Application of Flat-Panel Volume Computed Tomography to Evaluate Cerebral Hemorrhage After Mechanical Thrombectomy of Acute Embolic Stroke of the Anterior Circulation.

OBJECTIVE: The aim of the study was to evaluate cerebral hemorrhage (CH) and contrast media leakage (CML or commonly synonymous with "contrast staining") differentiation on flat-panel volume computed tomography (FPVCT) after intra-arterial mechanical thrombectomy. METHODS: We evaluated patients with hyperattenuation on FPVCT after intra-arterial mechanical thrombectomy between 2018 and 2021 by multiple parameters on CT angiography, FPVCT, CT, and/or magnetic resonance imaging. RESULTS: The CH (n = 43) versus CML (n = 24) groups revealed: (1) regional anatomical characteristics (preserved and distorted): 7 of 43 (9.6%) and 36 of 43 (83.7%) versus 22 of 24 (91.7%) and 2 of 24 (8.3%, P < 0.001); (2) thrombus in proximal two-thirds versus distal one-thirds M1 segment of middle cerebral artery (preserved and distorted): 17 of 21 (81.0%) and 4 of 21 (19.0%) versus 5 of 11 (45.5%) and 6 of 11 (54.5%, P = 0.040); and (3) average density ratio: 1.83 ± 0.65 versus 1.35 ± 0.13 (P = 0.004). CONCLUSIONS: Contrast media leakage can be differentiated from CH by preserved regional anatomical characteristics and relatively low average density ratio on FPVCT. Patients with CML who have embolism in proximal two thirds of M1 segment are more likely to develop hyperattenuation with preserved regional anatomy.

Contrast-induced acute kidney injury.

Although major advancements in the field of cardiology have allowed for an increasing number of patients to undergo minimally invasive imaging and interventional procedures, contrast-induced acute kidney injury (CI-AKI) continues to be a dreaded complication among patients receiving intravascular contrast media. CI-AKI is characterized by progressive decline in kidney function within a few days of contrast medium administration. Physiological changes resulting from the direct nephrotoxic effect of contrast media on tubular epithelial cells and release of vasoactive molecules have been implicated in creating a state of increased oxidative stress and subsequent ischemic renal cell injury. Over the last several years, preventive strategies involving intravenous hydration, pharmaceutical agents and renal replacement therapies have resulted in lower rates of CI-AKI. However, due to the evolving paradigm of diagnostic and therapeutic interventions, several unanswered questions remain. This review highlights the epidemiology, pathogenesis and preventive strategies of CI-AKI.

Management of Intravenous Infiltration Injuries.

BACKGROUND: Intravenous (IV) lines are ubiquitous in hospital settings. These lines can malfunction, leaking noxious contents into subcutaneous tissue. Existing literature describes invasive intervention and complex treatment protocols. These persist despite significant changes in the composition and administration of IV agents. The purpose of this study is to examine the consequences of IV infiltrations at a tertiary medical center to update protocols and treatment algorithms. MATERIALS AND METHODS: This study is an observational, retrospective chart review performed at a tertiary care medical center. All inpatient plastic surgery consultations for IV infiltration were reviewed from 2011 to 2017. Patients were included if IV infiltration was suspected or documented. Data were collected for each injury regarding patient demographics, substance, and intervention. RESULTS: The plastic surgery service evaluated 381 IV infiltration injuries from 2011 to 2017, with 363 meeting the criteria. Injuries per year progressively increased, with 32 consultations in 2011 and 102 consultations in 2017. The vast majority of injuries identified (91%) were treated with only elevation and observation. The minority consisted of wound care (7%) performed by nursing or any form of incision, aspiration, or antidote injection (2%) performed by the physician. Of the 363 injuries, the most common infiltrates were noncytotoxic (35%), radiographic contrast (27%), and known vesicants (18%). Interestingly, a large portion of consultations were requested by other surgical services (32%). CONCLUSIONS: Although there is an increase in expert involvement for cases of IV infiltration injuries, the vast majority of these injuries are managed with minimal intervention. This is most likely owing to recent changes that have decreased the potential for harmful infiltration. Contrary to existing literature, invasive intervention is almost never indicated.

