Nanotechnology-assisted intracellular delivery of antibody as a precision therapy approach for KRAS-driven tumors.

The Kirsten Rat Sarcoma Virus (KRAS) oncoprotein, one of the most prevalent mutations in cancer, has been deemed undruggable for decades. The hypothesis of this work was that delivering anti-KRAS monoclonal antibody (mAb) at the intracellular level could effectively target the KRAS oncoprotein. To reach this goal, we designed and developed tLyP1-targeted palmitoyl hyaluronate (HAC16)-based nanoassemblies (HANAs) adapted for the association of bevacizumab as a model mAb. Selected candidates with adequate physicochemical properties (below 150 nm, neutral surface charge), and high drug loading capacity (>10%, w/w) were adapted to entrap the antiKRASG12V mAb. The resulting antiKRASG12V-loaded HANAs exhibited a bilayer composed of HAC16 polymer and phosphatidylcholine (PC) enclosing a hydrophilic core, as evidenced by cryogenic-transmission electron microscopy (cryo-TEM) and X-ray photoelectron spectroscopy (XPS). Selected prototypes were found to efficiently engage the target KRASG12V and, inhibit proliferation and colony formation in KRASG12V-mutated lung cancer cell lines. In vivo, a selected formulation exhibited a tumor growth reduction in a pancreatic tumor-bearing mouse model. In brief, this study offers evidence of the potential to use nanotechnology for developing anti-KRAS precision therapy and provides a rational framework for advancing mAb intracellular delivery against intracellular targets.

Case report: Neuronal intranuclear inclusion disease presenting with acute encephalopathy.

Neuronal intranuclear inclusion disease (NIID), a neurodegenerative disease previously thought to be rare, is increasingly recognized despite heterogeneous clinical presentations. NIID is pathologically characterized by ubiquitin and p-62 positive intranuclear eosinophilic inclusions that affect multiple organ systems, including the brain, skin, and other tissues. Although the diagnosis of NIID is challenging due to phenotypic heterogeneity, a greater understanding of the clinical and imaging presentations can improve accurate and early diagnosis. Here, we present three cases of pathologically proven adult-onset NIID, all presenting with episodes of acute encephalopathy with protracted workups and lengthy time between symptom onset and diagnosis. Case 1 highlights challenges in the diagnosis of NIID when MRI does not reveal classic abnormalities and provides a striking example of hyperperfusion in the setting of acute encephalopathy, as well as unique pathology with neuronal central chromatolysis, which has not been previously described. Case 2 highlights the progression of MRI findings associated with multiple NIID-related encephalopathic episodes over an extended time period, as well as the utility of skin biopsy for antemortem diagnosis.

Topological network analysis of patient similarity for precision management of acute blood pressure in spinal cord injury.

Background: Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients. Methods: Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods. Results: Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-[104-117] mmHg associated with neurological recovery. Conclusions: We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention. Funding: NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB).

Spinal cord injury is a devastating condition that involves damage to the nerve fibers connecting the brain with the spinal cord, often leading to permanent changes in strength, sensation and body functions, and in severe cases paralysis. Scientists around the world work hard to find ways to treat or even repair spinal cord injuries but few patients with complete immediate paralysis recover fully. Immediate paralysis is caused by direct damage to neurons and their extension in the spinal cord. Previous research has shown that blood pressure regulation may be key in saving these damaged neurons, as spinal cord injuries can break the communication between nerves that is involved in controlling blood pressure. This can lead to a vicious cycle of dysregulation of blood pressure and limit the supply of blood and oxygen to the damaged spinal cord tissue, exacerbating the death of spinal neurons. Management of blood pressure is therefore a key target for spinal cord injury care, but so far, the precise thresholds to enable neurons to recover are poorly understood. To find out more, Torres-Espin, Haefeli et al. used machine learning software to analyze previously recorded blood pressure and heart rate data obtained from 118 patients that underwent spinal cord surgery after acute spinal cord injury. The analyses revealed that patients who suffered from either low or high blood pressure during surgery had poorer prospects of recovery. Statistical models confirming these findings showed that the optimal blood pressure range to ensure recovery lies between 76 to 104-117 mmHg. Any deviation from this narrow window would dramatically worsen the ability to recover. These findings suggests that dysregulated blood pressure during surgery affects to odds of recovery in patients with a spinal cord injury. Torres-Espin, Haefeli et al. provide specific information that could improve current clinical practice in trauma centers. In the future, such machine learning tools and models could help develop real-time models that could predict the likelihood of a patient's recovery following spinal cord injury and related neurological conditions.

