Visible-Light Driven Control Over Triply and Quadruply Hydrogen-Bonded Supramolecular Assemblies.

Supramolecular polymers offer tremendous potential to produce new "smart" materials, however, there remains a need to develop systems that are responsive to external stimuli. In this work, visible-light responsive hydrogen-bonded supramolecular polymers comprising photoresponsive supramolecular synthons (I-III) consisting of two hydrogen bonding motifs (HBMs) connected by a central ortho-tetrafluorinated azobenzene have been characterized by DOSY NMR and viscometry. Comparison of different hydrogen-bonding motifs reveals that assembly in the low and high concentration regimes is strongly influenced by the strength of association between the HBMs. I, Incorporating a triply hydrogen-bonded heterodimer, was found to exhibit concentration dependent switching between a monomeric pseudo-cycle and supramolecular oligomer through intermolecular hydrogen bonding interactions between the HBMs. II, Based on the same photoresponsive scaffold, and incorporating a quadruply hydrogen-bonded homodimer was found to form a supramolecular polymer which was dependent upon the ring-chain equilibrium and thus dependent upon both concentration and photochemical stimulus. Finally, III, incorporating a quadruply hydrogen-bonded heterodimer represents the first photoswitchable AB type hydrogen-bonded supramolecular polymer. Depending on the concentration and photostationary state, four different assemblies dominate for both monomers II and III, demonstrating the ability to control supramolecular assembly and physical properties triggered by light.

The Production of Polysarcosine-Containing Nanoparticles by Ring-Opening Polymerization-Induced Self-Assembly.

N-carboxyanhydride ring-opening polymerization-induced self-assembly (NCA ROPISA) offers a convenient route for generating poly(amino acid)-based nanoparticles in a single step, crucially avoiding the need for post-polymerization self-assembly. Most examples of NCA ROPISA make use of a poly(ethylene glycol) (PEG) hydrophilic stabilizing block, however this non-biodegradable, oil-derived polymer may cause an immunological response in some individuals. Alternative water-soluble polymers are therefore highly sought. This work reports the synthesis of wholly poly(amino acid)-based nanoparticles, through the chain-extension of a polysarcosine macroinitiator with L-Phenylalanine-NCA (L-Phe-NCA) and Alanine-NCA (Ala-NCA), via aqueous NCA ROPISA. The resulting polymeric structures comprise of predominantly anisotropic, rod-like nanoparticles, with morphologies primarily influenced by the secondary structure of the hydrophobic poly(amino acid) that enables their formation.

Risk factors for SARS-CoV-2 infection at a UK electricity-generating company: a test-negative design case-control study.

OBJECTIVES: Identify workplace risk factors for SARS-CoV-2 infection, using data collected by a UK electricity-generating company. METHODS: Using a test-negative design case-control study, we estimated the OR of infection by job category, site, test reason, sex, vaccination status, vulnerability, site outage and site COVID-19 weekly risk rating, adjusting for age, test date and test type. RESULTS: From an original 80 077 COVID-19 tests, there were 70 646 included in the final analysis. Most exclusions were due to being visitor tests (5030) or tests after an individual first tested positive (2968).Women were less likely to test positive than men (OR=0.71; 95% CI 0.58 to 0.86). Test reason was strongly associated with positivity and although not a cause of infection itself, due to differing test regimes by area, it was a strong confounder for other variables. Compared with routine tests, tests due to symptoms were highest risk (94.99; 78.29 to 115.24), followed by close contact (16.73; 13.80 to 20.29) and broader-defined work contact 2.66 (1.99 to 3.56). After adjustment, we found little difference in risk by job category, but some differences by site with three sites showing substantially lower risks, and one site showing higher risks in the final model. CONCLUSIONS: In general, infection risk was not associated with job category. Vulnerable individuals were at slightly lower risk, tests during outages were higher risk, vaccination showed no evidence of an effect on testing positive, and site COVID-19 risk rating did not show an ordered trend in positivity rates.

Exploiting breath figure reversibility for in situ pattern modulation and hierarchical design.