Pathophysiological Mechanism of Extravasation via Umbilical Venous Catheters.

A rare complication of umbilical venous catheter (UVC) insertion is the extravasation of the infusate into the peritoneal cavity. We report 3 cases of abdominal extravasation of parenteral nutrition (PN) fluid via UVCs. Two of these cases presented as "acute abdomen" which were assumed to be necrotizing enterocolitis clinically; however, during postmortem, PN ascites and liver necrosis were found. A further case is described in an infant with congenital diaphragmatic hernia. While we were unable to ascertain direct vessel perforation by the catheter in any of these cases, based on pathological and histological examination, the proposed mechanism of PN fluid extravasation is leakage through microinjuries of liver vessel walls and necrotic parenchyma. PN extravasation should be considered as a differential diagnosis of acute abdomen when PN is infused via an UVC presumably as PN may have a direct irritant effect on the peritoneum.

Retención de compuestos de gadolinio usados en resonancia magnética: revisión crítica y recomendaciones de las agencias regulatorias / Retention of gadolinium compounds used in magnetic resonance imaging: a critical review and the recommendations of regulatory agencies

La Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), basándose en las recomendaciones del Comité Europeo para la Evaluación de Riesgos en Farmacovigilancia, estableció el 11 de julio de 2017 que los beneficios clínicos no superan a los posibles riesgos derivados del uso de contrastes de resonancia magnética basados en gadolinio (Gd) de estructura lineal, incluyendo Omniscan(R), Magnevist(R) (actualmente no comercializado), Optimark(R) (abandonada su comercialización en España) y MultiHance(R). Recomienda la AEMPS suspender su comercialización para uso general argumentando la retención de estos compuestos en el cerebro. Por otro lado, justifica que se mantengan disponibles Primovist(R) y MultiHance(R) para estudios hepáticos, y Magnevist(R) de administración intraarticular (no comercializado en España). Aboga por el uso casi exclusivo de los contrastes de estructura macrocíclica (Gadovist(R), ProHance(R) y Dotarem(R)). Sin embargo, la retención de Gd se sabe que es diferente para cada medio de contraste. Todos los contrastes de Gd tienen una fase de distribución con retención tisular por intercambio muy lento en el intersticio de hueso, piel, riñón, encéfalo y otros órganos. No se han demostrado efectos histológicos ni sintomatología clínica asociados al acúmulo de estas cantidades traza de Gd. La mayor preocupación toxicológica con estos contrastes es la fibrosis sistémica nefrogénica (FSN). Dado que los perfiles de seguridad se relacionan principalmente con el espacio de retención intersticial en los tejidos, no parece justificado excluir los medios de contraste sin relación con la FSN. Por ello, se discrepa de la recomendación de la AEMPS de paralizar la comercialización de los contrastes lineales para uso general sin tener en cuenta los perfiles individuales de cada medio de contraste. Esta recomendación no se sustenta en los datos ni en los conocimientos existentes sobre la retención, la relajatividad y la eficiencia clínica de los compuestos de Gd. Es necesario realizar estudios prospectivos sobre la relevancia histológica y clínica de estos depósitos orgánicos de Gd (AU)

