Predictors of postsurgical retethering in pediatric fatty or tight filum terminale: a systematic review and meta-analysis of 1167 patients.

OBJECTIVE: The objective of this study was to characterize pediatric patients with tight filum terminale (TFT) or fatty filum terminale (FFT) who experienced retethering after transection of the filum, and to determine the risk factors for retethering. METHODS: A systematic review was conducted on May 31, 2023, using PubMed, Google Scholar, SCOPUS, and Web of Science databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies detailing retethering following transection for TFT or FFT. Studies were then screened using the Newcastle-Ottawa Scale for risk of bias assessment. RESULTS: Eleven articles met the inclusion criteria with an overall cohort of 1167 patients evaluated for retethering following transection for TFT or FFT. The combined retethering rate across all retrospective studies was 3.4% (95% CI 1.6%-5.2%). A random-effects model was used to estimate the prevalence of presenting symptoms, with the most common being lower-extremity weakness in the overall cohort (54.5%, 95% CI 32.6%-76.4%) and bowel or bladder dysfunction in the retethered cohort (57.9%, 95% CI 41.1%-74.8%). Patients who experienced retethering had a similar estimated prevalence of low-lying conus (71.1%, 95% CI 45.1%-97.1%) compared with the overall cohort (51.1%, 95% CI 39.3%-63.0%). The most common complication following surgery for the overall cohort was a wound complication (2.7%, 95% CI 0.8%-4.6%). Postoperative CSF leakage (OR 13.8, 95% CI 3.9-49.4) was a strong predictor of retethering. Sensory changes at initial presentation were also found to be a predictor of retethering (OR 2.9, 95% CI 1.3-6.5). Low-lying conus was not predictive of retethering. CONCLUSIONS: Preoperative sensory changes and postsurgical CSF leakage were associated with an increased retethering rate following transection of the filum in cases of tethered cord syndrome secondary to fatty filum terminale.

Presentation, management, and outcomes of pediatric hydrocephalus in Africa: a systematic review and meta-analysis of 12,355 patients.

OBJECTIVE: The prevalence, management, and outcomes of hydrocephalus remain underexplored in Africa. This study aimed to analyze demographic and clinical features, evaluate treatment strategies, and assess neurological outcomes of pediatric hydrocephalus in Africa. METHODS: A systematic review of the literature using the PubMed, Google Scholar, and Web of Science electronic databases was completed according to the PRISMA guidelines to identify articles describing pediatric patients in Africa with hydrocephalus. RESULTS: Seventy-four retrospective and prospective studies and 33 case reports involving 12,355 patients were included. In 54 retrospective articles reporting patient demographics, 53.8% (3926/7297) were male with a mean age of 12.3 months. Nineteen studies reported macrocephaly (80.2%, 1639/2043) as the most common presentation. The etiology of hydrocephalus was reported as postinfectious (41.0%, 2303/5614) across 27 articles and congenital (48.6%, 1246/2563) in 10 articles. Eleven articles reported 46.7% (609/1305) of patients had communicating hydrocephalus while 53.3% (696/1305) had obstructive hydrocephalus. Diagnostic imaging included CT (76.1%, 2435/3202; n = 29 articles), ultrasonography (72.9%, 2043/2801; n = 15 articles), and MRI (44.8%, 549/1225; n = 11 articles). In 51 articles, 83.1% (7365/8865) of patients had ventriculoperitoneal shunting (VPS) while 33 articles described 54.1% (2795/5169) receiving endoscopic third ventriculostomy (ETV) for hydrocephalus surgical management. Postoperative complications included sepsis (6.9%, 29/421; n = 4 articles), surgical site infections (5.1%, 11/218; n = 4 articles), and CSF leaks (2.0%, 15/748; n = 8 articles). Shunt-related complications included infections (4.3%, 117/2717; n = 21 articles) and blockages (4.1%, 34/829; n = 6 studies). In 15 articles, 9.0% (301/3358) of patients with shunts had revisions. The mean follow-up duration was 18.9 ± 16.7 months with an overall mortality rate of 7.4% (397/5383; n = 29 articles). In the analysis of comparative studies, the 160 patients undergoing ETV demonstrated significantly higher odds of a successful operation (OR 1.54, 95% CI 0.51-4.69; p = 0.03) and neurological improvement at last follow-up (OR 3.36, 95% CI 0.46-24.79; p < 0.01) compared with the 158 who received VPS, but no significant differences were observed for complications and mortality between the two groups (p > 0.05). CONCLUSIONS: This review offers a comprehensive summary of pediatric hydrocephalus in Africa, highlighting shunting as the primary treatment. However, the observed variations across studies highlight the need to establish standardized guidelines for reporting patient characteristics, management strategies, and outcomes to ensure consistency and comparability in articles.

