Lipids with negative spontaneous curvature decrease the solubility of the cancer drug paclitaxel in liposomes.

Paclitaxel (PTX) is a hydrophobic small-molecule cancer drug that loads into the membrane (tail) region of lipid carriers such as liposomes and micelles. The development of improved lipid-based carriers of PTX is an important objective to generate chemotherapeutics with fewer side effects. The lipids 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and glyceryl monooleate (GMO) show propensity for fusion with other lipid membranes, which has led to their use in lipid vectors of nucleic acids. We hypothesized that DOPE and GMO could enhance PTX delivery to cells through a similar membrane fusion mechanism. As an important measure of drug carrier performance, we evaluated PTX solubility in cationic liposomes containing GMO or DOPE. Solubility was determined by time-dependent kinetic phase diagrams generated from direct observations of PTX crystal formation using differential-interference-contrast optical microscopy. Remarkably, PTX was much less soluble in these liposomes than in control cationic liposomes containing univalent cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), which are not fusogenic. In particular, PTX was not substantially soluble in GMO-based cationic liposomes. The fusogenicity of DOPE and GMO is related to the negative spontaneous curvature of membranes containing these lipids, which drives formation of nonlamellar self-assembled phases (inverted hexagonal or gyroid cubic). To determine whether PTX solubility is governed by lipid membrane structure or by local intermolecular interactions, we used synchrotron small-angle X-ray scattering. To increase the signal/noise ratio, we used DNA to condense the lipid formulations into lipoplex pellets. The results suggest that local intermolecular interactions are of greater importance and that the negative spontaneous curvature-inducing lipids DOPE and GMO are not suitable components of liposomal carriers for PTX delivery.

Accurate neonatal heart rate monitoring using a new wireless, cap mounted device.

AIM: A device for newborn heart rate (HR) monitoring at birth that is compatible with delayed cord clamping and minimises hypothermia risk could have advantages over current approaches. We evaluated a wireless, cap mounted device (fhPPG) for monitoring neonatal HR. METHODS: A total of 52 infants on the neonatal intensive care unit (NICU) and immediately following birth by elective caesarean section (ECS) were recruited. HR was monitored by electrocardiogram (ECG), pulse oximetry (PO) and the fhPPG device. Success rate, accuracy and time to output HR were compared with ECG as the gold standard. Standardised simulated data assessed the fhPPG algorithm accuracy. RESULTS: Compared to ECG HR, the median bias (and 95% limits of agreement) for the NICU was fhPPG -0.6 (-5.6, 4.9) vs PO -0.3 (-6.3, 6.2) bpm, and ECS phase fhPPG -0.5 (-8.7, 7.7) vs PO -0.1 (-7.6, 7.1) bpm. In both settings, fhPPG and PO correlated with paired ECG HRs (both R2  = 0.89). The fhPPG HR algorithm during simulations demonstrated a near-linear correlation (n = 1266, R2  = 0.99). CONCLUSION: Monitoring infants in the NICU and following ECS using a wireless, cap mounted device provides accurate HR measurements. This alternative approach could confer advantages compared with current methods of HR assessment and warrants further evaluation at birth.

The impact of post-fall huddles on repeat fall rates and perceptions of safety culture: a quasi-experimental evaluation of a patient safety demonstration project.

BACKGROUND: Conducting post-fall huddles is considered an integral component of a fall-risk-reduction program. However, there is no evidence linking post-fall huddles to patient outcomes or perceptions of teamwork and safety culture. The purpose of this study is to determine associations between conducting post-fall huddles and repeat fall rates and between post-fall huddle participation and perceptions of teamwork and safety culture. METHODS: During a two-year demonstration project, we developed a system for 16 small rural hospitals to report, benchmark, and learn from fall events, and we trained them to conduct post-fall huddles. To calculate a hospital's repeat fall rate, we divided the total number of falls reported by the hospital by the number of unique medical record numbers associated with each fall. We used Spearman correlations with exact P values to determine the association between the proportion of falls followed by a huddle and the repeat fall rate. At study end, we used the TeamSTEPPS® Teamwork Perceptions Questionnaire (T-TPQ) to assess perceptions of teamwork support for fall-risk reduction and the Hospital Survey on Patient Safety Culture (HSOPS) to assess perceptions of safety culture. We added an item to the T-TPQ for respondents to indicate the number of post-fall huddles in which they had participated. We used a binary logistic regression with a logit link to examine the effect of participation in post-fall huddles on respondent-level percent positive T-TPQ and HSOPS scores. We accounted for clustering of respondents within hospitals with random effects using the GLIMMIX procedure in SAS/STAT. RESULT: Repeat fall rates were negatively associated with the proportion of falls followed by a huddle. As compared to hospital staff who did not participate in huddles, those who participated in huddles had more positive perceptions of four domains of safety culture and how team structure, team leadership, and situation monitoring supported fall-risk reduction. CONCLUSIONS: Post-fall huddles may reduce the risk of repeat falls. Staff who participate in post-fall huddles are likely to have positive perceptions of teamwork support for fall-risk reduction and safety culture because huddles are a team-based approach to reporting, adapting, and learning.