The Spanish Agency for Drugs and Healthcare Products (AEMPS), based on the recommendations of the European Committee for Risk Assessment in Pharmacovigilance, established on 13 March 2017 that linear gadolinium-based MR contrast media, such as MultiHance, Omniscan, Magnevist (currently not marketed) and Optimark (no longer marketed in Spain), the clinical benefits do not outweigh the potential risks derived from their use. AEMPS recommends to suspend its marketing for general use based on the retention of these compounds in the brain. On the other hand, the AEMPS justifies the maintenance of Primovist and MultiHance for liver studies, and Magnevist of intra-articular administration (not commercialized in Spain), and justified the almost exclusive use of macrocyclic structure contrasts (Gadovist, ProHance and Dotarem). However, this retention is known to be different for each of the contrast media. All existing gadolinium contrasts agents have a distribution phase with tissue retention, due to a very slow exchange, in the interstitium of bone, skin, kidney, brain and other organs. The existence of histological effects or clinical symptoms associated with the accumulation of these trace amounts of gadolinium has not been demonstrated. The major toxicological concern with these contrast agents is related to nephrogenic systemic fibrosis (NSF). Since the safety profiles are mainly related to the interstitial retention space in the tissues, it does not seem justified to actually exclude contrast media that do not have cases related to the NSF. Based on all of this, we disagree with the latest AEMPS recommendation suggesting the marketing stoppage of linear agents without considering the individual retention profiles. This recommendation is not based neither on the data nor existing knowledge about the retention, relaxivity and clinical efficiency of the Gd compounds. It is therefore necessary to carry out prospective studies on the histological and clinical relevance of these organic Gd deposits (AU)

Lesions Associated With Calcium Gluconate Extravasation: Presentation of 5 Clinical Cases and Analysis of Cases Published.

INTRODUCTION: Calcium gluconate extravasation is a process, which, while not common, occurs more frequently in neonatal intensive care units. The aim of this study is to present a number of cases of calcium gluconate extravasation, which have occurred in our hospital, and to carry out a review of those clinical cases published in the literature to obtain relevant epidemiological data. METHODS: Data were gathered on the medical histories of 5 patients who presented lesions secondary to calcium gluconate extravasation in our center. A review of the literature was also performed to include clinical cases of calcium gluconate extravasation already published. RESULTS: Data were collected on 60 cases published in 37 articles. Most patients (55%) were neonates. The average age of these neonates was 8 days. The commonest location of injuries was the back of the hand and wrist (42%). The 2 most frequent symptoms were the appearance of erythema (65%) and swelling/edema (48%) followed by the appearance of skin necrosis (47%), indurated skin (33%), and yellow-white plaques or papules (33%). Most cases are cured within a period of 3 to 6 months. Fifty percent of patients required surgery, and in 13% of cases, skin grafts were performed. The most frequent histological finding was the presence of calcium deposits. Other histological findings described were the presence of necrosis, lymphohistiocytic infíltrate, and granulomas. Most histological findings were located in the dermis. Most x-rays showing calcium deposits had been performed at 3 to 4 weeks. CONCLUSIONS: Calcium gluconate extravasation is a process, which, although infrequent, is associated with serious skin and soft-tissue lesions, mainly affecting infants. Further studies are needed to determine possible specific procedures to be carried out in these cases.

Extravasation injuries.

It is common for an intravascular catheter to be inserted to administer various types of therapy. Extravasation occurs frequently, and in the most severe cases plastic surgeons are often summoned to assess the extent of the injury and the possibility for reconstruction. The Department of Plastic and Reconstructive Surgery at Oslo University Hospital assesses approximately 15 severe cases of this type each year.

On the Use of DSC-MRI for Measuring Vascular Permeability.

