Hydrophilic Copolymers Research Articles

Complex Temperature and Concentration Dependent Self-Assembly of Poly(2-oxazoline) Block Copolymers.

The effect of polymer concentration on the temperature-induced self-association of a block copolymer comprising a poly(2-ethyl-2-oxazoline) block and a random copolymer block consisting of 2-ethyl-2-oxazoline and 2-n-propyl-2-oxazoline (PEtO80-block-P(EtOxx-stat-PropO40-x) with x = 0, 4, or 8 were investigated by dynamic light scattering (DLS) and transmittance measurements (turbidimetry). The polymers reveal a complex aggregation behavior with up to three relaxation modes in the DLS data and with a transmittance that first goes through a minimum before it declines at high temperatures. At low temperatures, unassociated polymer chains were found to co-exist with larger aggregates. As the temperature is increased, enhanced association and contraction of the aggregates results in a drop of the transmittance values. The aggregates fragment into smaller micellar-like clusters when the temperature is raised further, causing the samples to become optically clear again. At high temperatures, the polymers aggregate into large compact clusters, and the samples become turbid. Interestingly, very large aggregates were observed at low temperatures when the polymer concentrations were low. The formation of these aggregates was also promoted by a more hydrophilic copolymer structure. The formation of large aggregates with an open structure at conditions where the solvent conditions are improved is probably caused by depletion flocculation of the smaller aggregates.

Copolymer Composition and Nanoparticle Configuration Enhance in vitro Drug Release Behavior of Poorly Water-soluble Progesterone for Oral Formulations.

HypothesisDeveloping oral formulations to enable effective release of poorly water-soluble drugs like progesterone is a major challenge in pharmaceutics. Coaxial electrospray can generate drug-loaded nanoparticles of strategic compositions and configurations to enhance physiological dissolution and bioavailability of poorly water-soluble drug progesterone.ExperimentsSix formulations comprising nanoparticles encapsulating progesterone in different poly(lactide-co-glycolide) (PLGA) matrix configurations and compositions were fabricated and characterized in terms of morphology, molecular crystallinity, drug encapsulation efficiency and release behavior.FindingsA protocol of fabrication conditions to achieve 100% drug encapsulation efficiency in nanoparticles was developed. Scanning electron microscopy shows smooth and spherical morphology of 472.1±54.8 to 588.0±92.1 nm in diameter. Multiphoton Airyscan super-resolution confocal microscopy revealed core-shell nanoparticle configuration. Fourier transform infrared spectroscopy confirmed presence of PLGA and progesterone in all formulations. Diffractometry indicated amorphous state of the encapsulated drug. UV-vis spectroscopy showed drug release increased with hydrophilic copolymer glycolide ratio while core-shell formulations with progesterone co-dissolved in PLGA core exhibited enhanced release over five hours at 79.9±1.4% and 70.7±3.5% for LA:GA 50:50 and 75:25 in comparison with pure progesterone without polymer matrix in the core at 67.0±1.7% and 57.5±2.8%, respectively. Computational modeling showed good agreement with the experimental drug release behavior in vitro.

Coaxial Electrospun Fibermat of Poly(AM/DAAM)/ADH and PCL: Versatile Platform for Functioning Active Enzymes

Abstract In this study, we prepared and characterized enzyme (α-chymotrypsin or lactase)-encapsulating core-shell fibermats by electrospinning. The hydrophilic copolymer of acrylamide (AM) and diacetone acrylamide (DAAM), poly(AM/DAAM), was used as the base material to obtain the core unit of nanofibers. During electrospinning, poly(AM/DAAM) was crosslinked with the bifunctional crosslinker adipic acid dihydrazide (ADH) in the presence of enzyme molecules. The cores were wrapped with hydrophobic poly(ε-caprolactone) (PCL) layers as shell unit. Different from the fibermats of only poly(AM/DAAM)/ADH, the core-shell fibermat of poly(AM/DAAM)/ADH and PCL exhibited sufficient mechanical strength and stability of the stacked nanofibrous structure in a neutral-pH buffer. Furthermore, when the PCL-shell thickness was controlled to be less than 150 nm, the encapsulated enzymes exhibited an apparent activity of >70–80% for low-molecular weight substrates in an immersion buffer. These results indicate that the core-shell fibermats of poly(AM/DAAM)/ADH and PCL (or other hydrophobic polymer) could be used as effective enzyme-immobilizing platforms.

