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The acyclic ligands H4C3octapa and p-SCN-Bn-H4C3octapa were synthesized for the first time, using nosyl protection chemistry. These new ligands were compared to the previously studied ligands H4octapa and p-SCN-Bn-H4octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. Although only a single carbon atom was added to H4C3octapa and the metal donor atoms and denticity were not changed, the solution chemistry and radiochemistry properties were drastically altered, highlighting the importance of careful ligand design and radiometal-ligand matching. It was found that [In(C3octapa)]- and [Lu(C3octapa)]- were substantially different from the analogous H4octapa complexes, exhibiting fluxional isomerization and a higher number of isomers, as observed by ¹H NMR, VT-NMR, and 2D COSY/HSQC-NMR experiments. Past evaluation of the DFT structures of [In(octapa)]- and [Lu(octapa)]- revealed very symmetric complexes; in contrast, the [In(C3octapa)]- and [Lu(C3octapa)]- complexes were much less symmetric, suggesting lower symmetry and less rigidity than that of the analogous H4octapa complexes. Potentiometric titrations revealed the formation constants (log KML, pM) were ~2 units lower for the In3+ and Lu3+ complexes of H4C3octapa when compared to that of the more favorable H4octapa ligand (~2 orders of magnitude less thermodynamically stable). The bifunctional ligands p-SCN-Bn-H4C3octapa and p-SCN-Bn-H4octapa were conjugated to the antibody trastuzumab and radiolabeled with 111In and 177Lu. Over a 5 day stability challenge experiment in blood serum, 111In-octapa- and 111In-C3octapa-trastuzumab immunoconjugates were determined to be ~91 and ~24% stable, respectively, and 177Lu-octapa- and 177Lu-C3octapa-trastuzumab, ~89% and ~4% stable, respectively. This work suggests that 5-membered chelate rings are superior to 6-membered chelate rings for large metal ions like In3+ and Lu3+, which is a crucial consideration for the design of bifunctional chelates for bioconjugation to targeting vectors for in vivo work. [ABSTRACT FROM AUTHOR]

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The ligands H2dedpa, H2octapa, p-SCN-Bn-H4dedpa, and p-SCN-Bn-H4octapa were synthesized using a new protection chemistry approach, with labile tert-butyl esters replacing the previously used methyl esters as protecting groups for picolinic acid moieties. Additionally, the ligands H2dedpa and p-SCN-Bn- H2dedpa were synthesized using nosyl protection chemistry for the first time. The use of tert-butyl esters allows for deprotection at room temperature in trifluoroacetic acid (TFA), which compares favorably to the harsh conditions of refluxing HCl (6 M) or LiOH that were previously required for methyl ester cleavage. H4octapa has recently been shown to be a very promising 111In and 177Lu ligand for radiopharmaceutical applications; therefore, coordination chemistry studies with Y3+ are described to assess its potential for use with 86Y/90Y. The solution chemistry of H4octapa with Y3+ is shown to be suitable via solution NMR studies of the [Y(octapa)]- complex and density functional theory (DFT) calculations of the predicted structure, suggesting properties similar to those of the analogous In3+ and Lu3+ complexes. The molecular electrostatic potential (MEP) was mapped onto the molecular surface of the DFT-calculated coordination structures, suggesting very similar and even charge distributions between both the Lu3+ and Y3+ complexes of octapa4-, and coordinate structures between 8 (ligand only) and 9 (ligand and one H2O). Potentiometric titrations determined H4octapa to have a formation constant (log KML) with Y3+ of 18.3 ± 0.1, revealing high thermodynamic stability. This preliminary work suggests that H4octapa may be a competent ligand for future 86Y/90Y radiopharmaceutical applications. [ABSTRACT FROM AUTHOR]