Extraneural metastatic ependymoma: distant metastasis to the pleura, lungs, lymph nodes and bone.

Ependymomas are neuroepithelial tumours arising from ependymal cells surrounding the cerebral ventricles that rarely metastasise to extraneural structures. This spread has been reported to occur to the lungs, lymph nodes, liver and bone. We describe the case of a patient with recurrent CNS WHO grade 3 ependymoma with extraneural metastatic disease. He was treated with multiple surgical resections, radiation therapy and salvage chemotherapy for his extraneural metastasis to the lungs, bone, pleural space and lymph nodes.

MRI-based Neuropathy Score Reporting And Data System (NS-RADS): multi-institutional wider-experience usability study of peripheral neuropathy conditions among 32 radiology readers.

OBJECTIVE: To determine the inter-reader reliability and diagnostic performance of classification and severity scales of Neuropathy Score Reporting And Data System (NS-RADS) among readers of differing experience levels after limited teaching of the scoring system. METHODS: This is a multi-institutional, cross-sectional, retrospective study of MRI cases of proven peripheral neuropathy (PN) conditions. Thirty-two radiology readers with varying experience levels were recruited from different institutions. Each reader attended and received a structured presentation that described the NS-RADS classification system containing examples and reviewed published articles on this subject. The readers were then asked to perform NS-RADS scoring with recording of category, subcategory, and most likely diagnosis. Inter-reader agreements were evaluated by Conger's kappa and diagnostic accuracy was calculated for each reader as percent correct diagnosis. A linear mixed model was used to estimate and compare accuracy between trainees and attendings. RESULTS: Across all readers, agreement was good for NS-RADS category and moderate for subcategory. Inter-reader agreement of trainees was comparable to attendings (0.65 vs 0.65). Reader accuracy for attendings was 75% (95% CI 73%, 77%), slightly higher than for trainees (71% (69%, 72%), p = 0.0006) for nerves and comparable for muscles (attendings, 87.5% (95% CI 86.1-88.8%) and trainees, 86.6% (95% CI 85.2-87.9%), p = 0.4). NS-RADS accuracy was also higher than average accuracy for the most plausible diagnosis for attending radiologists at 67% (95% CI 63%, 71%) and for trainees at 65% (95% CI 60%, 69%) (p = 0.036). CONCLUSION: Non-expert radiologists interpreted PN conditions with good accuracy and moderate-to-good inter-reader reliability using the NS-RADS scoring system. CLINICAL RELEVANCE STATEMENT: The Neuropathy Score Reporting And Data System (NS-RADS) is an accurate and reliable MRI-based image scoring system for practical use for the diagnosis and grading of severity of peripheral neuromuscular disorders by both experienced and general radiologists. KEY POINTS: • The Neuropathy Score Reporting And Data System (NS-RADS) can be used effectively by non-expert radiologists to categorize peripheral neuropathy. • Across 32 different experience-level readers, the agreement was good for NS-RADS category and moderate for NS-RADS subcategory. • NS-RADS accuracy was higher than the average accuracy for the most plausible diagnosis for both attending radiologists and trainees (at 75%, 71% and 65%, 65%, respectively).

Association of plexiform and diffuse neurofibromas with malignant peripheral nerve sheath tumor in NF I patients: a whole-body MRI assessment.

