inhibition decreased expression of BCL2 in the high-responder samples, suggesting a putative mechanism for this combination activity. These results indicate that JAK inhibition may have major effects on CTCL cells, and that combination strategies using JAK inhibition may allow for more generalized cytotoxic effects against the malignant cells from patients with CTCL. Such preclinical assessments help inform prioritization for combination targeted drug approaches for clinical utilization in the treatment of CTCL.
Cutaneous T-cell lymphoma (CTCL) incidence increases with age, and blood involvement portends a worse prognosis. To advance our understanding of CTCL development and identify potential therapeutic targets, we performed integrative analyses of paired single-cell RNA and TCR sequencing of peripheral blood CD4+ T-cells from CTCL patients to reveal disease unifying features. The malignant CD4+ T-cells of CTCL show highly diverse transcriptomic profiles across patients, with most displaying a mature Th2 differentiation and T-cell exhaustion phenotype. TCR-CDR3 peptide prediction analysis suggested limited diversity between CTCL samples, consistent with a role for a common antigenic stimulus. PHATE affinity-based transition analysis identified putative precancerous circulating populations characterized by an intermediate stage of gene expression and mutation level between the normal CD4+ T-cells and malignant CTCL cells. We further revealed the therapeutic potential of targeting CD82 and JAK that endow the malignant CTCL cells with survival and proliferation advantages.
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