Nanotechnologies for the delivery of biologicals: Historical perspective and current landscape.

Biological macromolecule-based therapeutics irrupted in the pharmaceutical scene generating a great hope due to their outstanding specificity and potency. However, given their susceptibility to degradation and limited capacity to overcome biological barriers new delivery technologies had to be developed for them to reach their targets. This review aims at analyzing the historical seminal advances that shaped the development of the protein/peptide delivery field, along with the emerging technologies on the lead of the current landscape. Particularly, focus is made on technologies with a potential for transmucosal systemic delivery of protein/peptide drugs, followed by approaches for the delivery of antigens as new vaccination strategies, and formulations of biological drugs in oncology, with special emphasis on mAbs. Finally, a discussion of the key challenges the field is facing, along with an overview of prospective advances are provided.

A nanoemulsion/micelles mixed nanosystem for the oral administration of hydrophobically modified insulin.

The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (≈ 20-30%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration.

Exploration of surgical blood pressure management and expected motor recovery in individuals with traumatic spinal cord injury.

STUDY DESIGN: Retrospective analysis. OBJECTIVE: To assess the impact of mean arterial blood pressure (MAP) during surgical intervention for spinal cord injury (SCI) on motor recovery. SETTING: Level-one Trauma Hospital and Acute Rehabilitation Hospital in San Jose, CA, USA. METHODS: Twenty-five individuals with traumatic SCI who received surgical and acute rehabilitation care at a level-one trauma center were included in this study. The Surgical Information System captured intraoperative MAPs on a minute-by-minute basis and exposure was quantified at sequential thresholds from 50 to 104 mmHg. Change in International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor score was calculated based on physiatry evaluations at the earliest postoperative time and at discharge from acute rehabilitation. Linear regression models were used to estimate the rate of recovery across the entire MAP range. RESULTS: An exploratory analysis revealed that increased time within an intraoperative MAP range (70-94 mmHg) was associated with ISNCSCI motor score improvement. A significant regression equation was found for the MAP range 70-94 mmHg (F[1, 23] = 5.07, r2 = 0.181, p = 0.034). ISNCSCI motor scores increased 0.039 for each minute of exposure to the MAP range 70-94 mmHg during the operative procedure; this represents a significant correlation between intraoperative time with MAP 70-94 and subsequent motor recovery. Blood pressure exposures above or below this range did not display a positive association with motor recovery. CONCLUSIONS: Hypertension as well as hypotension during surgery may impact the trajectory of recovery in individuals with SCI, and there may be a direct relationship between intraoperative MAP and motor recovery.

Self-assembled hyaluronan nanocapsules for the intracellular delivery of anticancer drugs.

Preparation of sophisticated delivery systems for nanomedicine applications generally involve multi-step procedures using organic solvents. In this study, we have developed a simple self-assembling process to prepare docetaxel-loaded hyaluronic acid (HA) nanocapsules by using a self-emulsification process without the need of organic solvents, heat or high shear forces. These nanocapsules, which comprise an oily core and a shell consisting of an assembly of surfactants and hydrophobically modified HA, have a mean size of 130 nm, a zeta potential of -20 mV, and exhibit high docetaxel encapsulation efficiency. The nanocapsules exhibited an adequate stability in plasma. Furthermore, in vitro studies performed using A549 lung cancer cells, showed effective intracellular delivery of docetaxel. On the other hand, blank nanocapsules showed very low cytotoxicity. Overall, these results highlight the potential of self-emulsifying HA nanocapsules for intracellular drug delivery.

Intracellular Delivery of an Antibody Targeting Gasdermin-B Reduces HER2 Breast Cancer Aggressiveness.

PURPOSE: Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers. EXPERIMENTAL DESIGN: We have developed a new targeted nanomedicine based on hyaluronic acid-biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo. RESULTS: Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMB-overexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB. CONCLUSIONS: Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.

Stroke Characteristics, Risk Factors, and Outcomes in Transgender Adults: A Case Series.