OBJECTIVE: The aim of this study is to evaluate neurofibromatosis type 1 (NF1) patients with whole-body MRI (WBMRI) to investigate the frequency of plexiform neurofibromas (pNFs), diffuse neurofibromas (dNFs), and malignant peripheral nerve sheath tumors (MPNSTs). MATERIALS AND METHODS: In this retrospective cross-sectional study, between the years 2015 and 2023, 83 consecutive patients with known NF1 underwent a total of 110 WBMRI screenings for MPNST using a standardized institutional protocol. The lesions are categorized as discrete lesions, pNFs, dNFs, and MPNSTs. Histopathology served as the reference standard for all MPNSTs. RESULTS: Among the 83 patients analyzed, 53 (64%) were women and 30 were men (36%) of ages 36.94±14.43 years (range, 15-66 years). Of the 83 patients, 33 have a positive family history of NF1 and positive genetic studies. Seven of 83 (8%) have only dNF, 20/83 (24%) have pNF, 28/83 (34%) have both dNF and pNF, and 28/83 (34%) have neither. Of the 83 patients, eight (9.6%) were diagnosed with nine total MPNSTs. Age range for patients with MPNSTs at time of diagnosis was 22-51, with an average age of 33.4 years. Only one MPNST (11%) developed from underlying pNF 4 years after WBMRI along the right bronchial tree. Three of eight (37.5%) patients with MPNST died within 5 years of pathologic diagnosis. CONCLUSION: This study suggests the absence of a predisposition for development of MPNST from pNFs and dNFs in the setting of NF1. As such, these lesions may not need special surveillance compared to discrete peripheral nerve sheath tumors.

Comparison between ZOOMit DWI and conventional DWI in the assessment of foot and ankle infection: a prospective study.

OBJECTIVE: The study aimed to compare ZOOMit diffusion-weighted imaging (DWI) MRI with conventional DWI MRI for visualizing small bones in the foot, soft tissue abscesses, and osteomyelitis. MATERIALS AND METHODS: The cohort consisted of a consecutive series of patients with potential foot and ankle infections referred for MR imaging. Patients were imaged using both conventional and ZOOMit DWI in the same setting. Blinded reads were then conducted in separate settings and independent of known clinical diagnosis by two expert radiologists. The results from the reads were compared statistically using paired t-tests and with biopsy specimen analysis, both anatomopathological and microbiological. RESULTS: There was improvement in fat suppression using ZOOMit sequence compared to conventional DWI (p = .001) with no significant difference in motion artifacts (p = .278). ZOOMit had a higher rate of concordance with pathology findings for osteomyelitis (72%, 31/43 cases) compared with conventional DWI (60%, 26/43 cases). ZOOMit also identified 46 additional small bones of the foot and ankle (405/596, 68.0%) than conventional DWI (359/596, 60.2%). Conventional DWI however exhibited a more negative contrast-to-noise ratio (CNR) than ZOOMit (p = 0.001). CONCLUSION: ZOOMit DWI improves distal extremity proton diffusion assessment and helps visualize more bones in the foot, with less image distortion and improved fat saturation at the expense of reduced CNR. This makes it a viable option for assessing lower extremity infections. CLINICAL RELEVANCE STATEMENT: This study highlights the novel utilization of ZOOMit diffusion-weighted imaging (DWI) for the assessment of lower extremity lesions compared to conventional DWI. KEY POINTS: • Distal extremity diffusion-weighted imaging (DWI) is often limited. • ZOOMit DWI displayed improved fat suppression with less motion artifacts and better visualization of the lower extremity bones than conventional DWI. • ZOOMit shows decreased contrast-to-noise ratio than conventional DWI.

Diffusion weighted imaging of extremity bone tumors-inter-reader analysis and incremental value over conventional MR imaging.