Radiometals comprise many useful radioactive isotopes of various metallic elements. When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomography (SPECT, e.g. 67Ga, 99mTc, 111In, 177Lu) and positron emission tomography (PET, e.g. 68Ga, 64Cu, 44Sc, 86Y, 89Zr), as well as therapeutic applications (e.g. 47Sc, 114mIn, 177Lu, 90Y, 212/213Bi, 212Pb, 225Ac, 186/188Re). A fundamental critical component of a radiometal-based radiopharmaceutical is the chelator, the ligand system that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable molecular target in vivo. This article is a guide for selecting the optimal match between chelator and radiometal for use in these systems. The article briefly introduces a selection of relevant and high impact radiometals, and their potential utility to the fields of radiochemistry, nuclear medicine, and molecular imaging. A description of radiometal-based radiopharmaceuticals is provided, and several key design considerations are discussed. The experimental methods by which chelators are assessed for their suitability with a variety of radiometal ions is explained, and a large selection of the most common and most promising chelators are evaluated and discussed for their potential use with a variety of radiometals. Comprehensive tables have been assembled to provide a convenient and accessible overview of the field of radiometal chelating agents. [ABSTRACT FROM AUTHOR]

The acyclic chelator H6phospa and the bifunctional derivative p-SCN-Bn-H6phospa have been synthesized using nosyl protection chemistry and evaluated with 89Zr, 111In, and 177Lu. The p-SCN-Bn- H6phospa derivative was successfully conjugated to trastuzumab with isotopic dilution assays indicating 3.3 ± 0.1 chelates per antibody and in vitro cellular binding assays indicating an immunoreactivity value of 97.9 ± 2.6%. Radiolabeling of the H6phospa-trastuzumab immunoconjugate was achieved with 111In in 70-90% yields at room temperature in 30 minutes, while 177Lu under the same conditions produced more inconsistent yields of 40-80%. Stability experiments in human serum revealed the 111In-phospatrastuzumab complex to be 52.0 ± 5.3% intact after 5 days at 37 °C, while the 177Lu-phospa-trastuzumab to be only 2.0 ± 0.3% intact. Small animal SPECT/CT imaging using mice bearing subcutaneous SKOV-3 ovarian cancer xenografts was performed, and it was found that 111In-phospa-trastuzumab successfully identified and delineated small (~2 mm in diameter) tumors from surrounding tissues, despite visible uptake in the kidneys and bone due to moderate chelate instability. As predicted from stability assays in serum, the 177Lu-phospa-trastuzumab conjugate served as a negative control and displayed no tumor uptake, with high uptake in bones indicating rapid and complete radiometal dissociation and suggesting a potential application of H6phospa in transient lanthanide chelation for bone-delivery. Radiolabeling with 89Zr was attempted, but even with elevated temperatures of 37 °C, the maximum observed radiometal incorporation over 18 hours was 12%. It can be concluded from this work that H6phospa is not superior to the previously studied H4octapa for use with 111In and 177Lu, but improvements in 89Zr radiolabeling were observed over H4octapa, suggesting H6phospa to be an excellent starting point for elaboration of 89Zr-based radiopharmaceutical development. To our knowledge, H6phospa is the best desferrioxamine alternative for 89Zr radiolabeling to be studied to date. [ABSTRACT FROM AUTHOR]

A bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCN-Bn-H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes 111In and 177Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ~94-95%) than those based on DOTA-trastuzumab (60 min, 37 °C, ~50-88%). Further, antibody integrity was better preserved in the 111In- and 177Lu-octapa-trastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93-0.95 for 111In- and 177Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for 111In- and 177Lu-octapa-trastuzumab compared to 111In- and 177Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios. [ABSTRACT FROM AUTHOR]

Preliminary experiments with the novel acyclic triazole-containing bifunctional chelator H₂azapa and the radiometals 64Cu, 67Ga, 111In, and 177Lu have established its significant versatile potential as an alternative to 1,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid (DOTA) for metal-based radiopharmaceuticals. Unlike DOTA, H₂azapa radiolabels quantitatively with 64Cu, 67Ga, 111In, and 177Lu in 10 min at room temperature. In vitro competition experiments with human blood serum show that 64Cu remained predominantly chelate-bound, with only 2% transchelated to serum proteins after 20 h. Biodistribution experiments with [64Cu(azapa)] in mice reveal uptake in various organs, particularly in the liver, lungs, heart, intestines, and kidneys. When compared to [64Cu(DOTA)]2-, the lipophilic neutral [64Cu(azapa)] was cleared through the gastrointestinal tract and accumulated in the liver, which is common for lipophilic compounds or free 64Cu. The chelator H₂azapa is a model complex for a dick-based bifunctional chelating agent, and the lipophilic benzyl "place-holders" will be replaced by hydrophilic peptides to modulate the pharmacokinetics and direct activity away from the liver and gut. The solid-state molecular structure of [In(azapa)(H₂O)][ClO₄] reveals a very rare eight-coordinate distorted square antiprismatic geometry with one triazole arm bound, and the structure of [64Cu(azapa)] shows a distorted octahedral geometry. The present study demonstrates significant potential for bioconjugates of H₂azapa as alternatives to DOTA in copper-based radiopharmaceuticals, with the highly modular and "clickable" molecular scaffold of H₂azapa easily modified into a variety of bioconjugates. H₂azapa is a versatile addition to the "pa" family, joining the previously published H₂dedpa (67/68Ga and 64Cu), H₄octapa (111In, 177Lu, and 90Y), and H₅decapa (225Ac) to cover a wide range of important nuclides. [ABSTRACT FROM AUTHOR]