Disease outcomes in a cohort of women in Ireland infected by hepatitis C-contaminated anti-D immunoglobulin during 1970s.

BACKGROUND & AIM: In the mid-1990s, a group of Rh negative women was diagnosed with hepatitis C virus (HCV) genotype 1b infection, following administration of contaminated anti-D immunoglobulin in 1977-79. We aimed to describe their disease history and estimate the effect of selected host and treatment factors on disease progression. METHODS: We conducted a cohort study on the women infected with HCV. Information was collected from records at seven HCV treatment centres on demographics, treatment and health outcomes up to the 31st December 2013. We calculated cumulative incidence, case fatality, and sub hazard ratios (SHR) for disease progression using competing risks regression. RESULTS: Six hundred and eighty-two patients were included in the study. Among the chronically infected patients (n=374), 35% completed interferon-based antiviral treatment; 42% of whom had a sustained virological response. At the end of 2013, 19%, 1.9%, and 4.9% of chronically infected patients had developed cirrhosis, hepatocellular carcinoma, and liver-related death, respectively, compared with 10%, 0.8%, and 2.4% at the end of 2008. At the end of 2013, 321 (86%) of the chronically infected patients remained alive, 247 (77%) of whom were still chronically infected. Factors associated with increased cirrhosis rates included high alcohol intake (aSHR=4.9 [2.5-9.5]) and diabetes mellitus (aSHR=5.0 [2.9-8.8]). CONCLUSIONS: Development of liver-related outcomes accelerated with time, with the risk of cirrhosis, hepatocellular carcinoma, and liver-related death doubling in the last five years of follow-up, particularly in women with high alcohol consumption and diabetes mellitus. We recommend that patients with chronic HCV infection be advised of the additive harmful effect of alcohol, and that data be collected on this cohort after a further five years to analyse the effect of subsequent antiviral treatment during this rapidly evolving period in HCV treatment history. LAY SUMMARY: In the mid-1990s, a group of women were diagnosed with chronic hepatitis C virus (HCV) infection following receipt of contaminated anti-D immunoglobulin between 1977 and 1979 in Ireland. Seventy-two (19%) developed cirrhosis and 18 had died from liver-related causes (5%) after 36years of infection. Disease progression accelerated in the last five years of follow-up, particularly in women with diabetes mellitus and high alcohol consumption. We recommend that patients with chronic HCV infection be advised of the additive harmful effect of high alcohol consumption.

Anhydrobiosis: An Unsolved Problem with Applications in Human Welfare.

Anhydrobiosis (Life Without Water) has been known for millennia, but the underlying mechanisms have not been understood until recent decades, and we have achieved only a partial understanding. One of the chief sites of damage from dehydration is membranes, and we and others have provided evidence that this damage may be obviated by the production of certain sugars, particularly trehalose. The sugar stabilizes membranes by preventing fusion and fluidizing the dry bilayers. The mechanism by which this is accomplished has been controversial, and I review that controversy here. In the past decade evidence is accumulating for a role of stress proteins in addition to or as a substitute for trehalose. Genomic studies on anhydrobiotes are yielding rapid progress. Also in the past decade, numerous uses for trehalose in treating human diseases have been proposed, some of which are in clinical testing. I conclude that the mechanisms underlying anhydrobiosis are more complex than we thought 20 years ago, but progress is being made towards elucidating those mechanisms.

Correlates of hepcidin and NTBI according to HFE status in patients referred to a liver centre.