Effect of degree of deprotonation of maleic anhydride‐allyl polyethoxy carboxylic acid copolymer on calcium scale

AbstractA hydrophilic copolymer (MA‐APEA) containing carboxylic acid group and ethylene oxide group is synthesized from maleic anhydride (MA) and allyloxy polyethoxy carboxylic acid (APEA) in free radical polymerization and its structure is characterized using FT‐IR, 1H nuclear magnetic resonance spectrometer and gel permeation chromatographic techniques. Seven polymer solutions with different degrees of deprotonation are prepared by adding caustic solution to the polymer solution. Effects of the degree of deprotonation of the polymer on curbing calcium scale and the corrosion inhibition of low carbon steel are studied. Influences of the operating conditions on inhibition against CaCO3 scale by the polymer with different degrees of deprotonation are also investigated. Effects of the degree of deprotonation on CaCO3 deposits/precipitate are analyzed using scanning electronic microscope and X‐ray diffraction. The results show that different degrees of deprotonation of the polymer have different influences on different calcium scale and corrosion inhibition of low carbon steel. The performance of the polymer to withstand high alkalinity and high hardness and high temperature decreases with increase in the degree of deprotonation. The change in the degree of deprotonation influences the conversion of aragonite and vaterite to calcite, and hardly impacts the crystal morphology of CaCO3 crystals. MA‐APEA has proven to be an excellent calcium scale inhibitor.

Ex vivo investigations on bioinspired electrospun membranes as potential biomaterials for bone regeneration

ObjectivesTo assess the surface characteristics and composition that may enhance osteoblasts viability on novel electrospun composite membranes (organic polymer/silicon dioxide nanoparticles). MethodsMembranes are composed by a novel polymer blend, the mixture of two hydrophilic copolymers 2-hydroxyethylmethacrylate-co-methylmethacrylate and 2-hydroxyethylacrylate-co-methylacrylate, and they are doped with silicon dioxide nanoparticles. Then the membranes were functionalized with zinc or doxycycline. The membranes were morphologically characterized by atomic force and scanning electron microscopy (FESEM), and mechanically probed using a nanoindenter. Biomimetic calcium phosphate precipitation on polymeric tissues was assessed. Cell viability tests were performed using human osteosarcoma cells. Cells morphology was also studied by FESEM. Data were analyzed by ANOVA, Student-Newman-Keuls and Student t tests (p < 0.05). ResultsSilica doping of membranes enhanced bioactivity and increased mechanical properties. Membranes morphology and mechanical properties were similar to those of trabecular bone. Zinc and doxycycline doping did not exert changes but it increased novel membranes bioactivity. Membranes were found to permit osteoblasts proliferation. Silica-doping favored cells proliferation and spreading. As soon as 24 h after the seeding, cells in silica-doped membranes were firmly attached to experimental tissues trough filopodia, connected to each other. The cells produced collagen and minerals onto the surfaces. ConclusionsSilica nanoparticles enhanced surface properties and osteoblasts viability on electrospun membranes. Clinical significanceThe ability of silica-doped matrices to promote precipitation of calcium phosphate, together with their mechanical properties, observed non-toxicity, stimulating effect on osteoblasts and its surface chemistry allowing covalent binding of proteins, offer a potential strategy for bone regeneration applications.

Biodegradable Cell Microcarriers Based on Chitosan/Polyester Graft-Copolymers.

Self-stabilizing biodegradable microcarriers were produced via an oil/water solvent evaporation technique using amphiphilic chitosan-g-polyester copolymers as a core material in oil phase without the addition of any emulsifier in aqueous phase. The total yield of the copolymer-based microparticles reached up to 79 wt. %, which is comparable to a yield achievable using traditional emulsifiers. The kinetics of microparticle self-stabilization, monitored during their process, were correlated to the migration of hydrophilic copolymer’s moieties to the oil/water interface. With a favorable surface/volume ratio and the presence of bioadhesive natural fragments anchored to their surface, the performance of these novel microcarriers has been highlighted by evaluating cell morphology and proliferation within a week of cell cultivation in vitro.