BACKGROUND AND PURPOSE: Contrast agent extravasation has been shown to confound brain tumor perfusion measurements with DSC-MR imaging, necessitating the use of correction techniques (eg, Weisskoff, Bjornerud). Leakage parameters (K2 and K(a)) postulated to reflect vessel permeability can be extracted from these correction methods; however, the biophysical interpretation of these parameters and their relationship to commonly used MR imaging measures of vascular permeability (eg, contrast agent volume transfer constant, [K(trans)]) remain unclear. Given that vascular density, as assessed by blood volume, and vascular permeability, as reflected by K(trans) (and potentially K2 or K(a)), report on unique and clinically informative vascular characteristics, there is a compelling interest to simultaneously assess these features. MATERIALS AND METHODS: We acquired multiecho DSC-MR imaging data, allowing the simultaneous computation and voxelwise comparison of single- and dual-echo derived measures of K2, K(a) and K(trans) in patients with glioma. This acquisition enabled the investigation of competing T1 and T2* leakage effects and TE dependency on these parameters. RESULTS: K2 and K(a) displayed nonsignificant (P = .150 and P = .060, respectively) voxelwise linear correlations with K(trans), while a significant (P < .001) inverse relationship was observed between K2 and Ka (coefficient of determination [r(2)] = 0.466-0.984). Significantly different (P < .005) mean estimates were found between voxels exhibiting predominately T1 and T2* effects for K2 and K(a). K(trans), however, was observed to be similar between these voxels (0.109 versus 0.092 minutes(-1)). Significant differences (P < .001) in extracellular-extravascular volume fraction (v(e)) (0.285 versus 0.167) were also observed between cohorts. Additionally, K2 and K(a) were found to have a significant quadratic relationship (P = .031 and P = .005, respectively) with v(e). CONCLUSIONS: Estimates of vascular permeability in brain tumors may be simultaneously acquired from multiple-echo DSC-MR imaging via K(trans); however, caution should be used in assuming a similar relationship for K2 and K(a).

Fully automatic segmentation of fluorescein leakage in subjects with diabetic macular edema.

PURPOSE: To create and validate software to automatically segment leakage area in real-world clinical fluorescein angiography (FA) images of subjects with diabetic macular edema (DME). METHODS: Fluorescein angiography images obtained from 24 eyes of 24 subjects with DME were retrospectively analyzed. Both video and still-frame images were obtained using a Heidelberg Spectralis 6-mode HRA/OCT unit. We aligned early and late FA frames in the video by a two-step nonrigid registration method. To remove background artifacts, we subtracted early and late FA frames. Finally, after postprocessing steps, including detection and inpainting of the vessels, a robust active contour method was utilized to obtain leakage area in a 1500-µm-radius circular region centered at the fovea. Images were captured at different fields of view (FOVs) and were often contaminated with outliers, as is the case in real-world clinical imaging. Our algorithm was applied to these images with no manual input. Separately, all images were manually segmented by two retina specialists. The sensitivity, specificity, and accuracy of manual interobserver, manual intraobserver, and automatic methods were calculated. RESULTS: The mean accuracy was 0.86 ± 0.08 for automatic versus manual, 0.83 ± 0.16 for manual interobserver, and 0.90 ± 0.08 for manual intraobserver segmentation methods. CONCLUSIONS: Our fully automated algorithm can reproducibly and accurately quantify the area of leakage of clinical-grade FA video and is congruent with expert manual segmentation. The performance was reliable for different DME subtypes. This approach has the potential to reduce time and labor costs and may yield objective and reproducible quantitative measurements of DME imaging biomarkers.

Cholinergic neurotransmission links solitary chemosensory cells to nasal inflammation.

Solitary chemosensory cells (SCCs) of the nasal cavity are specialized epithelial chemosensors that respond to irritants through the canonical taste transduction cascade involving Gα-gustducin and transient receptor potential melastatin 5. When stimulated, SCCs trigger peptidergic nociceptive (or pain) nerve fibers, causing an alteration of the respiratory rate indicative of trigeminal activation. Direct chemical excitation of trigeminal pain fibers by capsaicin evokes neurogenic inflammation in the surrounding epithelium. In the current study, we test whether activation of nasal SCCs can trigger similar local inflammatory responses, specifically mast cell degranulation and plasma leakage. The prototypical bitter compound, denatonium, a well-established activator of SCCs, caused significant inflammatory responses in WT mice but not mice with a genetic deletion of elements of the canonical taste transduction cascade, showing that activation of taste signaling components is sufficient to trigger local inflammation. Chemical ablation of peptidergic trigeminal fibers prevented the SCC-induced nasal inflammation, indicating that SCCs evoke inflammation only by neural activity and not by release of local inflammatory mediators. Additionally, blocking nicotinic, but not muscarinic, acetylcholine receptors prevents SCC-mediated neurogenic inflammation for both denatonium and the bacterial signaling molecule 3-oxo-C12-homoserine lactone, showing the necessity for cholinergic transmission. Finally, we show that the neurokinin 1 receptor for substance P is required for SCC-mediated inflammation, suggesting that release of substance P from nerve fibers triggers the inflammatory events. Taken together, these results show that SCCs use cholinergic neurotransmission to trigger peptidergic trigeminal nociceptors, which link SCCs to the neurogenic inflammatory pathway.

