Asiri Ediriwickrema

Nanotherapy for Cancer: Targeting and Multifunctionality in the Future of Cancer Therapies

Cancer continues to be a prevalent and lethal disease, despite advances in tumor biology research and chemotherapy development. Major obstacles in cancer treatment arise from tumor heterogeneity, drug resistance, and systemic toxicities. Nanoscale delivery systems, or nanotherapies, are increasing in importance as vehicles for antineoplastic agents because of their potential for targeting and multifunctionality. We discuss the current field of cancer therapy and potential strategies for addressing obstacles in cancer treatment with nanotherapies. Specifically, we review the strategies for rationally designing nanoparticles for targeted, multimodal delivery of therapeutic agents.

Multi-layered nanoparticles for combination gene and drug delivery to tumors.

Drug resistance and toxicity are major obstacles in cancer chemotherapy. Combination therapies can overcome resistance, and synergies can minimize dosing. Polymer nanocarriers are interesting vehicles for cancer therapeutics for their delivery and tumor targeting abilities. We synthesized a multi-layered polymer nanoparticle (MLNP), comprising of poly(lactic-co-glycolic acid) with surface polyethyleneimine and functional peptides, for targeted drug and gene delivery. We confirmed the particles ability to inhibit tumor growth through synergistic action of the drug and gene product. MLNPs achieved transfection levels similar to lipofectamine, while maintaining minimal cytotoxicity. The particles delivered camptothecin (CPT), and plasmid encoding TNF related apoptosis inducing ligand (pTRAIL) (CT MLNPs), and synergistically inhibited growth of multiple cancer cells in vitro. The synergy of co-delivering CPT and pTRAIL via CT MLNPs was confirmed using the Chou-Talalay method: the combination index (CI) values at 50% inhibition ranged between 0.31 and 0.53 for all cell lines. Further, co-delivery with MLNPs resulted in a 3.1-15 fold reduction in CPT and 4.7-8.0 fold reduction in pTRAIL dosing. CT MLNPs obtained significant HCT116 growth inhibition in vivo compared to monotherapy. These results support our hypothesis that MLNPs can deliver both small molecules and genetic agents towards synergistically inhibiting tumor growth.

A sunblock based on bioadhesive nanoparticles

The majority of commercial sunblock preparations utilize organic or inorganic ultraviolet (UV) filters. Despite protecting against cutaneous phototoxicity, direct cellular exposure to UV filters has raised a variety of health concerns. Here, we show that the encapsulation of padimate O (PO) - a model UV filter - in bioadhesive nanoparticles (BNPs) prevents epidermal cellular exposure to UV filters while enhancing UV protection. BNPs are readily suspended in water, facilitate adherence to the stratum corneum without subsequent intra-epidermal or follicular penetration, and their interaction with skin is water-resistant yet the particles can be removed via active towel drying. Although the sunblock based on BNPs contained less than 5 wt% of the UV-filter concentration found in commercial standards, the anti-UV effect was comparable when tested in two murine models. Moreover, the BNP-based sunblock significantly reduced double-stranded DNA breaks when compared to a commercial sunscreen formulation.

Intracranial stenting as monotherapy in subarachnoid hemorrhage and sickle cell disease

Introduction Although there have been a few reports of coiling intracranial aneurysms in patients with sickle cell disease (SCD), there are no reports of intracranial stent placement in this patient population. A patient in whom stent placement was utilized as monotherapy to treat a blister-like aneurysm is described and the implications of SCD and endovascular treatment are discussed. Case report A 37-year-old man with SCD presented with diffuse subarachnoid hemorrhage. Angiography confirmed a 2 mm irregular aneurysm on the posterior cerebral artery which was treated with an oversized Neuroform 3 stent that was placed across the aneurysm neck by the senior author (KRB). Follow-up CT angiography showed no residual aneurysmal filling. The patient was discharged home in a stable condition, and he continues to do well 4 weeks following the procedure with no recurrence of the aneurysm. Discussion This report reviews hypercoagulability in SCD and the treatment options for intracranial aneurysms in patients with SCD. Additionally, the reported case suggests that intracranial stent placement may be a viable option for treating complex intracranial aneurysms in SCD patients.