Thin-film hydrogels with superior stiffness, strength, and stretchability

Thin-film polymers and hydrogels show great potential for applications in biomedical and engineering fields. However, owing to their defect sensitivity and weak behavior at micrometer-scale thicknesses, the recently developed thin-film hydrogels have limitations in their mechanical properties that impede their use in actual applications. To overcome these drawbacks, we adopted the hydrophobic–hydrophilic copolymer strategy for fabricating thin-film hydrogels with good mechanical properties using a novel benzene-based bulky hydrophobic monomer. Strong hydrophobic associations and benzene–benzene​ interactions of the hydrophobic-rich hard-phase regions of the copolymer gel imparted high stiffness and strength, and the concomitantly formed hydrophilic-rich soft-phase regions were sacrificed reversibly to achieve high stretchability and toughness. The resulting hydrogel, with a thickness of 550μm and ∼52 wt% water content, exhibits an excellent Young’s modulus (18.03 ± 5.92 MPa), tensile strength (4.3 ± 0.21 MPa), and work of extension (11.85 ± 2.17 MJ/m3). Moreover, our hydrogels show biocompatibility and high stability in different media such as water, seawater, and acidic and physiological solutions. These properties further strengthen their potential for applications in biomedical and engineering fields.

High-water-content hydrogels exhibiting superior stiffness, strength, and toughness

The low mechanical properties of high-water-content hydrogels often hinder their broad use in biomedical applications, especially in replacing/treating load-bearing tissues. Inspired by the protein structure of load-bearing tissues, we developed high-water-content hydrogels with excellent mechanical properties using a hydrophobic–hydrophilic copolymer strategy employing a benzene-based amphiphilic monomer, 5-acrylamidoisophthalic acid (AAI), as the major hydrophobic component and acrylamide (AAm) as the major hydrophilic component. The AAI monomer, connected with two –COOH functional groups, allowed the hydrogel to absorb excess water via H-bonding without compromising its homogeneity and structure. The AAI-rich hard-phase regions (via benzene–benzene interactions and hydrophobic associations) and AAm-rich soft-phase regions resulted in the high-water-content (∼80 wt%) hydrogel exhibiting a combination of good mechanical properties.

Metal-polymer Ag nanocomposites based on hydrophilic nitrogen- and sulfur-containing copolymers: control of nanoparticle size

New polymer nanocomposites containing silver nanoparticles, stabilized by hydrophilic copolymers of 1-vinyl-1,2,4-triazole with vinylsulfonic acid sodium salt of different composition, were synthesized. Nanocomposites formation was carried out by the method of chemical reduction of silver ions by sodium borohydride in an aqueous medium in the presence of co-polymer. It was established according to the results of transmission electron microscopy that obtained polymer nanocomposites consist of isolated silver nanoparticles of predominantly spherical shape with a diameter from 2 to 16 nm. It was found that composition of the stabilizing polymer matrix controls such nanocomposites parameters as the polydispersity index of nanoparticles (Dw/Dn = 1.44−1.34), hydrodynamic radii of macrocoils (266−1118 nm), and zeta potential (from −35.0 to −74.8 mV).

Water and oil resistance improvement of paper coated with aqueous mixture of hydrophilic and hydrophobic cross-linked copolymers

An aqueous mixture of hydrophilic and hydrophobic cross-linked copolymers was prepared and coated on the surface of filter paper to improve the water and oil resistances. The mixture was mainly composed of sodium alginate and hydroxyl-terminated polydimethylsiloxane (PDMS)-tetramethoxysilane (TMOS) cross-linked network. The results indicated that the resistances to both water and oil of the resulting paper were significantly enhanced. The water contact angle results demonstrated that the mixture enhanced the hydrophobic properties of the coated paper greatly with water contact angles higher than 110°, and the coated paper showed excellent oil resistance with a Kit number as high as 10.

Imidazole-functionalized hydrophilic rubbery comb copolymers: Microphase-separation and good gas separation properties

Imidazole groups have attracted considerable attention owing to their potential to be modified into ionic liquids, metal complexes, and biomimetic products. Herein, we report the synthesis of an imidazole-functionalized comb copolymer, i.e., poly(vinyl imidazole)-poly(oxyethylene methacrylate) (PVIm-POEM), via free-radical polymerization for a CO2 capture membrane. The imidazole group in PVIm-POEM exhibits a good interaction with the ethylene oxide groups of the POEM domain to cover the severe structural defects of PVIm domains. The selectivities of PVIm-POEM comb copolymer membranes were far greater than those of PVIm and POEM homopolymers. The PVIm domain not only provided a good physical property for generating a defect-free membrane but also generated an effective CO2-philic pathway via microphase separation and interactions with ethylene oxide groups. The highest performance was exhibited by PVIm-POEM37 (with a volumetric ratio of 3:7): the CO2 permeability reached 148.6 Barrer, and the CO2/N2 and CO2/CH4 selectivities reached 65.3 and 35.0, respectively, which represents one of the highest values for water/alcohol-soluble polymeric membranes without additives. The results suggest that the imidazole group-based copolymer provides avenues for future research through various types of reformation.