Management of extravasation injuries: a focused evaluation of noncytotoxic medications.

Extravasations are common manifestations of iatrogenic injury that occur in patients requiring intravenous delivery of known vesicants. These injuries can contribute substantially to patient morbidity, cost of therapy, and length of stay. Many different mechanisms are behind the tissue damage during extravasation injuries. In general, extravasations consist of four different subtypes of tissue injury: vasoconstriction, osmotic, pH related, and cytotoxic. Recognition of high-risk patients, appropriate cannulation technique, and monitoring of higher risk materials remain the standard of care for the prevention of extravasation injury. Prompt interdisciplinary action is often necessary for the treatment of extravasation injuries. Knowledge of the mechanism of extravasation-induced tissue injury, agents for reversal, and appropriate nonpharmacologic treatment methods is essential. The best therapeutic agent for treatment of vasopressor extravasation is intradermal phentolamine. Topical vasodilators and intradermal terbutaline may provide relief. Intradermal hyaluronidase has been effective for hyperosmotic extravasations, although its use largely depends on the risk of tissue injury and the severity of extravasation. Among the hyperosmotic agents, calcium extravasation is distinctive because it may present as an acute tissue injury or may possess delayed clinical manifestations. Extravasation of acidic or basic materials can produce significant tissue damage. Phenytoin is the prototypical basic drug that causes a clinical manifestation known as purple glove syndrome (PGS). This syndrome is largely managed through preventive and conservative treatment measures. Promethazine is acidic and can cause a devastating extravasation, particularly if administered inadvertently through the arteriolar route. Systemic heparin therapy remains the accepted treatment option for intraarteriolar administration of promethazine. Overall, the evidence for managing extravasations due to noncytotoxic medications is nonexistent or limited to case reports. More research is needed to improve knowledge of patient risk, prompt recognition of the extravasation, and time course for tissue injury, and to develop prevention and treatment strategies for extravasation injuries.

Quantitative volumetry of cement leakage in viscosity-controlled vertebroplasty.

STUDY DESIGN: This study was designed as a cohort study comparing a prospective sample to a historic control group. OBJECTIVE: The aim of the actual trial was to compare the rate of cement leakage by quantitative volumetry comparing viscosity-controlled and non-viscosity-controlled vertebroplasty. SUMMARY OF BACKGROUND DATA: Percutaneous vertebroplasty (PVP) is a widespread safe and effective technique in the treatment of osteoporotic compression fractures and vertebral metastatic lesions. However, cement leakage has been identified as a problem of this technique. The leakage rates are reported to range from 7% to 90%. The main influence factor for leakage has been demonstrated to be cement viscosity. Assessment of appropriate injection viscosity is highly subjective and observer dependent. Viscosity-controlled vertebroplasty (Vertecem system) has been developed to objectively measure cement viscosity before injection. It introduces a viscosimeter to measure the actual cement viscosity before injection into the vertebra, and therefore may prevent leakages resulting from low-viscosity cement injections. Despite more than 800 Pubmed citations on PVP, there is only 1 report on distinct measurement of cement leakage by semiquantitative volumetry. METHODS: A total of 111 vertebrae in 68 patients, in which PVP was performed for osteoporotic fractures, were included. Thirty-seven patients (76 operated vertebrae) were assessed prospectively using the viscosity-controlled vertebroplasty. The results were compared with a retrospective group of 31 patients (35 operated vertebrae) undergoing PVP without using a viscosimeter. RESULTS: : There were no significant differences between the 2 groups in the applied volume of cement per fractured vertebra (P=0.73). The frequency of cement leakage in viscosimete-assisted vertebroplasty was 42.1% and 58.3% in the historic group. Cement leakage into the basivertebral vein (type B), was detected in 6.6% with and in 11.1% without viscosimetry. CONCLUSIONS: The use of viscosity-controlled vertebroplasty led to a decrease in the leakage rate from 58.3% to 42.1%. Leakage into the basivertebral vein with the risk of compression of nerval structures was reduced to almost 50% when viscosimetry was performed. It revealed to be a helpful tool for more unexperienced surgeons to assess the appropriate viscosity for vertebroplasty.

