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Purpose We evaluated the role of a poly(ethylene glycol) (PEG) surface coating to increase residence times and alter the cellular fate of nano- and microparticles delivered to the lung. Methods Three sizes of PRINT hydrogel particles (80 × 320 nm, 1.5 and 6 μm donuts) with and without a surface PEG coating were instilled in the airways of C57/b6 mice. At time points of 1, 7, and 28 days, BALF and whole lungs were evaluated for the inflammatory cytokine Il-6 and chemokine MIP-2, histopathology, cellular populations of macrophages, dendritic cells (DCs), and granulocytes, and particulate uptake within these cells through flow cytometry, ELISAs, and fluorescent imaging. Results Particles of all sizes and surface chemistries were readily observed in the lung with minimal inflammatory response at all time points. Surface modification with PEGylation was found to significantly increase lung residence times and homogeneous lung distribution, delaying macrophage clearance of all sizes, with the largest increase in residence time observed for 80 × 320 nm particles. Additionally, it was observed that DCs were recruited to the airway following administration of unPEGylated particles and preferentially associated with these particles. Conclusions Pulmonary drug delivery vehicles designed with a PEG surface coating can be used to delay particle uptake and promote cell-specific targeting of therapeutics.

Pluronic polymers (pluronics) are a unique class of synthetic triblock copolymers containing hydrophobic polypropylene oxide (PPO) and hydrophilic polyethylene oxide (PEO) arranged in the PEO-PPO-PEO manner. Due to their excellent biocompatibility and amphiphilic properties, pluronics are an ideal and promising biological material, which is widely used in drug delivery, disease diagnosis, and treatment, among other applications. Through self-assembly or in combination with other materials, pluronics can form nano carriers with different morphologies, representing a kind of multifunctional pharmaceutical excipients. In recent years, the utilization of pluronic-based multi-functional drug carriers in tumor treatment has become widespread, and various responsive drug carriers are designed according to the characteristics of the tumor microenvironment, resulting in major progress in tumor therapy. This review introduces the specific role of pluronic-based polymer drug delivery systems in tumor therapy, focusing on their physical and chemical properties as well as the design aspects of pluronic polymers. Finally, using newer literature reports, this review provides insights into the future potential and challenges posed by different pluronic-based polymer drug delivery systems in tumor therapy.

Controlled matrix interactions were presented to pancreatic β-cells in three-dimensional culture within poly(ethylene glycol) hydrogels. Dispersed MIN6 β-cells were encapsulated in gel environments containing the following entrapped extracellular matrix (ECM) proteins: collagen type I, collagen type IV, fibrinogen, fibronectin, laminin, and vitronectin. In ECM-containing gels, β-cell survival was significantly better than in gels without ECM over 10 days. Correspondingly, apoptosis in encapsulated β-cells was less in the presence of each matrix protein, suggesting the ability of individual matrix interactions to prevent matrix signaling-related apoptosis (anoikis). MIN6 β-cells cultured in gels containing collagen type IV or laminin secreted more insulin in response to glucose stimulation than β-cells in all other experimental conditions. Variations in collagen type IV or laminin concentration between 10 μg/mL and 250 μg/mL did not affect insulin secretion. Finally, β-cell function in hydrogels presenting both collagen type IV and laminin revealed synergistic interactions. With a total protein concentration of 100 μg/mL, three gel compositions of varying ratios of collagen type IV to laminin (25:75, 50:50, and 75:25) were tested. In the presence of 25 μg/mL of collagen type IV and 75 μg/mL of laminin, β-cell insulin secretion was greater than with laminin or collagen type IV individually. These results demonstrate that specific, rationally designed extracellular environments promote isolated β-cell survival and function.

Characterization and control of proteolysis of peptides by specific cellular protease is a priori requisite for effective drug discovery. Here, we report the nanomechanical, in situ monitoring of proteolysis of peptide chain attributed to protease (Cathepsin B) by using a resonant nanomechanical microcantilever immersed in a liquid. Specifically, the detection is based on measurement of resonant frequency shift arising from proteolysis of peptides (leading to decrease of cantilever's overall mass, and consequently, increases in the resonance). It is shown that resonant microcantilever enables the quantification of proteolysis efficacy with respect to protease concentration. Remarkably, the nanomechanical, in situ monitoring of proteolysis allows us to gain insight into the kinetics of proteolysis of peptides, which is well depicted by Langmuir kinetic model. This implies that nanomechanical biosensor enables the characterization of specific cellular protease such as its kinetics.

Stimuli-responsive biomaterials that contain logic gates hold great potential for detecting and responding to pathological markers as part of clinical therapies. However, a major barrier is the lack of a generalized system that can be used to easily assemble different ligand-responsive units to form programmable nanodevices for advanced biocomputation. Here we develop a programmable polymer library by including responsive units in building blocks with similar structure and reactivity. Using these polymers, we have developed a series of smart nanocarriers with hierarchical structures containing logic gates linked to self-immolative motifs. Designed with disease biomarkers as inputs, our logic devices showed site-specific release of multiple therapeutics (including kinase inhibitors, drugs and short interfering RNA) in vitro and in vivo. We expect that this ‘plug and play’ platform will be expanded towards smart biomaterial engineering for therapeutic delivery, precision medicine, tissue engineering and stem cell therapy.A programmable polymer library that responds to external and internal stimuli has been developed and used to fabricate a series of nanocarriers for drug release. The carriers respond to disease biomarkers, triggering self-immolative motifs and leading to the site-specific release of therapeutics both in vitro and in vivo.