Thermo-associating polymers based on cross-linked 2-acrylamido-methylpropane sulfonic acid, part A: Synthesis and solution behavior

A novel thermo-thickening hydrophilic copolymer (CGBA) was prepared by free-radical copolymerization of sodium 2-acrylamido-2-methylpropane sulfonic acid (NaAMPS) with a newly-synthesized thermo-sensitive macromonomer (BA) and cross-linking N,N’-methylenebisacrylamide (MBA) in aqueous solution under optimal conditions. Its aqueous solution viscosity behavior with respect to temperature was preliminarily evaluated in comparison with its cross-linked sulfonated copolymer (CPAMPS) counterpart (without BA side-chains). Particular attention is dedicated to the thermo-thickening of the aqueous copolymer solutions as studied by the viscosity measurements. In pure water, and above 0.5 wt.%, CGBA manifested an abrupt macroscopic property above the critical association temperature (Tcass), while CPAMPS exhibited shear-thinning behavior following an Arrhenius law under the same conditions. The composition and length of BA side-chains were identified as the key parameters to envision the self-assembling behavior of CGBA. The results obtained from complementary experiments, performed by proton nuclear magnetic resonance (1H-NMR), Differential scanning calorimetry (DSC), and pyrene fluorescence showed the phase transition of BA side-chains above the Tcass. In addition, well above the Tcass (70 and 80 °C), the oscillatory shear experiments proved that the storage and loss modulus could be fitted with the single relation time Maxwell model at low frequencies. Furthermore, the magnitude of the thickening effect and the Tcass could be modulated using external factors such as shear rates, salinity, and pH. This, in combination with the cost-effectiveness, and the need to further broaden the established theory of thermo-sensitive comonomer, make this copolymer especially interesting for application not only in polymer flooding, but also in drilling fluid.

Antifogging/Antibacterial Coatings Constructed by N-Hydroxyethylacrylamide and Quaternary Ammonium-Containing Copolymers.

Endoscopic surgery has gained widespread applications in various clinical departments, and endoscope surfaces with antifogging and antibacterial properties are essential for elaborate procedures. In this work, novel antifogging/antibacterial coatings were developed from a cationic copolymer and a hydrophilic copolymer, polyhedral oligomeric silsesquioxane-poly(quaternary ammonium compound-co-2-aminoethyl methacrylate hydrochloride) [POSS-P(QAC-co-AEMA)] and poly(N-hydroxyethylacrylamide-co-glycidyl methacrylate) [P(HEAA-co-GMA)] via a facile and green blending method. Such transparent coatings showed excellent antifogging performance under both in vitro and in vivo fogging conditions, mainly attributed to the high water-absorbing capability of HEAA and QAC. Antibacterial assays proved that the blending coatings had a superior antibacterial property, which could be improved with the proportion of POSS-P(QAC-co-AEMA) because of the bactericidal efficiency of cationic QAC. Meanwhile, owing to the high hydratability of HEAA, the blending coatings exhibited a bacteria-repelling property. By simply tuning the blending ratio of POSS-P(QAC-co-AEMA) and P(HEAA-co-GMA), the comprehensive bacteria-killing and bacteria-repelling properties of the coatings were achieved. Moreover, after incubating with red blood cells, the prepared blending coatings presented a lower hemolytic rate of less than 5%. The findings provided a potential means for addressing the challenge of fogging and bacterial contamination occurring in endoscopic lenses and other medical devices.