OBJECTIVE: To determine whether the addition of diffusion-weighted imaging (DWI) to conventional MRI improves diagnostic accuracy of bone tumor characterization with the hypothesis that the DWI has incremental value in the diagnosis of osseous tumors. METHODS: In this multireader cross-sectional validation study, four musculoskeletal radiologists evaluated osseous tumors blinded to final diagnosis in two rounds-first without DWI or apparent diffusion coefficient (ADC) maps, then months later with these available. Each reader recorded a binary result as to whether the lesion is benign or malignant. Intraclass correlation (ICC) and Conger's κ were used. Diagnostic performance measures including area under the receiver operating curve (AUC) were reported. RESULTS: 133 osseous tumors of the extremities (76 benign, 57 malignant) were tested. Blinded to DWI, average reader sensitivity, specificity, positive-predictive value, and negative-predictive value were 0.83, 0.92, 0.94, and 0.82, respectively. With DWI, the values were 0.85, 0.92, 0.94, and 0.83, respectively. Interreader agreement was good for both rounds (0.67 and 0.71, respectively, p-value > 0.05). Average reader confidence was 4.1 and 4.4, respectively (p-value < 0.001). ADC values and DWI/ADC ratios showed significant differences between benign and malignant tumors. CONCLUSION: DWI and ADC show statistically significantly different values of benign from malignant osseous tumors and mildly increased radiologist confidence with similar interreader reliability. However, given similar diagnostic accuracy, conventional MR imaging is adequate for bone tumor characterization and incremental value of DWI is limited. ADVANCES IN KNOWLEDGE: This paper is the first of its kind to report the use of DWI/ADC ratio for the diagnosis of bone tumors.

Osseous-Tissue Tumor Reporting and Data System With Diffusion-Weighted Imaging of Bone Tumors-An Interreader Analysis and Whether It Adds Incremental Value on Tumor Grading Over Conventional Magnetic Resonance Imaging.

OBJECTIVE: The aim of the study is to determine whether the use of diffusion-weighted imaging (DWI) provides incremental increase in performance in the osseous-tissue tumor reporting and data system (OT-RADS) with the hypothesis that use of DWI improves interreader agreement and diagnostic accuracy. METHODS: In this multireader cross-sectional validation study, multiple musculoskeletal radiologists reviewed osseous tumors with DW images and apparent diffusion coefficient maps. Four blinded readers categorized each lesion using the OT-RADS categorizations. Intraclass correlation (ICC) and Conger κ were used. Diagnostic performance measures including area under the receiver operating curve were reported. These measures were then compared with the previously published work that validated OT-RADS but did not include incremental value assessment of DWI. RESULTS: One hundred thirty-three osseous tumors of the upper and lower extremities (76 benign, 57 malignant) were tested. Interreader agreement for OT-RADS with DWI (ICC = 0.69) was slightly lower (not statistically different) from the previously published work that did not incorporate DWI (ICC = 0.78, P > 0.05). The mean sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating curve including DWI of the 4 readers were 0.80, 0.95, 0.96, 0.79, and 0.91, respectively. In the previously published work without DWI, the mean values of the readers were 0.96, 0.79, 0.78, 0.96, and 0.94, respectively. CONCLUSIONS: The addition of DWI to the OT-RADS system does not allow significantly improved area under the curve diagnostic performance measure. Conventional magnetic resonance imaging can be prudently used for OT-RADS for reliable and accurate characterization of bone tumors.

Establishing a Robust and Reliable Response from a Potent Osmium-Based Photosensitizer Via Lipid Nanoformulation†.

Osmium (Os) based photosensitizers (PSs) are a unique class of nontetrapyrrolic metal-containing PSs that absorb red light. We recently reported a highly potent Os(II) PS, rac-[Os(phen)2 (IP-4T)](Cl)2 , referred to as ML18J03 herein, with light EC50 values as low as 20 pm. ML18J03 also exhibits low dark toxicity and submicromolar light EC50 values in hypoxia in some cell lines. However, owing to its longer oligothiophene chain, ML18J03 is not completely water soluble and forms 1-2 µm sized aggregates in PBS containing 1% DMSO. This aggregation causes variability in PDT efficacy between assays and thus unreliable and irreproducible reports of in vitro activity. To that end, we utilized PEG-modified DPPC liposomes (138 nm diameter) and DSPE-mPEG2000 micelles (10.2 nm diameter) as lipid nanoformulation vehicles to mitigate aggregation of ML18J03 and found that the spectroscopic properties important to biological activity were maintained or improved. Importantly, the lipid formulations decreased the interassay variance between the EC50 values by almost 20-fold, with respect to the unformulated ML18J03 when using broadband visible light excitation (P = 0.0276). Herein, lipid formulations are presented as reliable platforms for more accurate in vitro photocytotoxicity quantification for PSs prone to aggregation (such as ML18J03) and will be useful for assessing their in vivo PDT effects.