Cell adhesion has tremendous impact on the function of culture platforms and implants. Cell-adhesive proteins and peptides have been extensively used for decades to promote cell adhesion, however, their application suffers from their easy enzymatic degradation, difficulty in large-scale preparation and expensiveness. To develop the next-generation cell-adhesive materials, we mimic the cell adhesion functions and mechanisms of RGD and KRSR peptides and design cell-adhesive cationic-hydrophobic amphiphilic β-amino acid polymers that are stable upon proteolysis and easily prepared in large scale at low cost. The optimal polymer strongly promotes cell adhesion, using preosteoblast cell as a model, by following dual mechanisms that are independent of sequence and chirality of the statistic copolymer. Our strategy opens avenues in designing the next-generation cell-adhesive materials and may guide future studies and applications. Cell adhesion peptides like RGD are important to biomedical applications but suffer from proteolysis as well as processing and cost issues. Here, the authors report on the development of cationic-hydrophobic amphiphilic β-amino acid polymers which function as cell adhesion motifs but are resistant to proteolysis.

Following induction therapy and 4 g/m(2) cyclophosphamide, a single dose of 12 mg polyethyleneglycol-conjugated G-CSF (pegfilgrastim; n=12) or daily doses of unconjugated G-CSF (8.5 mug/kg/day) (n=12) were administered to myeloma patients. Pegfilgrastim was associated with an earlier leukocyte recovery (12 vs 14 days) and peripheral blood CD34+ cell peak (12 vs 15 days). The peripheral blood CD34+ cell peak was lower in the pegfilgrastim group (78 vs 111/mul). Following high-dose melphalan (200 mg/m(2)) and autografting, leukocyte and platelet reconstitution was similar in both groups and stable blood counts were observed 100 days post transplant. In summary, a single dose of pegfilgrastim after chemotherapy is capable of mobilizing a sufficient number of CD34+ cells for successful autografting with early engraftment and sustained hematological reconstitution in patients with myeloma. These data provide the basis for randomized studies evaluating the optimal dose and time of pegfilgrastim as well as long-term outcome in larger cohorts of patients.

Root water uptake is influenced by root system architecture, which is determined by root growth and branching and the hydraulics of root cells and tissues. The phytohormone abscisic acid (ABA) plays a major role in the adaptation of plants to water deficit (WD). Here we addressed at the whole-root level in Arabidopsis (Arabidopsis thaliana) the regulatory role of ABA in mechanisms that determine root hydraulic architecture. Root system architecture and root hydraulic conductivity (Lpr) were analyzed in hydroponically grown plants subjected to varying degrees of WD induced by various polyethylene glycol (PEG) concentrations. The majority of root traits investigated, including first- and second-order lateral root production and elongation and whole-root hydraulics, had a bell-shaped dependency on WD, displaying stimulation under mild WD conditions (25 g PEG L²¹) and repression under more severe conditions. These traits also showed a bell-shaped dependency on exogenous ABA, and their regulation by WD was attenuated in genotypes altered in ABA biosynthesis and response. Thus, we propose that ABA acts as a coordinator and an integrator of most root responses to mild and moderate WD, whereas responses to strong WD (150 g PEG L²¹) are largely ABA independent. We also found that roots exhibit different growth responses to both WD and ABA depending on their rank and age. Taken together, our results give further insights into the coordinated water acquisition strategies of roots deployed in relation to WD intensity.

ABSTRACT An increasing number of pegylated therapeutic proteins and drug targeting compounds are being introduced in the clinic. Pegylation is intended to increase circulation time and to reduce an immunogenic response. Recently however a number of publications have appeared claiming that the polyethylene glycol (PEG) moiety of these products in itself may be immunogenic and that the induced anti-PEG antibodies are linked to enhanced blood clearance and reduced efficacy of the products. A critical review of the literature shows that most, if not all assays for anti-PEG antibodies are flawed and lack specificity. Also the biological effects induced by anti-PEG antibodies lack the characteristics of a bona fide antibody reaction. Standardization of the anti-PEG assays and the development of reference sera are urgently needed.

Protective mucus coatings typically trap and rapidly remove foreign particles from the eyes, gastrointestinal tract, airways, nasopharynx, and female reproductive tract, thereby strongly limiting opportunities for controlled drug delivery at mucosal surfaces. No synthetic drug delivery system composed of biodegradable polymers has been shown to penetrate highly viscoelastic human mucus, such as non-ovulatory cervicovaginal mucus, at a significant rate. We prepared nanoparticles composed of a biodegradable diblock copolymer of poly(sebacic acid) and poly(ethylene glycol) (PSA-PEG), both of which are routinely used in humans. In fresh undiluted human cervicovaginal mucus (CVM), which has a bulk viscosity approximately 1,800-fold higher than water at low shear, PSA-PEG nanoparticles diffused at an average speed only 12-fold lower than the same particles in pure water. In contrast, similarly sized biodegradable nanoparticles composed of PSA or poly(lactic-co-glycolic acid) (PLGA) diffused at least 3,300-fold slower in CVM than in water. PSA-PEG particles also rapidly penetrated sputum expectorated from the lungs of patients with cystic fibrosis, a disease characterized by hyperviscoelastic mucus secretions. Rapid nanoparticle transport in mucus is made possible by the efficient partitioning of PEG to the particle surface during formulation. Biodegradable polymeric nanoparticles capable of overcoming human mucus barriers and providing sustained drug release open significant opportunities for improved drug and gene delivery at mucosal surfaces.