This preliminary investigation of the octadentate acyclic chelator H4octapa (N4O4) with 111In/115In3+ has demonstrated it to be an improvement on the shortcomings of the current industry "gold standards" DOTA (N4O4) and DTPA (N3O5). The ability of H4octapa to radiolabel quantitatively 111InCl3 at ambient temperature in 10 min with specific activities as high as 2.3 mCi/nmol (97.5% radiochemical yield) is presented. In vitro mouse serum stability assays have demonstrated the 111In complex of H4octapa to have improved stability when compared to DOTA and DTPA over 24 h. Mouse biodistribution studies have shown that the radiometal complex [111In(octapa)]- has exceptionally high in vivo stability over 24 h with improved clearance and stability compared to [111In(DOTA)]-, demonstrated by lower uptake in the kidneys, liver, and spleen at 24 h. 1H/13C NMR studies of the [In(octapa)]- complex revealed a 7-coordinate solution structure, which forms a single isomer and exhibits no observable fluxional behavior at ambient temperature, an improvement to the multiple isomers formed by [In(DTPA)]2- and [In(DOTA)]- under the same conditions. Potentiometric titrations have determined the thermodynamic formation constant of the [In(octapa)]- complex to be log KML = 26.8(1). Through the same set of analyses, the [111/115In(decapa)]2- complex was found to have nonoptimal stability, with H5decapa (N5O5) being more suitable for larger metal ions due to its higher potential denticity (e.g., lanthanides and actinides). Our initial investigations have revealed the acyclic chelator H4octapa to be a valuable alternative to the macrocycle DOTA for use with 111In, and a significant improvement to the acyclic chelator DTPA. [ABSTRACT FROM AUTHOR]

Tracheostomy-related emergencies (TREs) contribute significantly to preventable mortality. The retention of caregiver knowledge and skills acquired through simulation-based training (SBT) is unknown. This study aimed to assess the management of TREs by caregivers who did and did not receive SBT. A questionnaire containing 3 TRE scenarios and frequency of outpatient TREs was administered to 52 caregivers of children with tracheostomies; 34 caregivers had completed SBT. Most caregivers (80%) reported ≥1 TRE since discharge. Only 46% of caregivers answered all 3 TRE questions correctly. No differences were observed in correct responses for accidental decannulation (p = .16), oxygen desaturation (p = .84), and mucus plugging (p = .16) based on the completion of SBT. There were no differences between duration since SBT completion and correct responses for all 3 TRE questions. Caregivers showed knowledge deficiencies in TRE management regardless of SBT completion or duration since SBT. Periodic reassessment of knowledge may create targeted re-education opportunities for TRE management. [ABSTRACT FROM AUTHOR]

We have investigated novel bifunctional chelate alternatives to the arninocarboxylate macrocycles NOTA (N3O3) or DOTA (N4O4) for application of radloisotopes of Ga to diagnostic nuclear medicine and have found that the linear N4O2 chelate H2dedpa coordinates 67Ga quantitatively to form [67Ga(dedpa)]+ after 10 min at RT. Concentration-dependent coordination to H2dedpa of either 68Ga or 67Ga showed quantitative conversion to the desired products with ligand concentrations as low as 10-7 M. With 68Ga, specific activities as high as 9.8 mCi nmol-1 were obtained without purification. In a 2 h competition experiment against human apo-transferrin, [67Ga(dedpa)]+ showed no decomposition. Two bifunctional versions of H2dedpa are also described, and these both coordinate to 67Ga at RT within 10 min. Complete syntheses, characterizations, labeling studies, and biodistribution profiles of the 67Ga complexes are presented for the new platform chelates. The stability of these platform chelates is higher than that of DOTA. [ABSTRACT FROM AUTHOR]