The breath figure (BF) method employs condensation droplets as dynamic templates for patterning polymer films. In the classical approach, dropwise condensation and film solidification are simultaneously induced through solvent evaporation, leading to empirically derived patterns with limited predictability of the final design. Here we use the temporally arrested BF methodology, controlling condensation and polymerisation independently to create diverse BF patterns with varied pore size, arrangement and distribution. External temperature control enables us to further investigate and exploit the inherent reversibility of the phase change process that governs the pattern formation. We modulate the level of subcooling and superheating to achieve subsequent regimes of condensation and evaporation, permitting in situ regulation of the droplet growth and shrinkage kinetics. The full reversibility of the phase change processes joined with active photopolymerisation in the current approach thus allows arresting of predictable BF kinetics at intermediate stages, thereby accessing patterns with varied pore size and spacing for unchanged material properties and environmental conditions. This simultaneous active control over both the kinetics of phase change and polymer solidification offers affordable routes for the fabrication of diverse predictable porous surfaces; manufacture of monolithic hierarchical BF patterns are ultimately facilitated through the advanced control of the BF assembly using the method presented here.

Protection of Double-Stranded RNA via Complexation with Double Hydrophilic Block Copolymers: Influence of Neutral Block Length in Biologically Relevant Environments.

Interaction between the anionic phosphodiester backbone of DNA/RNA and polycations can be exploited as a means of delivering genetic material for therapeutic and agrochemical applications. In this work, quaternized poly(2-(dimethylamino)ethyl methacrylate)-block-poly(N,N-dimethylacrylamide) (PQDMAEMA-b-PDMAm) double hydrophilic block copolymers (DHBCs) were synthesized via reversible addition-fragmentation chain-transfer (RAFT) polymerization as nonviral delivery vehicles for double-stranded RNA. The assembly of DHBCs and dsRNA forms distinct polyplexes that were thoroughly characterized to establish a relationship between the length of the uncharged poly(N,N-dimethylacrylamide) (PDMA) block and the polyplex size, complexation efficiency, and colloidal stability. Dynamic light scattering reveals the formation of smaller polyplexes with increasing PDMA lengths, while gel electrophoresis confirms that these polyplexes require higher N/P ratio for full complexation. DHBC polyplexes exhibit enhanced stability in low ionic strength environments in comparison to homopolymer-based polyplexes. In vitro enzymatic degradation assays demonstrate that both homopolymer and DHBC polymers efficiently protect dsRNA from degradation by RNase A enzyme.

New Aldehyde-Functional Methacrylic Water-Soluble Polymers.

Aldehyde groups enable facile conjugation to proteins, enzymes, oligonucleotides or fluorescent dyes, yet there are no literature examples of water-soluble aldehyde-functional vinyl monomers. We report the synthesis of a new hydrophilic cis-diol-based methacrylic monomer (GEO5MA) by transesterification of isopropylideneglycerol penta(ethylene glycol) using methyl methacrylate followed by acetone deprotection via acid hydrolysis. The corresponding water-soluble aldehyde monomer, AGEO5MA, is prepared by aqueous periodate oxidation of GEO5MA at 22 °C. RAFT polymerization of GEO5MA yields the water-soluble homopolymer, PGEO5MA. Aqueous periodate oxidation of the terminal cis-diol units on PGEO5MA at 22 °C affords a water-soluble aldehyde-functional homopolymer (PAGEO5MA). Moreover, a library of hydrophilic statistical copolymers bearing cis-diol and aldehyde groups was prepared using sub-stoichiometric periodate/cis-diol molar ratios. The aldehyde groups on PAGEO5MA homopolymer were reacted in turn with three amino acids to demonstrate synthetic utility.

Inhibition of checkpoint kinase 1 following gemcitabine-mediated S phase arrest results in CDC7- and CDK2-dependent replication catastrophe.

Combining DNA-damaging drugs with DNA checkpoint inhibitors is an emerging strategy to manage cancer. Checkpoint kinase 1 inhibitors (CHK1is) sensitize most cancer cell lines to DNA-damaging drugs and also elicit single-agent cytotoxicity in 15% of cell lines. Consequently, combination therapy may be effective in a broader patient population. Here, we characterized the molecular mechanism of sensitization to gemcitabine by the CHK1i MK8776. Brief gemcitabine incubation irreversibly inhibited ribonucleotide reductase, depleting dNTPs, resulting in durable S phase arrest. Addition of CHK1i 18 h after gemcitabine elicited cell division cycle 7 (CDC7)- and cyclin-dependent kinase 2 (CDK2)-dependent reactivation of the replicative helicase, but did not reinitiate DNA synthesis due to continued lack of dNTPs. Helicase reactivation generated extensive single-strand (ss)DNA that exceeded the protective capacity of the ssDNA-binding protein, replication protein A. The subsequent cleavage of unprotected ssDNA has been termed replication catastrophe. This mechanism did not occur with concurrent CHK1i plus gemcitabine treatment, providing support for delayed administration of CHK1i in patients. Alternative mechanisms of CHK1i-mediated sensitization to gemcitabine have been proposed, but their role was ruled out; these mechanisms include premature mitosis, inhibition of homologous recombination, and activation of double-strand break repair nuclease (MRE11). In contrast, single-agent activity of CHK1i was MRE11-dependent and was prevented by lower concentrations of a CDK2 inhibitor. Hence, both pathways require CDK2 but appear to depend on different CDK2 substrates. We conclude that a small-molecule inhibitor of CHK1 can elicit at least two distinct, context-dependent mechanisms of cytotoxicity in cancer cells.