Highly effective anti-tumor nanomedicines based on HPMA copolymer conjugates with pirarubicin prepared by controlled RAFT polymerization

Here, we describe innovative synthesis of well-defined biocompatible N-(2-hydroxypropyl) methacrylamide (HPMA)-based polymer carriers and their drug conjugates with pirarubicin intended for controlled drug delivery and pH-triggered drug activation in tumor tissue. Polymer carrier synthesis was optimized to obtain well-defined linear HPMA-based polymer precursor with dispersity close to 1 and molar mass close to renal threshold with minimal synthesis steps. The developed synthesis enables preparation of tailored polymer nanomedicines with highly enhanced biological behavior in vivo, especially the biodistribution, urine elimination, tumor accumulation and anticancer activity. Statement of SignificanceThe manuscript reports on novel synthesis and detailed physicochemical characterization and in vivo evaluation of well-defined biocompatible hydrophilic copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) and their drug conjugates with pirarubicin enabling controlled drug delivery and pH-triggered drug activation in tumor tissue. Polymer carrier synthesis was optimized to obtain well-defined linear HPMA-based polymer precursor with minimal synthesis steps using controlled polymerization. Compared to previously published HPMA-based polymer drug conjugates whose polymer carriers were prepared by classical route via free radical polymerization, the newly prepared polymer drug conjugates exhibited enhanced biological behavior in vivo, especially the prolonged blood circulation, urine elimination, tumor accumulation and excellent anticancer activity. We believe that the newly prepared well-defined polymer conjugates could significantly enhance tumor therapy in humans.

FORMULATION AND DETAILED CHARACTERIZATION OF VORICONAZOLE LOADED IN SITU GELS FOR OCULAR APPLICATION

Objective: This study was aimed to prepare, characterize and evaluate in situ gel formulation for a sustained ocular delivery of voriconazole. Material and Method: In situ gels were prepared with three different hydrophilic co-polymers: Poloxamer 188, 407 and 388. The formulations were characterized in terms of their clarity, pH, viscosity drug content uniformity and mechanical/rheological properties. Moreover, in vitro drug release and stabilitystudies were performed. Result and Discussion: The results showed that the optimized in situ gel formulation had desired in vitro properties and a good stability over the period of 3 months. Texture profile analysis presented that formulations offered suitable adhesive and mechanical properties. P2-V formulation exhibited pseudo-plastic flow and typical gel-type mechanical spectra (G′ > G″) at different frequecy values and at different temperatures. Moreover, all formulations showed a sustained drug release for 24 hours. In conclusion, voriconazole loaded in situ gel could be offered as an encouraging strategy as ocular systems for ocular infections treatment.

Formation of highly elastomeric and property-tailorable poly(glycerol sebacate)-co-poly(ethylene glycol) hydrogels through thiol-norbornene photochemistry.

Poly(glycerol sebacate) (PGS) is a synthetic biorubber that presents good biocompatibility, excellent elasticity and desirable mechanical properties for biomedical applications; however, the inherent hydrophobicity and traditional thermal curing of PGS restrict its use in the fabrication of hydrogels for advanced bioapplications. Here, we designed a new class of hydrophilic PGS-based copolymers that allow hydrogel formation through thiol-norbornene chemistry. Poly(glycerol sebacate)-co-polyethylene glycol (PGS-co-PEG) macromers were synthesized through a stepwise polycondensation reaction, and then the norbornene functional groups were introduced to the PGS-co-PEG structure to form norbornene-functionalized PGS-co-PEG (Nor_PGS-co-PEG). Nor_PGS-co-PEG macromers can be crosslinked using dithiols to prepare hydrogels in the presence of light and photoinitiators. The mechanical, swelling and degradation properties of Nor_PGS-co-PEG hydrogels can be controlled by altering the crosslinker amount. In particular, the elongation of Nor_PGS-co-PEG hydrogels can be modulated up to 950%. Nor_PGS-co-PEG can be processed using electrospinning and 3D printing techniques to generate microfibrous scaffolds and printed structures, respectively. In addition, the cytocompatibility of Nor_PGS-co-PEG was also demonstrated using in vitro cellular viability studies. These results indicate that Nor_PGS-co-PEG is a promising biomaterial with definable properties for scaffold manufacturing, presenting a great potential for biomedical applications.

Expansion of Ion Effects on Water Induced by a High Hydrophilic Surface of a Polymer Network.

