Toral R. Patel

Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery

Many synthetic polycationic vectors for non-viral gene delivery show high efficiency in vitro, but their usually excessive charge density makes them toxic for in vivo applications. Here we describe the synthesis of a series of high molecular weight terpolymers with low charge density, and show that they exhibit efficient gene delivery, some surpassing the efficiency of the commercial transfection reagents Polyethylenimine and Lipofectamine 2000. The terpolymers were synthesized via enzyme-catalyzed copolymerization of lactone with dialkyl diester and amino diol, and their hydrophobicity adjusted by varying the lactone content and by selecting a lactone comonomer of specific ring size. Targeted delivery of the pro-apoptotic TRAIL gene to tumour xenografts by one of the terpolymers results in significant inhibition of tumour growth, with minimal toxicity both in vitro and in vivo. Our findings suggest that the gene delivery ability of the terpolymers stems from their high molecular weight and increased hydrophobicity, which compensates for their low charge density.

Polymeric nanoparticles for drug delivery to the central nervous system

The central nervous system (CNS) poses a unique challenge for drug delivery. The blood-brain barrier significantly hinders the passage of systemically delivered therapeutics and the brain extracellular matrix limits the distribution and longevity of locally delivered agents. Polymeric nanoparticles represent a promising solution to these problems. Over the past 40years, substantial research efforts have demonstrated that polymeric nanoparticles can be engineered for effective systemic and local delivery of therapeutics to the CNS. Moreover, many of the polymers used in nanoparticle fabrication are both biodegradable and biocompatible, thereby increasing the clinical utility of this strategy. Here, we review the major advances in the development of polymeric nanoparticles for drug delivery to the CNS.

Octa-functional PLGA nanoparticles for targeted and efficient siRNA delivery to tumors.

Therapies based on RNA interference, using agents such as siRNA, are limited by the absence of safe, efficient vehicles for targeted delivery in vivo. The barriers to siRNA delivery are well known and can be individually overcome by addition of functional modules, such as conjugation of moieties for cell penetration or targeting. But, so far, it has been impossible to engineer multiple modules into a single unit. Here, we describe the synthesis of degradable nanoparticles that carry eight synergistic functions: 1) polymer matrix for stabilization/controlled release; 2) siRNA for gene knockdown; 3) agent to enhance endosomal escape; 4) agent to enhance siRNA potency; 5) surface-bound PEG for enhancing circulatory time; and surface-bound peptides for 6) cell penetration; 7) endosomal escape; and 8) tumor targeting. Further, we demonstrate that this approach can provide prolonged knockdown of PLK1 and control of tumor growth in vivo. Importantly, all elements in these octa-functional nanoparticles are known to be safe for human use and each function can be individually controlled, giving this approach to synthetic RNA-loaded nanoparticles potential in a variety of clinical applications.

Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma

Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma

Purpose Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase ( IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment. Data were analyzed in patient cohorts representing the major phases of the glioma clinical course and were further subgrouped by histology and treatment type to evaluate 2HG. Histologic correlations were performed. Results Quantitative 2HG MRS was technically and biologically reproducible. 2HG concentration > 1 mM could be reliably detected with high confidence. During the period of indolent disease, 2HG concentration varied by less than ± 1 mM, and it increased sharply with tumor progression. 2HG concentration was positively correlated with tumor cellularity and significantly differed between high- and lower-grade gliomas. In response to cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q codeleted oligodendrogliomas and with a slower time course in astrocytomas and mixed gliomas. The magnitude and time course of the decrease in 2HG concentration and magnitude of the decrease in tumor volume did not differ between oligodendrogliomas treated with temozolomide or carmustine. Criteria for 2HG MRS were established to make a presumptive molecular diagnosis of an IDH mutation in gliomas technically unable to undergo a surgical procedure. Conclusion 2HG concentration as measured by MRS was reproducible and reliably reflected the disease state. These data provide a basis for incorporating 2HG MRS into clinical management of IDH-mutated gliomas.

Secondary Neoplasms After Stereotactic Radiosurgery

OBJECTIVE The use of medical radiation has increased 6-fold in the past 30 years. Within neurosurgery, the advent of stereotactic radiosurgery (SRS) has significantly altered the treatment paradigm for both benign and malignant central nervous system diseases. With this increased reliance on radiation has come a responsibility to identify the long-term risks, including the potential development of radiation-induced neoplasms. Although the data regarding traditional radiation exposure and its subsequent risks are well-defined, the data for SRS is less developed. METHODS We reviewed the published literature to more accurately define the risk of developing secondary neoplasms after stereotactic radiosurgery. RESULTS A total of 36 cases of SRS-induced neoplasms were identified. More than half of the cases had an initial diagnosis of vestibular schwannoma. Overall, the risk of developing an SRS-induced neoplasm is approximately 0.04% at 15 years. CONCLUSION The risk of developing an SRS-induced neoplasm is low but not zero. Thus, long-term surveillance imaging is advised for patients treated with SRS.

Radiolabeling of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with biotinylated F-18 prosthetic groups and imaging of their delivery to the brain with positron emission tomography.

The avidin–biotin interaction permits rapid and nearly irreversible noncovalent linkage between biotinylated molecules and avidin-modified substrates. We designed a biotinylated radioligand intended for use in the detection of avidin-modified polymer nanoparticles in tissue with positron emission tomography (PET). Using an F-18 labeled prosthetic group, [18F]4-fluorobenzylamine, and a commercially available biotin derivate, NHS-PEG4-biotin, [18F]-fluorobenzylamide-poly(ethylene glycol)4-biotin ([18F]NPB4) was prepared with high purity and specific activity. The attachment of the [18F]NPB4 radioligand to avidin-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles was tested by using PET imaging to measure the kinetics of convection-enhanced delivery (CED) of nanoparticles of varying size to the rat brain. PET imaging enabled the direct observation of nanoparticle delivery by measurement of the spatial volume of distribution of radiolabeled nanoparticles as a function of time, both during and after the infusion. This work thus validates new methods for radiolabeling PEG-biotin derivatives and also provides insight into the fate of nanoparticles that have been infused directly into the brain.

Cerebral bypass surgery for skull base lesions: technical notes incorporating lessons learned over two decades

OBJECT Despite advancements in endovascular neurosurgery, there remains an important role for cerebral bypass surgery in the treatment of skull base lesions. The authors describe their replacement cerebral bypass surgery techniques incorporating lessons learned over 2 decades. METHODS The authors performed a retrospective review of cerebral bypass surgery performed by the senior author for skull base lesions between 1986 and 2006. One hundred patients had adjunct bypass surgery for skull base lesions. RESULTS The bypass surgeries performed are conceptually divided into Skull Base Bypass I, II, and III. The majority of lesions requiring bypass surgery were giant cavernous carotid artery aneurysms or skull base meningiomas. There were no deaths in this case series. There was a 7% morbidity rate. CONCLUSIONS The ability to perform this surgery is an important adjunct in the armamentarium of skull base/cerebrovascular neurosurgeons.

Detection of 2‐hydroxyglutarate in brain tumors by triple‐refocusing MR spectroscopy at 3T in vivo

To test the efficacy of triple‐refocusing MR spectroscopy (MRS) for improved detection of 2‐hydroxyglutarate (2HG) in brain tumors at 3T in vivo.

Management of brain metastases: surgery, radiation, or both?

A significant number of cancer patients will develop intracranial metastases. In general, treatment of these lesions uses a combination of surgery and radiation. However, over the past several decades the specifics of this treatment paradigm have evolved significantly. This article describes the current standard of care with respect to intracranial metastases, highlighting the latest therapeutic developments.