Diffusion-weighted MR imaging of musculoskeletal tissues: incremental role over conventional MR imaging in bone, soft tissue, and nerve lesions.

Diffusion-weighted imaging is increasingly becoming popular in musculoskeletal radiology for its incremental role over conventional MR imaging in the diagnostic strategy and assessment of therapeutic response of bone and soft tissue lesions. This article discusses the technical considerations of diffusion-weighted imaging, how to optimize its performance, and outlines the role of this novel imaging in the identification and characterization of musculoskeletal lesions, such as bone and soft tissue tumors, musculoskeletal infections, arthritis, myopathy, and peripheral neuropathy. The readers can use the newly learned concepts from the presented material containing illustrated case examples to enhance their conventional musculoskeletal imaging and interventional practices and optimize patient management, their prognosis, and outcomes.

Acetabular paralabral cysts demonstrating perineural propagation.

OBJECTIVE: Acetabular paralabral cysts are common and are almost always associated with labral tears. Uncommonly, they extend into the periacetabular soft tissues or may propagate along peripheral nerves causing pain and hip dysfunction. The aim was to evaluate the clinical and MRI presentations of such cases including perineural propagation. METHODS: Retrospective cross-sectional study with a search of electronic health records for cases of acetabular paralabral cysts demonstrating perineural propagation was performed. Clinical and MR imaging features were tabulated after re-review by experienced musculoskeletal radiologists, and available outcomes were recorded. Descriptive statistics were performed. RESULTS: 14 cases were recorded. The mean age was 56.9 years (range = 30-79 years) and female:male ratio was 1:2.6. The commonest presenting complaint was hip pain (10/14, 71.4%). Other complaints included groin pain, perineal pain and hip dysfunction. No symptoms were attributed to the acetabular paralabral cyst in 3/14 patients (21.4%). None had foot drop. The cysts were multilocular in all cases and were homogenously T2 hyperintense in 13/14 (92.9%). Labral tears were identified in 11/14 cases (78.6%). The sciatic nerve was most commonly involved in 5/14 cases (35.7%) with the obturator, medial femoral cutaneous nerve, femoral nerve, superior and inferior gluteal nerves also affected.No intervention was undertaken in 9/14 cases (64.3%). 5/14 (35.7%) underwent image guided aspiration and corticosteroid injection. 4/5 such patients reported reduced pain following the procedure. CONCLUSION: Paralabral cysts demonstrating perineural propagation are uncommon and exhibit varied presentations. Most patients who underwent image-guided or surgical interventions reported an improvement in symptoms. ADVANCES IN KNOWLEDGE.: This is the first description of a series of patients with acetabular paralabral cysts demonstrating perineural propagation in the literature. A comprehensive description of their clinical and imaging characteristics and interventions/outcomes where relevant is provided.

Deep-Tissue Activation of Photonanomedicines: An Update and Clinical Perspectives.

With the continued development of nanomaterials over the past two decades, specialized photonanomedicines (light-activable nanomedicines, PNMs) have evolved to become excitable by alternative energy sources that typically penetrate tissue deeper than visible light. These sources include electromagnetic radiation lying outside the visible near-infrared spectrum, high energy particles, and acoustic waves, amongst others. Various direct activation mechanisms have leveraged unique facets of specialized nanomaterials, such as upconversion, scintillation, and radiosensitization, as well as several others, in order to activate PNMs. Other indirect activation mechanisms have leveraged the effect of the interaction of deeply penetrating energy sources with tissue in order to activate proximal PNMs. These indirect mechanisms include sonoluminescence and Cerenkov radiation. Such direct and indirect deep-tissue activation has been explored extensively in the preclinical setting to facilitate deep-tissue anticancer photodynamic therapy (PDT); however, clinical translation of these approaches is yet to be explored. This review provides a summary of the state of the art in deep-tissue excitation of PNMs and explores the translatability of such excitation mechanisms towards their clinical adoption. A special emphasis is placed on how current clinical instrumentation can be repurposed to achieve deep-tissue PDT with the mechanisms discussed in this review, thereby further expediting the translation of these highly promising strategies.