OBJECTIVES: To describe the clinical characteristics and risk factors of male-to-female transgender (transwomen) patients with acute stroke. METHODS: The study population included all patients admitted for stroke at San Francisco General Hospital from October 1, 2010 through August 31, 2017 who self-identified as transwomen. Patient charts were reviewed by the study coauthors for demographics, stroke risk factors, stroke characteristics, and clinical outcomes. Means, percentiles, and ranges were calculated. RESULTS: Eight transwomen (average age, 50±9 y; range, 38 to 61 y) were admitted for stroke (average NIHSS, 8; range, 0 to 27). The majority of patients presented subacutely. The most common type of stroke was ischemic stroke (4, 50%), followed by intracerebral hemorrhage (2, 22%), transient ischemic attack (1, 13%), and concurrent ischemic stroke with subarachnoid hemorrhage (1, 13%). While traditional stroke risk factors were present, these patients also disproportionally had alternative risk factors: stimulant use (5, 63%), tobacco use (5, 63%), hepatitis C (5, 63%), human immunodeficiency virus (3, 38%), and prior stroke or transient ischemic attack (2, 25%). Six patients (75%) used estradiol (oral or injection) or conjugated estrogen as part of gender-affirming treatment at the time of stroke; one patient used estrogen remotely. Only 2 patients (33%) were prescribed their hormone therapy on discharge. CONCLUSIONS: Understanding unique vulnerabilities of the transgender community for cerebrovascular events is essential to provide culturally appropriate counseling for harm reduction.

Influence of the surface properties of nanocapsules on their interaction with intestinal barriers.

Despite the convenience of the oral route for drug administration, the existence of different physiological barriers associated with the intestinal tract greatly lowers the bioavailability of many active compounds. We have previously suggested the potential polymeric nanocapsules, consisting of an oily core surrounded by a polymer shell, as oral drug delivery carriers. Here we present a systematic study of the influence of the surface properties of these nanocapsules on their interaction with the intestinal barriers. Two different surfactants, Pluronic®F68 (PF68) and F127 (PF127), and two polymeric shells, chitosan (CS) and polyarginine (PARG) were chosen for the formulation of the nanocapsules. We analyzed nine different combinations of these polymers and surfactants, and studied the effect of each specific combination on their colloidal stability, enzymatic degradation, and mucoadhesion/mucodiffusion. Our results indicate that both, the polymer shell and the surfactants located at the oil/water interface, influence the interaction of the nanocapsules with the intestinal barriers. More interestingly, according to our observations, the shell components of the nanosystems may have either synergic or disruptive effects on their capacity to overcome the intestinal barriers.

Polyarginine nanocapsules: A versatile nanocarrier with potential in transmucosal drug delivery.

The objective of this work was to investigate the potential utility of nanocapsules composed of an oily core decorated with a single polyarginine (PARG), or double PARG/polyacrylic acid (PAA) layer as oral peptide delivery carrier. A step-by-step formulation optimization process was designed, which involved the study of the influence of the surfactants, oils and polymer shells (PARG of different molecular weight and PAA) on the nanocapsules physicochemical properties, peptide loading efficiency, stability in simulated intestinal fluids (SIF) and capacity to enhance the permeability of the intestinal epithelium. Despite the lipophilic nature of the nanocapsules, it was possible to achieve a moderate loading of the hydrophilic model peptide salmon calcitonin and control its release in SIF, by adjusting the formulation conditions. Finally, studies in the Caco-2 epithelial cell line showed the capacity of the nanocapsules to reduce the transepithelial electric resistance of the monolayer, without compromising their viability. Overall, these properties suggest the capacity of polyarginine nanocapsules for enhancing the transport of peptides across epithelia.

Polyarginine Nanocapsules as a Potential Oral Peptide Delivery Carrier.

We have previously reported the development of novel nanocapsules made of polyarginine (PArg) specifically designed for the delivery of small anticancer drugs into cells. Our goal, in this work, has been to investigate the potential of these nanocarriers for oral delivery of peptide anticancer drugs. To reach this objective, we chose the antitumoral peptide, elisidepsin, and evaluated the characteristics of the PArg nanocapsules in terms of drug loading capacity, stability in simulated intestinal fluids, and ability to interact with the intestinal epithelium both in vitro (Caco-2 model cell line) and in vivo. Our results suggest that elisidepsin can be effectively loaded into the nanocapsules by adjusting the formulation parameters, using a solvent displacement technique. The resulting nanocapsules were stable upon incubation in simulated intestinal fluids and had the ability to reduce, in a transient manner, the transepithelial electrical resistance of the Caco-2 cell monolayer. Confocal images also revealed that PArg nanocapsules were internalized by the monolayer without evident signs of cytotoxicity. Finally, the in vivo fluorescent imaging study illustrates the retention of the nanocapsules in the gastrointestinal tract upon oral administration. Overall, the results underline the potential interest of PArg nanocapsules as carriers for the oral administration of peptide drugs.

Enhanced in vivo therapeutic efficacy of plitidepsin-loaded nanocapsules decorated with a new poly-aminoacid-PEG derivative.