Flow diverters and a tale of two aneurysms.

Flow-diverting devices offer an exciting alternative for the management of large and giant intracranial aneurysms. However, the risk and mechanism of delayed aneurysmal rupture and hemorrhage following placement of these devices are not clearly understood. Two patients with similar symptomatic giant paraclinoid internal carotid artery aneurysms are described. Both patients were treated with SILK flow-diverting devices. In both patients the SILK device was placed without technical complication. The first patient continued to do well 1 year postoperatively with complete aneurysm occlusion. The second patient had a delayed subarachnoid hemorrhage despite markedly decreased filling of the aneurysm immediately following the procedure. Flow-diverting devices are an exciting technology which provide an alternative treatment modality in the management of giant intracranial aneurysms. However, caution must be exercised as the risks of delayed complications have yet to be fully elucidated. Similar aneurysms may have drastically different outcomes due to the unpredictability of this technology.

Tissue plasminogen activator via cross-collateralization for tandem internal carotid and middle cerebral artery occlusion

Tandem internal carotid and middle cerebral artery occlusion after carotid dissection predicts poor outcome after systemic thrombolysis. Current treatments include the use of endovascular carotid stenting, which carries with it a high risk of propagating further embolic events and worsening the dissection. New strategies for avoiding the aforementioned side-effects include recanalization using cross-collaterals for delivery of intra-lesional tissue plasminogen activator (tPA). We present two cases that provide further support for this novel approach. Both patients presented with a National Institute of Health Stroke Scale of 20, received intra-arterial tPA via cross-collateralization, and made full recoveries without the need for stenting.

Crescentic Glomerulonephritis With Immunoglobulin G4–Related Disease: Case Report and Review of the Literature

&NA; Immunoglobulin G4 (IgG4)‐related disease is an uncommon autoimmune disease that affects multiple organ systems. Renal involvement typically presents as tubulointerstitial nephritis and less commonly as membranous glomerulonephritis. In this case report, we discuss a 68‐year‐old patient who presented with rapidly progressive glomerulonephritis. His renal biopsy revealed a membranoproliferative pattern of injury with fibrocellular crescents and extensive infiltration of the tubulointerstitium with IgG4‐positive plasma cells. We treated the patient with both corticosteroids and rituximab because of the aggressive nature of crescentic glomerulonephritis. The patient demonstrated a partial improvement in kidney function after 2 cycles of rituximab with a decrease in serum creatinine levels from 6.9‐4.7 mg/dL after 6 months from presentation. This case illustrates the importance of considering IgG4‐related disease in cases of rapidly progressive glomerulonephritis and the need for effective treatments for more aggressive forms of this recently recognized disease entity.

Acute bitemporal hemianopsia from a compressive anterior communicating artery aneurysm

Anterior communicating artery aneurysms (AcoA) often present as subarachnoid hemorrhage (SAH) associated with focal deficits. Despite the close proximity of the optic chiasm to the Circle of Willis, visual symptoms from AcoA are rare, especially bitemporal hemianopsia (BTH). A 49-year-old man presented with acute right eye temporal field cut. Magnetic resonance angiography showed a 6-mm AcoA compressing the prechiasmatic portions of both optic nerves (Fig. 1a–d). Automated perimetry detected BTH (Fig. 1e). The patient subsequently underwent successful endovascular coil embolization (Fig. 1f,g). Case reports of BTH from AcoA describe intra-operative observations of large AcoA wrapped around the genu that compresses the entire chiasmatic apparatus, similar to the mechanism of pituitary adenomas. Early consideration of aneurysms in cases of acute BTH can prevent devastating consequences.