A review of recent literature on materialist and psychosocial models for racial and ethnic disparities in birth outcomes in the US, 2000-2014.

OBJECTIVE: Material and psychosocial factors exacerbate racial disparities in health outcomes. This review sought to ascertain recent knowledge of the effects of materialist and psychosocial factors on differences in low birthweight (LBW) and preterm delivery (PTD) outcomes between Black and White mothers. DESIGN: Search and review was conducted for studies that examined: (a) neighborhood-level deprivation as an indicator of material conditions, and (b) racial discrimination or occupational stressors as indicators of psychosocial stress. The outcomes of interest were LBW and PTD. RESULTS: Material and psychosocial factors significantly and negatively affected Blacks more than Whites, and were associated with increased adverse outcomes. Of five studies with a homogeneous Black study sample, three reported no effect on outcomes in women exposed to material or psychosocial factors. CONCLUSION: Through this review we find that in comparison to White women, Black women are at higher risk of adverse outcomes due to both psychosocial stress and meso-level deprivation, after accounting for personal factors. A better understanding of effects on health outcomes of material and psychosocial factors in Black women is needed. Further investigation into materialist and psychosocial factors, will allow us to better understand the factors driving PTD and LBW disparities in the US.

Testing the vesicular morphology to destruction: birth and death of diblock copolymer vesicles prepared via polymerization-induced self-assembly.

Small angle X-ray scattering (SAXS), electrospray ionization charge detection mass spectrometry (CD-MS), dynamic light scattering (DLS), and transmission electron microscopy (TEM) are used to characterize poly(glycerol monomethacrylate)55-poly(2-hydroxypropyl methacrylate)x (G55-Hx) vesicles prepared by polymerization-induced self-assembly (PISA) using a reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization formulation. A G55 chain transfer agent is utilized to prepare a series of G55-Hx diblock copolymers, where the mean degree of polymerization (DP) of the membrane-forming block (x) is varied from 200 to 2000. TEM confirms that vesicles with progressively thicker membranes are produced for x = 200-1000, while SAXS indicates a gradual reduction in mean aggregation number for higher x values, which is consistent with CD-MS studies. Both DLS and SAXS studies indicate minimal change in the overall vesicle diameter between x = 400 and 800. Fitting SAXS patterns to a vesicle model enables calculation of the membrane thickness, degree of hydration of the membrane, and the mean vesicle aggregation number. The membrane thickness increases at higher x values, hence the vesicle lumen must become smaller if the external vesicle dimensions remain constant. Geometric considerations indicate that this growth mechanism lowers the total vesicle interfacial area and hence reduces the free energy of the system. However, it also inevitably leads to gradual ingress of the encapsulated water molecules into the vesicle membrane, as confirmed by SAXS analysis. Ultimately, the highly plasticized membranes become insufficiently hydrophobic to stabilize the vesicle morphology when x exceeds 1000, thus this PISA growth mechanism ultimately leads to vesicle "death".

Disulfide-Functionalized Diblock Copolymer Worm Gels.