Neuropathy Score Reporting and Data System (NS-RADS): MRI Reporting Guideline of Peripheral Neuropathy Explained and Reviewed.

A standardized guideline and scoring system should be used for the MR imaging diagnosis of peripheral neuropathy. The MR imaging-based Neuropathy Score Reporting and Data System (NS-RADS) is a newly devised classification system (in press in AJR) that can be used to communicate both type and severity of peripheral neuropathy in the light of clinical history and examination findings. The spectrum of neuropathic conditions and peripheral nerve disorders covered in this system includes nerve injury, entrapment, neoplasm, diffuse neuropathy, and post-interventional states. This classification system also describes the temporal MR imaging appearances of regional muscle denervation changes. This review article is based on the multicenter validation study pre-published in American journal of Roentgenology and discusses technical considerations of optimal MR imaging for peripheral nerve evaluation and discusses the NS-RADS classification and its severity scales with illustration of conditions that fall under each classification. The readers can gain knowledge of the NS-RADS classification system and learn to apply it in their practices for improved inter-disciplinary communications and timely patient management.

Neuropathy Score Reporting and Data System: A Reporting Guideline for MRI of Peripheral Neuropathy With a Multicenter Validation Study.

BACKGROUND. A standardized guideline and scoring system would improve evaluation and reporting of peripheral neuropathy (PN) on MRI. OBJECTIVE. The objective of this study was to create and validate a neuropathy classification and grading system, which we named the Neuropathy Score Reporting and Data System (NS-RADS). METHODS. This retrospective study included 100 patients with nerve imaging studies and known clinical diagnoses. Experts crafted NS-RADS using mutually agreed-on qualitative criteria for the classification and grading of PN. Different classes were created to account for the spectrum of underlying pathologies: unremarkable (U), injury (I), neoplasia (N), entrapment (E), diffuse neuropathy (D), not otherwise specified (NOS), and postintervention state (PI). Subclasses were established to describe the severity or extent of the lesions. Validation testing was performed by 11 readers from 10 institutions with experience levels ranging from 3 to 18 years after residency. After initial reader training, cases were presented to readers who were blinded to the final clinical diagnoses. Interobserver agreement was assessed using correlation coefficients and the Conger kappa, and accuracy testing was performed. RESULTS. Final clinical diagnoses included normal (n = 5), nerve injury (n = 25), entrapment (n = 15), neoplasia (n = 33), diffuse neuropathy (n = 18), and persistent neuropathy after intervention (n = 4). The miscategorization rate for NS-RADS classes was 1.8%. Final diagnoses were correctly identified by readers in 71-88% of cases. Excellent inter-reader agreement was found on the NS-RADS pathology categorization (κ = 0.96; 95% CI, 0.93-0.98) as well as muscle pathology categorization (κ = 0.76; 95% CI, 0.68-0.82). The accuracy for determining milder versus more severe categories per radiologist ranged from 88% to 97% for nerve lesions and from 86% to 94% for muscle abnormalities. CONCLUSION. The proposed NS-RADS classification is accurate and reliable across different reader experience levels and a spectrum of PN conditions. CLINICAL IMPACT. NS-RADS can be used as a standardized guideline for reporting PN and improved multidisciplinary communications.

Is Tumor Cell Specificity Distinct from Tumor Selectivity In Vivo?: A Quantitative NIR Molecular Imaging Analysis of Nanoliposome Targeting.

The significance and ability for receptor targeted nanoliposomes (tNLs) to bind to their molecular targets in solid tumors in vivo has been questioned, particularly as the efficiency of their tumor accumulation and selectivity is not always predictive of their efficacy or molecular specificity. This study presents, for the first time, in situ NIR molecular imaging-based quantitation of the in vivo specificity of tNLs for their target receptors, as opposed to tumor selectivity, which includes influences of enhanced tumor permeability and retention. Results show that neither tumor delivery nor selectivity (tumor-to-normal ratio) of cetuximab and IRDye conjugated tNLs correlate with EGFR expression in U251, U87 and 9L tumors, and in fact underrepresent their imaging-derived molecular specificity by up to 94.2%. Conversely, their in vivo specificity, which we quantify as the concentration of tNL-reported tumor EGFR provided by NIR molecular imaging, correlates positively with EGFR expression levels in vitro and ex vivo (Pearson's r= 0.92 and 0.96, respectively). This study provides a unique opportunity to address the problematic disconnect between tNL synthesis and in vivo specificity. The findings encourage their continued adoption as platforms for precision medicine, and facilitates intelligent synthesis and patient customization in order to improve safety profiles and therapeutic outcomes.