Hyperacute injury marker (HARM) in primary hemorrhage: a distinct form of CNS barrier disruption.

OBJECTIVE: The objective of the study was to characterize a previously unreported form of CNS barrier disruption in intracerebral hemorrhage (ICH): hyperacute injury marker (HARM). METHODS: In this retrospective cohort analysis of patients presenting with primary ICH, precontrast and postcontrast MRI scans obtained within 5 days of symptom onset were analyzed. The presence of CNS barrier disruption was defined by (1) perihematomal or intrahematomal enhancement visualized on postcontrast T1-weighted MRI or (2) HARM: sulcal or ventricular hyperintensity visualized on postcontrast fluid-attenuated inversion recovery sequences (graded on a 5-point scale). RESULTS: Forty-six patients were included in the analysis. Mean age was 65 years, median NIH Stroke Scale score was 7, and mean ICH volume was 12.2 mL (range 0.3-46.9 mL). HARM was visualized in 85% of patients, and this was moderate to severe in 50%. In all cases, the sulcal enhancement was noncontiguous with the hematoma. Of those patients with postcontrast T1-weighted imaging, perihematomal or intrahematomal contrast enhancement was visualized in 75% of patients. CONCLUSIONS: This study demonstrates that HARM occurs in intracerebral hemorrhage and that it likely represents a second type of CNS barrier disruption distinct from parenchymal postcontrast T1-weighted enhancement. Similar to T1 enhancement, this phenomenon may serve as a clinically useful biomarker to test therapies aimed at stabilizing acute ICH and CNS barrier disruption. Future studies are needed to further define the time course and prognostic implications of this finding.

A new approach to management of intravenous infiltration in pediatric patients: pathophysiology, classification, and treatment.

Intravenous (IV) infiltrations are problematic complications associated with hospitalization. Treatment methods vary greatly on the basis of physician judgment and institutional protocol, and uniform methods for effective prevention and economical treatment of IV infiltrations are necessary. Common in neonatal and infant patients, infiltration is frequently associated with cosmetic and functional complications. Medicolegal issues for physicians and institutions also accompany many cases of infiltration. This article discusses the pathophysiology of IV infiltrations. It also presents a new scale for IV infiltrations that more accurately reflects issues common to neonatal and pediatric patients and describes a novel, noninvasive treatment. A quantitative study of the decrease in morbidity after implementing this protocol will be conducted pending institutional approval.

[Quantification of fluorescein angiography in patients with non-arteritic anterior ischemic optic neuropathy]. / Quantifizierung von Fluoreszenzangiographien bei Patienten mit nichtarteriitischer anteriorer ischämischer Optikusneuropathie.