BACKGROUND/AIMS: Innately low hepcidin levels lead to iron overload in HFE-associated hereditary haemochromatosis. METHODS: This study compared hepcidin and non-transferrin bound iron (NTBI) levels in untreated iron-loaded and non-iron-loaded C282Y homozygotes to levels in C282Y/H63D compound heterozygotes and individuals with other HFE genotypes associated with less risk of iron overload. RESULTS: As the genotypic risk for iron overload increased, transferrin saturation and serum NTBI levels increased while serum hepcidin levels decreased. Overweight and obese male C282Y homozygotes had significantly higher hepcidin levels than male C282Y homozygotes with a normal BMI. Pearson product-moment analysis showed that serum hepcidin levels significantly correlated with HFE status, serum ferritin, age, NTBI, transferrin saturation, gender and BMI. Subsequent multiple regression analysis showed that HFE status and serum ferritin were significant independent correlates of serum hepcidin levels. CONCLUSIONS: In summary, this study has shown that while serum ferritin and HFE status are the most important determinants of hepcidin levels, factors such age, gender, BMI, transferrin saturation and NTBI all interact closely in the matrix of homeostatic iron balance.

Pegylated interferon-α induced hypoferremia is associated with the immediate response to treatment in hepatitis C.

UNLABELLED: Pegylated interferon-α (PEG-IFN-α) forms an integral part of the current treatment for hepatitis C virus (HCV) infection. PEG-IFN-α suppresses HCV production by augmenting the innate antiviral immune response. Recent studies have reported the induction of hepcidin, the iron regulatory hormone, by IFN-α in vitro. As hepcidin plays an important role in innate immunity, we hypothesized that this finding may be of clinical relevance to HCV and investigated the changes in iron homeostasis during the first 24 hours of treatment. Blood samples were obtained from HCV patients immediately prior to and 6, 12, and 24 hours following the first dose of PEG-IFN-α/ribavirin (RBV). Samples were analyzed for hepcidin, cytokine, iron levels, and HCV viral load, and hepcidin messenger RNA (mRNA) expression was quantified in peripheral blood mononuclear cells. Hepcidin induction by IFN-α was further analyzed in cell culture. In HCV patients a single dose of PEG-IFN-α/RBV resulted in a significant increase in serum hepcidin, peaking at 12 hours, coinciding with a 50% reduction in serum iron and transferrin saturation over the 24-hour period. Patients with a ≥ 2 log decline in HCV viral load over the first 24 hours had significantly lower SI and TS levels at 12 and 24 hours. Moreover, 24-hour SI levels were an independent predictor of the immediate HCV viral decline, an indicator of ultimate treatment outcome. In cell culture, a direct induction of hepcidin by IFN-α was seen, controlled by the STAT3 transcription factor. CONCLUSION: Hepcidin induction occurs following the initiation of PEG-IFN-α treatment for HCV, and is mediated by way of STAT3 signaling. The subsequent hypoferremia was greatest in those with the most significant decline in viral load, identifying systemic iron withdrawal as a marker of immediate interferon-α efficacy in HCV patients.

Laser doppler blood flow imaging using a CMOS imaging sensor with on-chip signal processing.

The first fully integrated 2D CMOS imaging sensor with on-chip signal processing for applications in laser Doppler blood flow (LDBF) imaging has been designed and tested. To obtain a space efficient design over 64 × 64 pixels means that standard processing electronics used off-chip cannot be implemented. Therefore the analog signal processing at each pixel is a tailored design for LDBF signals with balanced optimization for signal-to-noise ratio and silicon area. This custom made sensor offers key advantages over conventional sensors, viz. the analog signal processing at the pixel level carries out signal normalization; the AC amplification in combination with an anti-aliasing filter allows analog-to-digital conversion with a low number of bits; low resource implementation of the digital processor enables on-chip processing and the data bottleneck that exists between the detector and processing electronics has been overcome. The sensor demonstrates good agreement with simulation at each design stage. The measured optical performance of the sensor is demonstrated using modulated light signals and in vivo blood flow experiments. Images showing blood flow changes with arterial occlusion and an inflammatory response to a histamine skin-prick demonstrate that the sensor array is capable of detecting blood flow signals from tissue.

Lipids with negative spontaneous curvature decrease the solubility of the cancer drug paclitaxel in liposomes.