Two strategies for introducing disulfide groups at the outer surface of RAFT-synthesized poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) (PGMA-PHPMA, or Gx-Hy for brevity) diblock copolymer worms are investigated. The first approach involved statistical copolymerization of GMA with a small amount of disulfide dimethacrylate (DSDMA, or D) comonomer to afford a G54-D0.50 macromolecular chain transfer agent (macro-CTA); this synthesis was conducted in relatively dilute solution in order to ensure mainly intramolecular cyclization and hence the formation of linear chains. Alternatively, a new disulfide-based bifunctional RAFT agent (DSDB) was used to prepare a G45-S-S-G45 (or (G45-S)2) macro-CTA. A binary mixture of a non-functionalized G55 macro-CTA was utilized with each of these two disulfide-based macro-CTAs in turn for the RAFT aqueous dispersion polymerization of 2-hydroxypropyl methacrylate (HPMA). By targeting a PHPMA DP of 130 and systematically varying the molar ratio of the two macro-CTAs, a series of disulfide-functionalized diblock copolymer worm gels were obtained. For both formulations, oscillatory rheology studies confirmed that higher disulfide contents led to stronger gels, presumably as a result of inter-worm covalent bond formation via disulfide/thiol exchange. Using the DSDB-based macro-CTA led to the strongest worm gels, and this formulation also proved to be more effective in suppressing the thermosensitive behavior that is observed for the nondisulfide-functionalized control worm gel. However, macroscopic precipitation occurred when the proportion of DSDB-based macro-CTA was increased to 50 mol %, whereas the DSDMA-based macro-CTA could be utilized at up to 80 mol %. Finally, the worm gel modulus could be reduced to that of a nondisulfide-containing worm gel by reductive cleavage of the inter-worm disulfide bonds using excess tris(2-carboxyethyl)phosphine (TCEP) to yield thiol groups. These new biomimetic worm gels are expected to exhibit enhanced muco-adhesion.

Disulfide-Based Diblock Copolymer Worm Gels: A Wholly-Synthetic Thermoreversible 3D Matrix for Sheet-Based Cultures.

It is well-known that 3D in vitro cell cultures provide a much better model than 2D cell cultures for understanding the in vivo microenvironment of cells. However, significant technical challenges in handling and analyzing 3D cell cultures remain, which currently limits their widespread application. Herein, we demonstrate the application of wholly synthetic thermoresponsive block copolymer worms in sheet-based 3D cell culture. These worms form a soft, free-standing gel reversibly at 20-37 °C, which can be rapidly converted into a free-flowing dispersion of spheres on cooling to 5 °C. Functionalization of the worms with disulfide groups was found to be essential for ensuring sufficient mechanical stability of these hydrogels to enable long-term cell culture. These disulfide groups are conveniently introduced via statistical copolymerization of a disulfide-based dimethacrylate under conditions that favor intramolecular cyclization and subsequent thiol/disulfide exchange leads to the formation of reversible covalent bonds between adjacent worms within the gel. This new approach enables cells to be embedded within micrometer-thick slabs of gel with good viability, permits cell culture for at least 12 days, and facilitates recovery of viable cells from the gel simply by incubating the culture in buffer at 4 °C (thus, avoiding the enzymatic degradation required for cell harvesting when using commercial protein-based gels, such as Matrigel).

Effect of an office ergonomic randomised controlled trial among workers with neck and upper extremity pain.

BACKGROUND: Office computer workers are at increased risk for neck/upper extremity (UE) musculoskeletal pain. METHODS: A seven-month office ergonomic intervention study evaluated the effect of two engineering controls plus training on neck/UE pain and mechanical exposures in 113 computer workers, including a 3-month follow-up period. Participants were randomised into an intervention group, who received a keyboard/mouse tray (KBT), touch pad (TP) for the non-dominant hand and keyboard shortcuts, and a control group who received keyboard shortcuts. Participants continued to have available a mouse at the dominant hand. Outcomes were pain severity, computer rapid upper limb assessment (RULA), and hand activity level. Prevalence ratios (PRs) evaluated intervention effects using dichotomised pain and exposure scores. RESULTS: In the intervention group, the dominnt proximal UE pain PR=0.9, 95% CI 0.7 to 1.2 and the dominant distal UE PR=0.8, 95% CI 0.5 to 1.3, postintervention. The non-dominant proximal UE pain PR=1.0, 95% CI 0.8 to 1.4, while the non-dominant distal UE PR=1.2, 95% CI 0.6 to 2.2, postintervention. Decreases in non-neutral postures were found in two RULA elements (non-dominant UE PR=0.9, 95% CI 0.8 to 0.9 and full non-dominant RULA PR=0.8, 95% CI 0.8 to 0.9) of the intervention group. Hand activity increased on the non-dominant side (PR=1.4, 95% CI 1.2 to 1.6) in this group. CONCLUSIONS: While the intervention reduced non-neutral postures in the non-dominant UE, it increased hand activity in the distal region of this extremity. To achieve lower hand activity, a KBT and TP used in the non-dominant hand may not be the best devices to use.

Long range order and two-fluid behavior in heavy electron materials.