The focus of this study is to disclose a new delivery carrier intended to improve the pharmacokinetic characteristics of the anticancer drug plitidepsin and to favor its accumulation within the tumor. These nanocarriers named as nanocapsules, consist of an oily core surrounded by a highly PEGylated polyglutamic acid (PGA-PEG) shell loaded with plitidepsin. They showed a size of around 190 nm, a zeta potential of -24 mV and were able to encapsulate a high percentage (85%) of plitidepsin. In vivo studies, following intravenous injection in healthy mice, indicated that the encapsulation of the drug within PGA-PEG nanocapsules led to an important increase in its area under the curve (AUC) which is related to the important decrease of the clearance, as compared to the values observed for the drug dissolved in a Cremophor(®) EL solution. This improvement of the pharmacokinetic profile of the encapsulated plitidepsin was accompanied by a high increase (2.5-fold) of the maximum tolerated dose (MTD) in comparison to that of plitidepsin Cremophor(®) EL solution. The efficacy study performed in a xenograft tumor mice model evidenced the capacity of PGA-PEG nanocapsules to significantly reduce tumor growth. These promising results highlight the potential of PGA-PEG nanocapsules as an effective drug delivery system for cancer therapy.

Polyglutamic acid-PEG nanocapsules as long circulating carriers for the delivery of docetaxel.

Recently we reported for the first time a new type of nanocapsules consisting of an oily core and a polymer shell made of a polyglutamic acid-polyethylene glycol (PEG-PGA) grafted copolymer with a 24% w/w PEG content. The goal of the work presented here has been to develop a new version of these nanocapsules, in which the shell is made of a di-block PEG-PGA copolymer with a 57% w/w PEG content and to evaluate their potential for improving the biodistribution and pharmacokinetics of the anticancer drug docetaxel (DCX). A comparative analysis of the biodistribution of fluorescently labeled PGA-PEG nanocapsules versus PGA nanocapsules or a control nanoemulsion (containing the same oil than the nanocapsules) showed that the nanocapsules, and in particular PEGylated nanocapsules, have significantly higher half-life, MRT (Mean Residence Time) and AUC (Area under the Curve) than the nanoemulsion. On a separate set of experiments, PGA-PEG nanocapsules were loaded with DCX and their antitumor efficacy was evaluated in a xenograft U87MG glioma mouse model. The results showed that the survival rate for mice treated with DCX-loaded nanocapsules was significantly increased over the control Taxotere®, while the antitumoral effect of both formulations was comparable (60% tumor growth inhibition with respect to the untreated mice). These results highlight the potential use of these novel nanocapsules as a new drug delivery platform in cancer therapy.

In vivo evaluation of poly-l-asparagine nanocapsules as carriers for anti-cancer drug delivery.

Here, we report the in vivo proof of-concept of a novel nanocarrier, poly-l-asparagine (PASN) nanocapsules, as an anticancer targeted drug delivery system. The nanocapsules were loaded with the fluorescent marker DiD (1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate) and also with the model drug docetaxel to evaluate the biodistribution and efficacy profiles in healthy and glioma-bearing mice, respectively. Regardless of their cargo, the nanocapsules presented a size close to 180 nm, a surface charge around -40 mV and an encapsulation efficiency of 75-90%. The biodistribution study in healthy mice showed that PASN nanocapsules led to a two- and three-fold increment in the mean residence time (MRT) and area under the curve (AUC) values, respectively, compared to those of a non-polymeric nanoemulsion. Finally, the efficacy/toxicity study indicated that the encapsulated drug was as efficacious as the commercial formulation (Taxotere(®)), with the additional advantage of being considerably less toxic. Overall, these results suggest the potential of PASN nanocapsules as drug nanocarriers in anticancer therapy.

Hyaluronan nanocapsules as a new vehicle for intracellular drug delivery.

Here we report the development of new drug nanocarriers - named hyaluronan nanocapsules - for the intracellular delivery of hydrophobic anticancer drugs. These nanocapsules are composed of a lipid core and a shell of hyaluronic acid (HA). Nanocapsules were produced by a modified solvent displacement technique, which allows the formation of the polymer shell around the oily core using a cationic surfactant as an interphase bridge. The resulting nanocapsules have a size of ∼200 nm, a negative zeta potential and a spherical shape. The model drug docetaxel could be efficiently encapsulated within their core. The in vitro cell culture studies (NCI-H460 cancer cell line) showed that the cytotoxicity of docetaxel could be significantly enhanced due to its encapsulation within the nanocapsules. Interestingly, the nanocapsules were stable during storage and they could also be transformed into a powder by freeze-drying. These novel nanostructures hold promise as intracellular drug delivery systems.