Paclitaxel (PTX) is a hydrophobic small-molecule cancer drug that loads into the membrane (tail) region of lipid carriers such as liposomes and micelles. The development of improved lipid-based carriers of PTX is an important objective to generate chemotherapeutics with fewer side effects. The lipids 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and glyceryl monooleate (GMO) show propensity for fusion with other lipid membranes, which has led to their use in lipid vectors of nucleic acids. We hypothesized that DOPE and GMO could enhance PTX delivery to cells through a similar membrane fusion mechanism. As an important measure of drug carrier performance, we evaluated PTX solubility in cationic liposomes containing GMO or DOPE. Solubility was determined by time-dependent kinetic phase diagrams generated from direct observations of PTX crystal formation using differential-interference-contrast optical microscopy. Remarkably, PTX was much less soluble in these liposomes than in control cationic liposomes containing univalent cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), which are not fusogenic. In particular, PTX was not substantially soluble in GMO-based cationic liposomes. The fusogenicity of DOPE and GMO is related to the negative spontaneous curvature of membranes containing these lipids, which drives formation of nonlamellar self-assembled phases (inverted hexagonal or gyroid cubic). We used synchrotron small-angle x-ray scattering to determine whether PTX solubility is governed by lipid membrane structure (condensed with DNA in pellet form) or by local intermolecular interactions. The results suggest that local intermolecular interactions are of greater importance and that the negative spontaneous curvature-inducing lipids DOPE and GMO are not suitable components of lipid carriers for PTX delivery regardless of carrier structure.

Feasibility of a Novel ECG Electrode Placement Method in Newborn Infants.

BACKGROUND: International newborn resuscitation guidelines recommend electrocardiogram (ECG) heart rate (HR) monitoring at birth. We evaluated the application time of pre-set ECG electrodes fixed to a polyethene patch allowing adhesive-free attachment to the wet skin of the newborn chest. OBJECTIVES: Using a three-electrode pre-set ECG patch configuration, application success was calculated using video analysis and measured at three time points, the time to (1) apply electrodes; (2) detect recognizable QRS complexes after application; and (3) display a HR after application. METHOD: A prospective observational study in two UK tertiary maternity units was undertaken with 71 newborns including 23 who required resuscitation. RESULTS: The median (IQR) time for ECG patch application was 8 (6-10) seconds, detection of recognizable QRS complexes 8 (2-12) seconds, and time to output HR was 23 (15-37) seconds. CONCLUSION: Pre-set ECG chest electrodes allow rapid HR information at birth without electrode detachment or compromising skin integrity.

Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis.

UNLABELLED: Hereditary hemochromatosis (HH) is a common inherited iron overload disorder. The vast majority of patients carry the missense Cys282Tyr mutation of the HFE gene. Hepcidin, the central regulator of iron homeostasis, is deficient in HH, leading to unchecked iron absorption and subsequent iron overload. The bone morphogenic protein (BMP)/small mothers against decapentaplegic (Smad) signaling cascade is central to the regulation of hepcidin. Recent data from HH mice models indicate that this pathway may be defective in the absence of the HFE protein. Hepatic BMP/Smad signaling has not been characterized in a human HFE-HH cohort to date. Hepatic expression of BMP/Smad-related genes was examined in 20 HFE-HH males with significant iron overload, and compared to seven male HFE wild-type controls using quantitative real-time reverse transcription polymerase chain reaction. Hepatic expression of BMP6 was appropriately elevated in HFE-HH compared to controls (P = 0.02), likely related to iron overload. Despite this, no increased expression of the BMP target genes hepcidin and Id1 was observed, and diminished phosphorylation of Smad1/Smad5/Smad8 protein relative to iron burden was found upon immunohistochemical analysis, suggesting that impaired BMP signaling occurs in HFE-HH. Furthermore, Smad6 and Smad7, inhibitors of BMP signaling, were up-regulated in HFE-HH compared to controls (P = 0.001 and P = 0.018, respectively). CONCLUSION: New data arising from this study suggest that impaired BMP signaling underlies the hepcidin deficiency of HFE-HH. Moreover, the inhibitory Smads, Smad6, and Smad7 are identified as potential disruptors of this signal and, hence, contributors to the pathogenesis of this disease.

Smartphone monitoring of in-ambulance vibration and noise.