What NIR photodynamic activation offers molecular targeted nanomedicines: Perspectives into the conundrum of tumor specificity and selectivity.

Near infrared (NIR) photodynamic activation is playing increasingly critical roles in cutting-edge anti-cancer nanomedicines, which include spatiotemporal control over induction of therapy, photodynamic priming, and phototriggered immunotherapy. Molecular targeted photonanomedicines (mt-PNMs) are tumor-specific nanoscale drug delivery systems, which capitalize on the unparalleled spatio-temporal precision of NIR photodynamic activation to augment the accuracy of tumor tissue treatment. mt-PNMs are emerging as a paradigm approach for the targeted treatment of solid tumors, yet remain highly complex and multifaceted. While ligand targeted nanomedicines in general suffer from interdependent challenges in biophysics, surface chemistry and nanotechnology, mt-PNMs provide distinct opportunities to synergistically potentiate the effects of ligand targeting. This review provides what we believe to be a much-need demarcation between the processes involved in tumor specificity (biomolecular recognition events) and tumor selectivity (preferential tumor accumulation) of ligand targeted nanomedicines, such as mt-PNMs, and elaborate on what NIR photodynamic activation has to offer. We discuss the interplay between both tumor specificity and tumor selectivity and the degree to which both may play central roles in cutting-edge NIR photoactivable nanotechnologies. A special emphasis is made on NIR photoactivable biomimetic nanotechnologies that capitalize on both specificity and selectivity phenomena to augment the safety and efficacy of photodynamic anti-tumor regimens.

Membrane composition is a functional determinant of NIR-activable liposomes in orthotopic head and neck cancer.

Near-infrared (NIR)-activable liposomes containing photosensitizer (PS)-lipid conjugates are emerging as tunable, high-payload, and tumor-selective platforms for photodynamic therapy (PDT)-based theranostics. To date, the impact that the membrane composition of a NIR-activable liposome (the chemical nature and subsequent conformation of PS-lipid conjugates) has on their in vitro and in vivo functionality has not been fully investigated. While their chemical nature is critical, the resultant physical conformation dictates their interactions with the immediate biological environments. Here, we evaluate NIR-activable liposomes containing lipid conjugates of the clinically-used PSs benzoporphyrin derivative (BPD; hydrophobic, membrane-inserting conformation) or IRDye 700DX (hydrophilic, membrane-protruding conformation) and demonstrate that membrane composition is critical for their function as tumor-selective PDT-based platforms. The PS-lipid conformations were primarily dictated by the varying solubilities of the two PSs and assisted by their lipid conjugation sites. Conformation was further validated by photophysical analysis and computational predictions of PS membrane partitioning (topological polar surface area [tPSA], calculated octanol/water partition [cLogP], and apparent biomembrane permeability coefficient [Papp]). Results show that the membrane-protruding lipo-IRDye700DX exhibits 5-fold more efficient photodynamic generation of reactive molecular species (RMS), 12-fold expedited phototriggered burst release of entrap-ped agents, and 15-fold brighter fluorescence intensity as compared to the membrane-inserting lipo-BPD-PC (phosphatidylcholine conjugate). Although the membrane-inserting lipo-BPD-PC exhibits less efficient photo-dynamic generation of RMS, it allows for more sustained phototriggered release, 10-fold greater FaDu cancer cell phototoxicity, and 7.16-fold higher tumor-selective delivery in orthotopic mouse FaDu head and neck tumors. These critical insights pave the path for the rational design of emerging NIR-activable liposomes, whereby functional consequences of membrane composition can be tailored toward a specific therapeutic purpose.