A new potential nano-oncological therapy based on polyamino acid nanocapsules.

A critical objective in cancer therapy is to reduce the systemic toxicity through the modification of the biodistribution of anticancer drugs. Herein, we disclose a new biodegradable nanocarrier, polyglutamic acid (PGA) nanocapsules, and present the in vivo pharmacokinetics/toxicity proof-of-concept for the anticancer drug plitidepsin. These novel nanocapsules were prepared using a modified solvent displacement technique where the polyamino acid was electrostatically deposited onto the lipid core. The nanocapsules exhibited an average size of 200 nm, a negative zeta potential and a great capacity for the encapsulation of plitidepsin (encapsulation efficiency above 90%). In addition, the nanocapsules could be freeze-dried and showed an adequate stability profile upon storage. Finally, the in vivo proof-of-concept studies performed in mice indicated that the encapsulation provided the drug with a prolonged blood circulation and a significantly reduced toxicity. In fact, the maximum tolerated dose of the nanoencapsulated drug was more than 3 times that of the reference formulation (Cremophor® EL plitidepsin solution). Overall, beyond the value of this specific formulation, the work reported here represents the evidence of the potential of polyamino acid nanocapsules in nano-oncological therapy.

Anti-tumor efficacy of chitosan-g-poly(ethylene glycol) nanocapsules containing docetaxel: anti-TMEFF-2 functionalized nanocapsules vs. non-functionalized nanocapsules.

The development and evaluation of PEGylated chitosan (CS) nanocapsules (NCs) conjugated to a monoclonal antibody anti-TMEFF-2 (CS-PEG-anti-TMEFF-2 mAb NCs) for targeted delivery of docetaxel (DCX) is presented. CS-PEG-Biotin NCs, displaying biotin tags at their surface, were obtained and efficiently functionalized with an anti-TMEFF-2 mAb through a convenient avidin-biotin approach. Cell cycle analysis after treatment with different DCX-loaded CS-PEG NC formulations indicated that the encapsulated drug remained fully active, showing a similar functional behavior to free DCX. In vivo efficacy studies using a non-small cell lung carcinoma xenograft revealed that CS-PEG-anti-TMEFF-2 NCs resulted as effective as free DCX (Taxotere®). Interestingly, differences on the pharmacodynamic behavior among the different DCX formulations were observed. Thus, while free DCX exhibited a fast and short effect on tumor volume reduction, CS-PEG-anti-TMEFF-2 mAb NCs showed a delayed and prolonged action, with no significant side effects of treatments.

A new drug nanocarrier consisting of polyarginine and hyaluronic acid.

The purpose of this study was to produce and characterize a variety of nanostructures comprised of the polyaminoacid polyarginine (PArg) and the polysaccharide hyaluronic acid (HA) as a preliminary stage before evaluating their potential application in drug delivery. PArg was combined with high- or low-molecular-weight HA (HMWHA or LMWHA, respectively) to form nanoparticles by simply mixing polymeric aqueous solutions at room temperature. The average size of the resulting nanocarriers was between 116 and 155 nm, and their zeta potential value ranged from +31.3 to -35.9 mV, indicating that the surface composition of the particle could be conveniently modified according to the mass ratio of the polymers. Importantly, the systems prepared with HMWHA remained stable after isolation by centrifugation and in conditions that mimic the physiological medium, whereas particles that incorporated LMWHA were unstable. Transmission electron microscopy showed that the nanostructures made with HMWHA were spherical. Finally, the systems were stable for at least three months at storage conditions (4°C).

Thallium-201 SPECT in brain gliomas: Quantitative assessment in differential diagnosis between tumor recurrence and radionecrosis.

OBJECTIVE: To compare various published thallium-201 uptake indexes in the differential diagnosis in recurrent brain gliomas. MATERIAL AND METHODS: Thallium-201 SPECT studies were performed in 79 patients previously treated for glial tumor with clinical or radiologic suspicion of recurrence. Regions of interest were established in the tumor area and in other sites with normal uptake. RESULTS: A high linear correlation was found among indices, with significant differences between all index pairs. Logistic regression analysis confirmed high colinearity among indexes, with index 3 (mean counts in tumor/mean counts in contralateral hemisphere) showing a slightly superior predictive power to differentiate tumor absence from tumor presence and tumor absence from low-grade recurrence. These findings were supported by analysis of areas under the ROC curve. CONCLUSIONS: The uptake indices studied behave similarly in the evaluation of a possible recurrence of a glial brain lesion and should be considered complementary to visual evaluation as a semi-objective tool.