Transferring sick premature infants between hospitals increases the risk of severe brain injury, potentially linked to the excessive exposure to noise, vibration and driving-related accelerations. One method of reducing these levels may be to travel along smoother and quieter roads at an optimal speed, however this requires mass data on the effect of roads on the environment within ambulances. An app for the Android operating system has been developed for the purpose of recording vibration, noise levels, location and speed data during ambulance journeys. Smartphone accelerometers were calibrated using sinusoidal excitation and the microphones using calibrated pink noise. Four smartphones were provided to the local neonatal transport team and mounted on their neonatal transport systems to collect data. Repeatability of app recordings was assessed by comparing 37 journeys, made during the study period, along an 8.5 km single carriageway. The smartphones were found to have an accelerometer accurate to 5% up to 55 Hz and microphone accurate to 0.8 dB up to 80 dB. Use of the app was readily adopted by the neonatal transport team, recording more than 97,000 km of journeys in 1 year. To enable comparison between journeys, the 8.5 km route was split into 10 m segments. Interquartile ranges for vehicle speed, vertical acceleration and maximum noise level were consistent across all segments (within 0.99 m . s-1, 0.13 m · s-2 and 1.4 dB, respectively). Vertical accelerations registered were representative of the road surface. Noise levels correlated with vehicle speed. Android smartphones are a viable method of accurate mass data collection for this application. We now propose to utilise this approach to reduce potential harmful exposure, from vibration and noise, by routing ambulances along the most comfortable roads.

A tribute to Dr. Serge N. Timasheff, our mentor.

Dr. Serge N. Timasheff, our mentor and friend, passed away in 2019. This article is a collection of tributes from his postdoctoral fellows, friends, and daughter, who all have been associated with or influenced by him or his research. Dr. Timasheff is a pioneer of research on thermodynamic linkage between ligand interaction and macromolecular reaction. We all learned a great deal from Dr. Timasheff, not only about science but also about life.

Assessment of a Program for SARS-CoV-2 Screening and Environmental Monitoring in an Urban Public School District.

Importance: Scalable programs for school-based SARS-CoV-2 testing and surveillance are needed to guide in-person learning practices and inform risk assessments in kindergarten through 12th grade settings. Objectives: To characterize SARS-CoV-2 infections in staff and students in an urban public school setting and evaluate test-based strategies to support ongoing risk assessment and mitigation for kindergarten through 12th grade in-person learning. Design, Setting, and Participants: This pilot quality improvement program engaged 3 schools in Omaha, Nebraska, for weekly saliva polymerase chain reaction testing of staff and students participating in in-person learning over a 5-week period from November 9 to December 11, 2020. Wastewater, air, and surface samples were collected weekly and tested for SARS-CoV-2 RNA to evaluate surrogacy for case detection and interrogate transmission risk of in-building activities. Main Outcomes and Measures: SARS-CoV-2 detection in saliva and environmental samples and risk factors for SARS-CoV-2 infection. Results: A total of 2885 supervised, self-collected saliva samples were tested from 458 asymptomatic staff members (mean [SD] age, 42.9 [12.4] years; 303 women [66.2%]; 25 Black or African American [5.5%], 83 Hispanic [18.1%], 312 White [68.1%], and 35 other or not provided [7.6%]) and 315 students (mean age, 14.2 [0.7] years; 151 female students [48%]; 20 Black or African American [6.3%], 201 Hispanic [63.8%], 75 White [23.8%], and 19 other race or not provided [6.0%]). A total of 46 cases of SARS-CoV-2 (22 students and 24 staff members) were detected, representing an increase in cumulative case detection rates from 1.2% (12 of 1000) to 7.0% (70 of 1000) among students and from 2.1% (21 of 1000) to 5.3% (53 of 1000) among staff compared with conventional reporting mechanisms during the pilot period. SARS-CoV-2 RNA was detected in wastewater samples from all pilot schools as well as in air samples collected from 2 choir rooms. Sequencing of 21 viral genomes in saliva specimens demonstrated minimal clustering associated with 1 school. Geographical analysis of SARS-CoV-2 cases reported district-wide demonstrated higher community risk in zip codes proximal to the pilot schools. Conclusions and Relevance: In this study of staff and students in 3 urban public schools in Omaha, Nebraska, weekly screening of asymptomatic staff and students by saliva polymerase chain reaction testing was associated with increased SARS-CoV-2 case detection, exceeding infection rates reported at the county level. Experiences differed among schools, and virus sequencing and geographical analyses suggested a dynamic interplay of school-based and community-derived transmission risk. Collectively, these findings provide insight into the performance and community value of test-based SARS-CoV-2 screening and surveillance strategies in the kindergarten through 12th grade educational setting.

Macroscopic domain formation during cooling in the platelet plasma membrane: an issue of low cholesterol content.