Recently, several radiometalated peptides have been approved for clinical imaging and/or therapy (theranostics) of several types of cancer; nonetheless, the primary challenge that most of these peptides confront is significant renal uptake and retention, which is often dose limiting and can cause nephrotoxicity. In response to this, numerous methods have been employed to reduce the uptake of radiometalated peptides in the kidneys, and among these is adding a linker to modulate polarity and/or charge. To better understand the influence of net charge on the biodistribution of radiometalated peptides, we selected the clinically popular construct DOTA-TATE (NETSPOT/LUTATHERA) as a model system. We synthesized derivatives using manual solid-phase peptide synthesis methods including mechanical and ultrasonic agitation to effectively yield the gold standard DOTA-TATE and a series of derivatives with different net charges (+2, +1, 0, -1, -2). Dynamic PET imaging from 0 to 90 min in healthy female mice (CD1) revealed high accumulation and retention of activity in the kidneys for the net-neutral (0) charged [ 68 Ga]Ga-DOTA-TATE and even higher for positively charged derivatives, whereas negatively charged derivatives exhibited low accumulation and fast renal excretion. Ex vivo biodistribution at 2 h post injection demonstrated a significant retention of [ 68 Ga]Ga-DOTA-TATE (∼74 %ID/g) in the kidneys, which increased as the net positive charge per molecule increased to +1 and +2 (∼272 %ID/g and ∼333 %ID/g, respectively), but the -1 and -2 net charged molecules exhibited lower renal uptake (∼15 %ID/g and 16 %ID/g, respectively). Interestingly, the net -2 charged [ 68 Ga]Ga-DOTA-(Glu) 2 -PEG 4 -TATE was stable in blood serum but had much higher healthy organ uptake (lungs, liver, spleen) than the net -1 compound, suggesting instability in vivo . Although the [ 68 Ga]Ga-DOTA-PEG 4 -TATE derivative with a net charge of 0 also showed a decrease in kidney uptake, it also showed instability in blood serum and in vivo . Despite the superior pharmacokinetics of the net -1 charged [ 68 Ga]Ga-DOTA-Glu-PEG 4 -TATE in healthy mice with respect to kidney uptake and overall profile, dynamic PET images and ex vivo biodistribution in male mice (NSG) bearing AR42J (SSTR2 overexpressing) subcutaneous tumor xenografts showed significantly diminished tumor uptake when compared to the gold standard [ 68 Ga]Ga-DOTA-TATE. Taken together, these findings indicate unambiguously that kidney uptake and retention are significantly influenced by the net charge of peptide-based radiotracers. In addition, it was illustrated that the negatively charged peptides had substantially decreased kidney uptake, but in this instantiation the tumor uptake was also impaired.