PURPOSE: The aim of this study was to evaluate the retinal hemodynamics and optic disc leakage by fluorescein angiography in patients with non-arteritic anterior ischemic optic neuropathy (NAION) and to correlate fluorescein angiography findings with the extent and topography of visual field loss. METHODS: A total of 26 patients with acute NAION were included in the study. Fluorescein angiograms were performed by means of a scanning laser ophthalmoscope. The extent of early-phase optic disc leakage was assessed using a semiquantitative approach (focal versus diffuse type of leakage). Retinal arteriovenous passage (AVP) times were measured using dye dilution curves and digital image analysis for each hemisphere. The number of defective visual field points (StatPac: p<0.5%, uncorrected deviation plot) were evaluated (30/2 SITA, Humphrey-Zeiss) for the hemifields and different sectors. RESULTS: In this study of patients with NAION the mean AVP was 1.79 s±0.43 which was not significantly correlated to the number of defective points. Furthermore, AVP was not significantly different in focal versus diffuse optic disc leakage. The number of defective points were not significantly different in focal versus diffuse leakage of the optic disc (p=0.57). CONCLUSION: Retinal perfusion is not linked to the type and topography of disc leakage or the extent and topography of visual field damage in NAION. A global circulatory disorder e.g. due to a compartment syndrome of the optic nerve might account for these results.

Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects.

The success of an effective drug delivery system using liposomes for solid tumor targeting based on EPR effects is highly dependent on both size ranging from 100-200 nm in diameter and prolonged circulation half-life in the blood. A major development was the synthesis of PEG-liposomes with a prolonged circulation time in the blood. Active targeting of immunoliposomes to the solid tumor tissue can be achieved by the Fab' fragment which is better than whole IgG in terms of designing PEG-immunoliposomes with prolonged circulation. For intracellular targeting delivery to solid tumors based on EPR effects, transferrin-PEG-liposomes can stay in blood circulation for a long time and extravasate into the extravascular of tumor tissue by the EPR effect as PEG-liposomes. The extravasated transferrin-PEG-liposomes can maintain anti cancer drugs in interstitial space for a longer period, and deliver them into the cytoplasm of tumor cells via transferrin receptor-mediated endocytosis. Transferrin-PEG-liposomes improve the safety and efficacy of anti cancer drug by both passive targeting by prolonged circulation and active targeting by transferrin.

A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the PEG dilemma.

Gene and nucleic acid therapy are expected to play a major role in the next generation of medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel non-viral gene delivery system. Poly(ethylene glycol) (PEG)ylation is a useful method for achieving a longer circulation time for delivery of the MEND to a tumour via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity for the delivery system. For successful gene delivery for cancer treatment, the crucial issue associated with the use of PEG, the 'PEG dilemma' must be addressed. In this review, we describe the development and applications of MEND, and discuss strategies for overcoming the PEG dilemma, based on the manipulation of intracellular trafficking of cellular uptake and endosomal release using functional devices such as specific ligands, cleavable PEG systems and endosomal fusogenic/disruptic peptides.

PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect.

As mortality due to cancer continues to rise, advances in nanotechnology have significantly become an effective approach for achieving efficient drug targeting to tumour tissues by circumventing all the shortcomings of conventional chemotherapy. During the past decade, the importance of polymeric drug-delivery systems in oncology has grown exponentially. In this context, poly(lactic-co-glycolic acid) (PLGA) is a widely used polymer for fabricating 'nanoparticles' because of biocompatibility, long-standing track record in biomedical applications and well-documented utility for sustained drug release, and hence has been the centre of focus for developing drug-loaded nanoparticles for cancer therapy. Such PLGA nanoparticles have also been used to develop proteins and peptides for nanomedicine, and nanovaccines, as well as a nanoparticle-based drug- and gene-delivery system for cancer therapy, and nanoantigens and growth factors. These drug-loaded nanoparticles extravasate through the tumour vasculature, delivering their payload into the cells by the enhanced permeability and retention (EPR) effect, thereby increasing their therapeutic effect. Ongoing research about drug-loaded nanoparticles and their delivery by the EPR effect to the tumour tissues has been elucidated in this review with clarity.