There has been ample debate on whether cell membranes can present macroscopic lipid domains as predicted by three-component phase diagrams obtained by fluorescence microscopy. Several groups have argued that membrane proteins and interactions with the cytoskeleton inhibit the formation of large domains. In contrast, some polarizable cells do show large regions with qualitative differences in lipid fluidity. It is important to ask more precisely, based on the current phase diagrams, under what conditions would large domains be expected to form in cells. In this work we study the thermotropic phase behavior of the platelet plasma membrane by FTIR, and compare it to a POPC/Sphingomyelin/Cholesterol model representing the outer leaflet composition. We find that this model closely reflects the platelet phase behavior. Previous work has shown that the platelet plasma membrane presents inhomogeneous distribution of DiI18:0 at 24 degrees C, but not at 37 degrees C, which suggests the formation of macroscopic lipid domains at low temperatures. We show by fluorescence microscopy, and by comparison with published phase diagrams, that the outer leaflet model system enters the macroscopic domain region only at the lower temperature. In addition, the low cholesterol content in platelets ( approximately 15 mol%), appears to be crucial for the formation of large domains during cooling.

Finding Comfortable Routes for Ambulance Transfers of Newborn Infants.

Early inter-hospital ambulance transport of premature babies is associated with more severe brain injury. The mechanism is unclear, but they are exposed to excessive noise and vibration. Smart-routing may help minimise these exposure levels and potentially improve outcomes.An app for Android smartphones was developed to collect vibration, noise and location data during ambulance journeys. Four smartphones, with the app installed, were provided to the local neonatal transport group to attach to their incubator trolleys. An example of route comparison was performed on the roads used between Nottingham City Hospital (NCH) and Leicester Royal Infirmary (LRI).Almost 1,700 journeys were recorded over the space of a year. 39 of these journeys travelled from NCH to LRI, comprising of 9 different routes. Analysis was performed on all recorded data which travelled along each road. For routes from NCH to LRI, the route with least vibration was also the quickest. Noise levels, however, were found to increase with vehicle speed. Ambulance drivers in the study did not tend to take the quickest, smoothest or quietest route.Android smartphones are a practical method of gathering information about the in-ambulance environment. Routes were found to vary in vibration, noise and speed, suggesting these could be minimised. The next step is to combine recorded and clinical data to try and define an ideal neonatal comfort metric which can then be fed into the routing. Roll-out of the app around the UK is also planned.Clinical relevance-Transferring preterm neonatal infants to specialist units lead to worse outcomes. By reducing the levels of vibration and noise the infants are exposed to during transport, we hope to improve outcomes.

PEGylation of Paclitaxel-Loaded Cationic Liposomes Drives Steric Stabilization of Bicelles and Vesicles thereby Enhancing Delivery and Cytotoxicity to Human Cancer Cells.

Poly(ethylene glycol) (PEG) is a polymer used widely in drug delivery to create "stealth" nanoparticles (NPs); PEG coatings suppress NP detection and clearance by the immune system and beneficially increase NP circulation time in vivo. However, NP PEGylation typically obstructs cell attachment and uptake in vitro compared to the uncoated equivalent. Here, we report on a cationic liposome (CL) NP system loaded with the hydrophobic cancer drug paclitaxel (PTX) in which PEGylation (i.e., PEG-CLPTX NPs) unexpectedly enhances, rather than diminishes, delivery efficacy and cytotoxicity to human cancer cells. This highly unexpected enhancement occurs even when the PEG-chains coating the NP are in the transition regime between the mushroom and brush conformations. Cryogenic transmission electron microscopy (TEM) of PEG-CLPTX NPs shows that PEG causes the proliferation of a mixture of sterically stabilized nanometer-scale vesicles and anisotropic micelles (e.g., bicelles). Remarkably, the onset of bicelles at sub-monolayer concentrations of the PEG coat has to our knowledge not been previously reported; it was previously thought that PEG-lipid in this composition regime was incorporated into vesicles but did not alter their shape. Confocal microscopy and flow cytometry reveal significantly greater PTX cell uptake from stabilized PEG-CLPTX NPs (vesicles and bicelles) in contrast to bare CLPTX NPs, which can aggregate in cell medium. This underscores the ability of steric stabilization to facilitate NP entry into cells via distinct size-dependent endocytic pathways, some of which cannot transport large NP aggregates into cells. This study highlights the value of understanding how PEGylation alters NP shape and structure, and thus NP efficacy, to design next-generation stealth drug carriers that integrate active cell-targeting strategies into NPs for in vivo delivery.