Immuno-PET using desferrioxamine (DFO)-conjugated zirconium-89 ([ 89 Zr]Zr 4+ )-labeled antibodies is a powerful tool used for preclinical and clinical molecular imaging. However, a comprehensive study evaluating the variables involved in DFO-conjugation and 89 Zr-radiolabeling of antibodies and their impact on the in vitro and in vivo behavior of the resulting radioimmunoconjugates has not been adequately performed. Here, we synthesized different DFO-conjugates of the HER2-targeting antibody (Ab)-trastuzumab, dubbed T5, T10, T20, T60, and T200-to indicate the molar equivalents of DFO used for bioconjugation. Next we radiolabeled the immunoconjugates with ([ 89 Zr]Zr 4+ ) under a comprehensive set of reaction conditions including different buffers (PBS, chelexed-PBS, TRIS/HCl, HEPES; ± radioprotectants), different reaction volumes (0.1-1 mL), variable amounts of DFO-conjugated Ab (5, 25, 50 μg), and radioactivity (0.2-1.0 mCi; 7.4-37 MBq). We evaluated the effects of these variables on radiochemical yield (RCY), molar activity ( A m )/specific activity ( A s ), immunoreactive fraction, and ultimately the in vivo biodistribution profile and tumor targeting ability of the trastuzumab radioimmunoconjugates. We show that increasing the degree of DFO conjugation to trastuzumab increased the RCY (∼90%) and A m / A s (∼194 MBq/nmol; 35 mCi/mg) but decreased the HER2-binding affinity (3.5×-4.6×) and the immunoreactive fraction of trastuzumab down to 50-64%, which translated to dramatically inferior in vivo performance of the radioimmunoconjugate. Cell-based immunoreactivity assays and standard binding affinity analyses using surface plasmon resonance (SPR) did not predict the poor in vivo performance of the most extreme T200 conjugate. However, SPR-based concentration free calibration analysis yielded active antibody concentration and was predictive of the in vivo trends. Positron emission tomography (PET) imaging and biodistribution studies in a HER2-positive xenograft model revealed activity concentrations of 38.7 ± 3.8 %ID/g in the tumor and 6.3 ± 4.1 %ID/g in the liver for ([ 89 Zr]Zr 4+ )-T5 (∼1.4 ± 0.5 DFOs/Ab) at 120 h after injection of the radioimmunoconjugates. On the other hand, ([ 89 Zr]Zr 4+ )-T200 (10.9 ± 0.7 DFOs/Ab) yielded 16.2 ± 3.2 %ID/g in the tumor versus 27.5 ± 4.1 %ID/g in the liver. Collectively, our findings suggest that synthesizing trastuzumab immunoconjugates bearing 1-3 DFOs per Ab (T5 and T10) combined with radiolabeling performed in low reaction volumes using Chelex treated PBS or HEPEs without a radioprotectant provided radioimmunoconjugates having high A m / A s (97 MBq/nmol; 17.5 ± 2.2 mCi/mg), highly preserved immunoreactive fractions (86-93%), and favorable in vivo biodistribution profile with excellent tumor uptake.

Cancer is one of the leading causes of death and chromosomal instability (CIN) is a hallmark feature of cancer. CIN, a source of genetic variation in either altered chromosome number or structure contributes to tumor heterogeneity and has become a hot topic in recent years prominently for its role in therapeutic responses. Synthetic lethality and synthetic rescue based approaches, for example, advancing CRISPR-Cas9 platform, are emerging as a powerful strategy to identify new potential targets to selectively eradicate cancer cells. Unfortunately, only few of them are further explored therapeutically due to the difficulty in linking these targets to small molecules for pharmacological intervention. This, however, can be alleviated by the efforts to bring chemical, bioactivity, and genomic data together, as well as established computational approaches. In this chapter, we will discuss some of these advances, including established databases and in silico target-ligand prediction, with the aim to navigate through the synthetically available chemical space to the biologically targetable landscape, and eventually, to the chemical modeling of synthetic lethality and synthetic rescue interactions, that are of great clinical and pharmaceutical relevance and significance., (© 2021. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The hepatocyte growth factor (HGF) binding antibody rilotumumab (AMG102) was modified for use as a 89 Zr-based immuno-PET imaging agent to noninvasively determine the local levels of HGF protein in tumors. Because recent clinical trials of HGF-targeting therapies have been largely unsuccessful in several different cancers (e.g., gastric, brain, lung), we have synthesized and validated 89 Zr-DFO-AMG102 as a companion diagnostic for improved identification and selection of patients having high local levels of HGF in tumors. To date, patient selection has not been performed using the local levels of HGF protein in tumors. Methods: The chelator p -SCN-Bn-DFO was conjugated to AMG102, radiolabeling with 89 Zr was performed in high radiochemical yields and purity (>99%), and binding affinity of the modified antibody was confirmed using an enzyme-linked immunosorbent assay (ELISA)-type binding assay. PET imaging, biodistribution, autoradiography and immunohistochemistry, and ex vivo HGF ELISA experiments were performed on murine xenografts of U87MG (HGF-positive, MET-positive) and MKN45 (HGF-negative, MET-positive) and 4 patient-derived xenografts (MET-positive, HGF unknown). Results: Tumor uptake of 89 Zr-DFO-AMG102 at 120 h after injection in U87MG xenografts (HGF-positive) was high (36.8 ± 7.8 percentage injected dose per gram [%ID/g]), whereas uptake in MKN45 xenografts (HGF-negative) was 5.0 ± 1.3 %ID/g and a control of nonspecific human IgG 89 Zr-DFO-IgG in U87MG tumors was 11.5 ± 3.3 %ID/g, demonstrating selective uptake in HGF-positive tumors. Similar experiments performed in 4 different gastric cancer patient-derived xenograft models showed low uptake of 89 Zr-DFO-AMG102 (∼4-7 %ID/g), which corresponded with low HGF levels in these tumors (ex vivo ELISA). Autoradiography, immunohistochemical staining, and HGF ELISA assays confirmed that elevated levels of HGF protein were present only in U87MG tumors and that 89 Zr-DFO-AMG102 uptake was closely correlated with HGF protein levels in tumors. Conclusion: The new immuno-PET imaging agent 89 Zr-DFO-AMG102 was successfully synthesized, radiolabeled, and validated in vitro and in vivo to selectively accumulate in tumors with high local levels of HGF protein. These results suggest that 89 Zr-DFO-AMG102 would be a valuable companion diagnostic tool for the noninvasive selection of patients with elevated local concentrations of HGF in tumors for planning any HGF-targeted therapy, with the potential to improve clinical outcomes., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