The spatial extent and anion-cation cooperativity of the ion effect on the structure and dynamics of water have long been debated but are still controversial. Previously, we experimentally demonstrated the extensive and cooperative effect of ions on water in a polyamide network by measuring the reflection wavelength (λ) on the ion sensor of poly(N-isopropylacrylamide) (PNIPAAm) hydrogel-immobilized photonic crystals. In the present study, we investigated the influence of the polymer surface on the ion effect by adopting a highly hydrophilic poly(N-isopropylacrylamide-co-N-acryloylaza-18-crown-6) hydrogel as a sensor matrix. In alkaline earth metal salt solutions, the copolymer hydrogel membrane sensor showed the redshift of λ for the specific combination of cations and anions, that is, Ca2+/Cl- and Sr2+/NO3-, which resulted from the concerted binding of ion pairs to the copolymer receptor. In alkali metal salt solutions, the ion sensor showed the blueshift of λ originating from the osmotic dehydration suppressed by the salts. The strength of the ion effect was evaluated by the average osmotic pressure (ΠA) required for the salt-inhibited dehydration in the early stage of hydrogel contraction. From the calculation results of ΠA for the copolymer and PNIPAAm hydrogels, it was found that the high hydrophilic copolymer surface more significantly enhanced the ion effect of structure-making cations (i.e., Li+) compared with borderline (Na+) and structure-breaking (K+ and Cs+) cations. Furthermore, the ion effect exhibited the higher ion cooperativity in combination with chloride anions than with nitrate anions. The enhancement of the long-range cooperative ion effect is derived from the expansion of the interactions between ions, water molecules, and the hydrophilic polymer network.

Thermal and pH responsive ZnO-based nanoparticles for efficient drug delivery

In this paper, we reported a ZnO quantum dot (QD) based nano drug delivery system by surface modification of hydrophilic copolymer poly(methacrylate-co-N-isopropylacrylamide-co-polyethylene glycol methyl acrylate) (ZnO@PMNE) that was synthesized by the one step copolymerization method. The ZnO@PMNE nanoparticles (ZnO@PMNE NPs) have excellent stability and photoluminescence performance in water. Moreover, it is temperature responsive and biodegradable in an acid microenvironment. ZnO@PMNE NPs loaded with doxorubicin (DOX) will degrade to zinc ions (Zn2+) and DOX at an acidic tumor microenvironment. Moreover, the cytotoxicity of cancer cells was significantly increased because the ZnO QDs exhibited cytotoxicity postdissolution compared to normal cells, which will achieve a synergistic antitumor effect to improve the therapeutic index.

Copper-containing nanosystems based on macromolecular hydrophilic stabilizers

An original method for the synthesis of copper-containing nanosystems for biomedical applications using hydrazine hydrate as a reducing agent, intermediate stage of formation of complex ion [Cu(NH3)4]2+, which allows to obtain Cu0 nanoparticles without impurities of oxides has been developed. As a macromolecular hydrophilic stabilizer copolymer of 2-deoxy‑2-methacrylamido-D‑glucose with 2-dimethylaminoethylmethaacrylate or bovine serum albumin were used. It has been shown that such stabilization allows to achieve almost unimodal distribution of copper nanoparticles in aqueous solutions due to their rather good shielding by macromolecules.

Development of a Tumor-Responsive Nanopolyplex Targeting Pancreatic Cancer Cells and Stroma.

Desmoplasia plays a pivotal role in promoting pancreatic cancer progression and is associated with poor clinical outcome. Targeting the desmoplastic tumor microenvironment in combination with chemotherapy is therefore a promising strategy for pancreatic cancer therapy. Here, we report a novel biodegradable copolymer to codeliver LY2109761 (a TGF-β receptor I/II inhibitor) and CPI-613 (a novel chemotherapy agent) to desmoplastic stroma and tumor cells, respectively, in the tumor microenvironment. Hydrophobic CPI-613 is conjugated to the hydrophilic copolymer via a newly designed MMP-2-responsive linker to form a trigger-responsive nanopolyplex. LY2109761 is hydrophobic and encapsulated into the hydrophobic core of the nanopolyplex. The resulting nanopolyplex is modified with a plectin-1-targeting peptide to enhance the accumulation of the nanopolyplex in pancreatic tumors. The nanopolyplex aims to normalize the stroma by blocking the interaction between tumor cells and pancreatic stellate cells to inhibit the activation of pancreatic stellate cells and subsequently reduce the dense extracellular matrix. Normalized stroma increases the penetration of the nanopolyplex into the tumor. The nanopolyplex shows enhanced accumulation in xenograft pancreatic tumors in a biodistribution study. Moreover, the targeted nanopolyplex markedly inhibits tumor growth in an orthotopic pancreatic cancer mouse model by dual-targeting tumor cells and stroma. Overall, the multifunctional nanopolyplex is a promising platform for pancreatic cancer therapy.