The heavy electron Kondo liquid is an emergent state of condensed matter that displays universal behavior independent of material details. Properties of the heavy electron liquid are best probed by NMR Knight shift measurements, which provide a direct measure of the behavior of the heavy electron liquid that emerges below the Kondo lattice coherence temperature as the lattice of local moments hybridizes with the background conduction electrons. Because the transfer of spectral weight between the localized and itinerant electronic degrees of freedom is gradual, the Kondo liquid typically coexists with the local moment component until the material orders at low temperatures. The two-fluid formula captures this behavior in a broad range of materials in the paramagnetic state. In order to investigate two-fluid behavior and the onset and physical origin of different long range ordered ground states in heavy electron materials, we have extended Knight shift measurements to URu(2)Si(2), CeIrIn(5), and CeRhIn(5). In CeRhIn(5) we find that the antiferromagnetic order is preceded by a relocalization of the Kondo liquid, providing independent evidence for a local moment origin of antiferromagnetism. In URu(2)Si(2) the hidden order is shown to emerge directly from the Kondo liquid and so is not associated with local moment physics. Our results imply that the nature of the ground state is strongly coupled with the hybridization in the Kondo lattice in agreement with phase diagram proposed by Yang and Pines.

pH-responsive non-ionic diblock copolymers: ionization of carboxylic acid end-groups induces an order-order morphological transition.

A carboxylic acid based reversible additionfragmentation transfer (RAFT) agent is used to prepare gels composed of worm-like diblock copolymers using two non-ionic monomers, glycerol monomethacrylate (GMA) and 2-hydroxypropyl methacrylate (HPMA). Ionization of the carboxylic acid end-group on the PGMA stabilizer block induces a worm-to-sphere transition, which in turn causes immediate degelation. This morphological transition is fully reversible as determined by TEM and rheology studies and occurs because of a subtle change in the packing parameter for the copolymer chains. A control experiment where the methyl ester derivative of the RAFT agent is used to prepare the same diblock copolymer confirms that no pH-responsive behavior occurs in this case. This end-group ionization approach is important for the design of new pH-responsive copolymer nano-objects as, unlike polyacids or polybases, only a minimal amount of added base (or acid) is required to drive the morphological transition.

Polymerization-induced self-assembly of block copolymer nano-objects via RAFT aqueous dispersion polymerization.

In this Perspective, we discuss the recent development of polymerization-induced self-assembly mediated by reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization. This approach has quickly become a powerful and versatile technique for the synthesis of a wide range of bespoke organic diblock copolymer nano-objects of controllable size, morphology, and surface functionality. Given its potential scalability, such environmentally-friendly formulations are expected to offer many potential applications, such as novel Pickering emulsifiers, efficient microencapsulation vehicles, and sterilizable thermo-responsive hydrogels for the cost-effective long-term storage of mammalian cells.

RAFT aqueous dispersion polymerization yields poly(ethylene glycol)-based diblock copolymer nano-objects with predictable single phase morphologies.

A poly(ethylene glycol) (PEG) macromolecular chain transfer agent (macro-CTA) is prepared in high yield (>95%) with 97% dithiobenzoate chain-end functionality in a three-step synthesis starting from a monohydroxy PEG113 precursor. This PEG113-dithiobenzoate is then used for the reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization of 2-hydroxypropyl methacrylate (HPMA). Polymerizations conducted under optimized conditions at 50 °C led to high conversions as judged by (1)H NMR spectroscopy and relatively low diblock copolymer polydispersities (M(w)/M(n) < 1.25) as judged by GPC. The latter technique also indicated good blocking efficiencies, since there was minimal PEG113 macro-CTA contamination. Systematic variation of the mean degree of polymerization of the core-forming PHPMA block allowed PEG113-PHPMA(x) diblock copolymer spheres, worms, or vesicles to be prepared at up to 17.5% w/w solids, as judged by dynamic light scattering and transmission electron microscopy studies. Small-angle X-ray scattering (SAXS) analysis revealed that more exotic oligolamellar vesicles were observed at 20% w/w solids when targeting highly asymmetric diblock compositions. Detailed analysis of SAXS curves indicated that the mean number of membranes per oligolamellar vesicle is approximately three. A PEG113-PHPMA(x) phase diagram was constructed to enable the reproducible targeting of pure phases, as opposed to mixed morphologies (e.g., spheres plus worms or worms plus vesicles). This new RAFT PISA formulation is expected to be important for the rational and efficient synthesis of a wide range of biocompatible, thermo-responsive PEGylated diblock copolymer nano-objects for various biomedical applications.