We demonstrate that nanoscale aggregates similar to those formed via amphiphilic block copolymer self-assembly at the air-water interface, including strands, networks, and continents, can be generated by the simple spreading of PS homopolymer solutions on water. Two different PS homopolymers of different molecular weight (PS-405k, M(n) = 405 000 g mol(-1) and PS-33k, M(n) = 33 000 g mol(-1)) are spread at the air-water interface at various spreading concentrations ranging from 0.25 to 3.0 mg/mL. Aggregate formation is driven by PS dewetting from water as the spreading solvent evaporates. We propose that a high spreading concentration or a high molecular weight lead to chain entanglements that restrict macromolecular mobility in the solution, enabling the kinetic trapping of nanostructures associated with early and intermediate stages of PS dewetting. Comparison of PS-405k with a mainly hydrophobic PS-b-PEO block copolymer of similar molecular weight (PSEO-392k, M(n) = 392 000 g mol(-1), 2.0 wt % PEO) allows the effect of a relatively short surface active block on aggregate formation to be investigated. We show that whereas the PEO block is not a required component for the formation of strands and other nonglobular aggregates, it does increase the number of these aggregates at a given spreading concentration and decreases the minimum spreading concentration at which these aggregates are observed, along with decreasing the dimensions and polydispersity of specific surface features. The results provide supporting evidence for the role of PS dewetting in the generation of multiple PS-b-PEO aggregate morphologies at the air-water interface, as originally described in earlier paper from our group.

Block copolymer microphase separation in the bulk is coupled to amphiphilic block copolymer self-assembly at the air-water interface to yield hierarchical Langmuir-Blodgett (LB) structures combining organization at the meso- and nanoscales. A blend of polystyrene-b-poly(ethylene oxide) (PS-b-PEO) (Mn=141K, 11.4 wt % PEO) and polystyrene-b-poly(butadiene) (PS-b-PB) (Mn=31.9K, 28.5 wt % PB) containing a PS-b-PB weight fraction of f=0.75 was deposited at the air-water interface, resulting in the spontaneous generation of aggregates with multiscale organization, including nanoscale cylinders in mesoscale strands, via evaporation of the spreading solvent. The resulting features were characterized in LB films via AFM and TEM and at the air-water interface via Langmuir compression isotherms. Blends containing lower PS-b-PB contents formed mesoscale aggregate morphologies of continents and strands (f=0.50) or mesoscale continents with holes (f=0.25), but without the internal nanoscale organization found in the f=0.75 blend. The interfacial self-assembly of pure PS-b-PB at the air-water interface (f=1) yielded taller and more irregularly shaped aggregates than blends containing PS-b-PEO, indicating the integral role of the amphiphilic copolymer in regulating the mesoscale organization of the hierarchically structured features.