Polymersome-mediated intracellular delivery of antibiotics to treat Porphyromonas gingivalis-infected oral epithelial cells.

The gram-negative anaerobe Porphyromonas gingivalis colonizes the gingival crevice and is etiologically associated with periodontal disease that can lead to alveolar bone damage and resorption, promoting tooth loss. Although susceptible to antibiotics, P. gingivalis can evade antibiotic killing by residing within gingival keratinocytes. This provides a reservoir of organisms that may recolonize the gingival crevice once antibiotic therapy is complete. Polymersomes are nanosized amphiphilic block copolymer vesicles that can encapsulate drugs. Cells internalize polymersomes by endocytosis into early endosomes, where they are disassembled by the low pH, causing intracellular release of their drug load. In this study, polymersomes were used as vehicles to deliver antibiotics in an attempt to kill intracellular P. gingivalis within monolayers of keratinocytes and organotypic oral mucosal models. Polymersome-encapsulated metronidazole or doxycycline, free metronidazole, or doxycycline, or polymersomes alone as controls, were used, and the number of surviving intracellular P. gingivalis was quantified after host cell lysis. Polymersome-encapsulated metronidazole or doxycycline significantly (P<0.05) reduced the number of intracellular P. gingivalis in both monolayer and organotypic cultures compared to free antibiotic or polymersome alone controls. Polymersomes are effective delivery vehicles for antibiotics that do not normally gain entry to host cells. This approach could be used to treat recurrent periodontitis or other diseases caused by intracellular-dwelling organisms.

Fully synthetic polymer vesicles for intracellular delivery of antibodies in live cells.

There is an emerging need both in pharmacology and within the biomedical industry to develop new tools to target intracellular mechanisms. The efficient delivery of functionally active proteins within cells is potentially a powerful research strategy, especially through the use of antibodies. In this work, we report on a nanovector for the efficient encapsulation and delivery of antibodies into live cells with no significant loss of cell viability or any deleterious effect on cell metabolic activity. This delivery system is based on poly[2-(methacryloyloxy)ethyl phosphorylcholine]-block-[2-(diisopropylamino)ethyl methacrylate] (PMPC-PDPA), a pH-sensitive diblock copolymer that self-assembles to form nanometer-sized vesicles, also known as polymersomes, at physiological pH. Polymersomes can successfully deliver relatively high antibody payloads within different types of live cells. We demonstrate that these antibodies can target their respective epitope showing immunolabeling of γ-tubulin, actin, Golgi protein, and the transcription factor NF-κB in live cells. Finally, we demonstrate that intracellular delivery of antibodies can control specific subcellular events, as well as modulate cell activity and proinflammatory processes.

Polymersome-mediated delivery of combination anticancer therapy to head and neck cancer cells: 2D and 3D in vitro evaluation.

Polymersomes have the potential to encapsulate and deliver chemotherapeutic drugs into tumor cells, reducing off-target toxicity that often compromises anticancer treatment. Here, we assess the ability of the pH-sensitive poly 2-(methacryloyloxy)ethyl phosphorylcholine (PMPC)- poly 2-(diisopropylamino)ethyl methacrylate (PDPA) polymersomes to encapsulate chemotherapeutic agents for effective combinational anticancer therapy. Polymersome uptake and ability to deliver encapsulated drugs into healthy normal oral cells and oral head and neck squamous cell carcinoma (HNSCC) cells was measured in two and three-dimensional culture systems. PMPC-PDPA polymersomes were more rapidly internalized by HNSCC cells compared to normal oral cells. Polymersome cellular uptake was found to be mediated by class B scavenger receptors. We also observed that these receptors are more highly expressed by cancer cells compared to normal oral cells, enabling polymersome-mediated targeting. Doxorubicin and paclitaxel were encapsulated into pH-sensitive PMPC-PDPA polymersomes with high efficiencies either in isolation or as a dual-load for both singular and combinational delivery. In monolayer culture, only a short exposure to drug-loaded polymersomes was required to elicit a strong cytotoxic effect. When delivered to three-dimensional tumor models, PMPC-PDPA polymersomes were able to penetrate deep into the center of the spheroid resulting in extensive cell damage when loaded with both singular and dual-loaded chemotherapeutics. PMPC-PDPA polymersomes offer a novel system for the effective delivery of chemotherapeutics for the treatment of HNSCC. Moreover, the preferential internalization of PMPC polymersomes by exploiting elevated scavenger receptor expression on cancer cells opens up the opportunity to target polymersomes to tumors.