Water-soluble nanoparticles from random copolymer and oppositely charged surfactant, 3a. Nanoparticles of poly(ethylene glycol)-based cationic random copolymer and fatty acid salts

In this report, we investigate the nanoparticle formation between random copolymers (RCPs) of methoxy-poly(ethylene glycol) monomethacrylate (MePEGMA) and (3-(methacryloylamino)propyl)trimethylammonium chloride (MAPTAC) and oppositely charged natural surfactants, sodium oleate and sodium laurate, using turbidimetric titration, steady-state fluorescence, dynamic light scattering, and electron microscopy. Though sodium oleate and sodium laurate are sparingly soluble in water, the nanoparticle complexes formed between the RCPs and these surfactants are soluble in the entire range of compositions studied here, including the stoichiometric electronetural complexes. The spherical nature of these nanoparticle complexes is revealed by electron microscopic (EM) analysis. Dynamic light scattering (DLS) showed that the average diameters of the nanoparticles are in the range 50 to 150 nm, which is supported by EM analysis. Pyrene fluorescence experiments suggested that these soluble nanoparticles have hydrophobic cores, which may solubilize hydrophobic drug molecules. The polarity index (I(1)/I(3)) obtained from the pyrene fluorescence spectra and the conductometric measurements showed that the critical concentration of fatty acid salts needed to obtain nanoparticles are in the order of 10(-4) M. Further, the complexation of such poorly water-soluble amphiphilic surfactants with polymers offers a useful method for the immobilization of hydrophobic compounds towards water-soluble drug carrier formulations. The formation of water-soluble nanoparticles by the self-assembly of fatty acid salts upon interacting with oppositely charged poly(ethylene glycol)-based polyions.     

Nanosegregated polymeric domains on the surface of Fe3O4@SiO2 particles

Multifunctional, biocompatible, and brush‐grafted poly(ethylene glycol)/poly(ε‐caprolactone) (PEG/PCL) nanoparticles have been synthesized, characterized, and used as vehicles for transporting hydrophobic substances in water. For anchoring the polymer mixed brushes, we used magnetic‐silica particles of 40 nm diameter produced by the reverse microemulsion method. The surface of the silica particle was functionalized with biocompatible polymer brushes, which were synthesized by the combination of “grafting to” and “grafting from” techniques. PEG was immobilized on the particles surface, by “grafting to,” whereas PCL was growth by ROP using the “grafting from” approach. By varying the synthetic conditions, it was possible to control the amount of PCL anchored on the surface of the nanoparticles and consequently the PEG/PCL ratio, which is a vital parameter connected with the arrangement of the polymer brushes as well as the hydrophobic/hydrophilic balance of the particles. Thus, adjusting the PEG/PCL ratio, it was possible to obtain a system formed by PEG and PCL chains grafted on the particle's surface that collapsed in segregated domains depending on the solvent used. For instance, the nanoparticles are colloidally stable in water due to the PEG domains and at the same time are able to transport, entrapped within the PCL portion, highly water‐insoluble drugs. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2966–2975     

Design and Preparation of Single‐Chain Nanocarriers Mimicking Disordered Proteins for Combined Delivery of Dermal Bioactive Cargos

Inspired by the multifunctionality of vitamin D‐binding protein and the multiple transient‐binding behavior of some intrinsically disordered proteins (IDPs), a polymeric platform is designed, prepared, and characterized for combined delivery of dermal protective and anticancer bioactive cargos on the basis of artificial single‐chain nano‐objects mimicking IDPs. For the first time ever, simultaneous delivery of folic acid or vitamin B₉, and hinokitiol, a relevant natural bioactive compound that exhibits anticancer activity against human malignant melanoma cells, from these multidirectionally self‐assembled unimolecular nanocarriers is illustrated.

     

Biological and Medical Applications of Calcium Phosphate Nanoparticles

Calcium phosphate nanoparticles have a high biocompatibility and biodegradability due to their chemical similarity to human hard tissue, for example, bone and teeth. They can be used as efficient carriers for different kinds of biomolecules such as nucleic acids, proteins, peptides, antibodies, or drugs, which alone are not able to enter cells where their biological effect is required. They can be loaded with cargo molecules by incorporating them, unlike solid nanoparticles, and also by surface functionalization. This offers protection, for example, against nucleases, and the possibility for cell targeting. If such nanoparticles are functionalized with fluorescing dyes, they can be applied for imaging in vitro and in vivo. Synthesis, functionalization and cell uptake mechanisms of calcium phosphate nanoparticles are discussed together with applications in transfection, gene silencing, imaging, immunization, and bone substitution. Biodistribution data of calcium phosphate nanoparticles in vivo are reviewed.     

Chemical Design of Nuclear‐Targeting Mesoporous Silica Nanoparticles for Intra‐nuclear Drug Delivery

Targeted drug delivery has been widely explored for efficient tumor therapy with desired efficacy but minimized side effects. It is widely known that large numbers of DNA‐toxins, such as doxorubicin, genes, reactive oxygen species, serving as therapeutic agents, can result in maximized therapeutic effects via the interaction directly with DNA helix. So after cellular uptake, these agents should be further delivered into cell nuclei to play their essential roles in damaging the DNA helix in cancer cells. Here, we demonstrate the first paradigm established in our laboratory in developing nuclear‐targeted drug delivery systems (DDSs) based on MSNs for enhanced therapeutic efficiency in the hope of speeding their translation into the clinics. Firstly, nuclear‐targeting DDSs based on MSNs, capable of intranuclear accumulation and drug release therein, were designed and constructed for the first time, resulting in much enhanced anticancer effects both in vitro and in vivo. Such an MSNs‐based and nuclear‐targeted drug/agent delivery strategy was further applied to overcome multidrug resistance (MDR) of malignant tumors, intra‐nuclearly deliver therapeutic genes, photosensitizers, radio‐enhancement agents and photothermal agents to realize efficient gene therapy, photodynamic therapy, radiation therapy and photothermal therapy, respectively.     

One‐Step Synthesis of Small‐Sized and Water‐Soluble NaREF4 Upconversion Nanoparticles for In Vitro Cell Imaging and Drug Delivery

Small (2–28 nm) NaREF₄ (rare earth (RE)=Nd–Lu, Y) nanoparticles (NPs) were prepared by an oil/water two‐phase approach. Meanwhile, hydrophilic NPs can be obtained through a successful phase‐transition process by introducing the amphiphilic surfactant sodium dodecylsulfate (SDS) into the same reaction system. Hollow‐structured NaREF₄ (RE=Y, Yb, Lu) NPs can be fabricated in situ by electron‐beam lithography on solid NPs. The MTT assay indicates that these hydrophilic NPs with hollow structures exhibit good biocompatibility. The as‐prepared hollow‐structured NPs can be used as anti‐cancer drug carriers for drug storage/release investigations. Doxorubicin hydrochloride (DOX) was taken as model drug. The release of DOX from hollow α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ exhibits a pH‐sensitive release patterns. Confocal microscopy observations indicate that the NPs can be taken up by HeLa cells and show obvious anti‐cancer efficacy. Furthermore, α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ NPs show bright‐red emission under IR excitation, making both the excitation and emission light fall within the “optical window” of biological tissues. The application of α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ in the luminescence imaging of cells was also investigated, which shows a bright‐red emission without background noise.     

pH-Responsive Self-assembled Nanoparticles of Simulated P(AA-co-SA)-g-PEG for Drug Release

Simulated graft copolymer of poly(acrylic acid-co-stearyl acylate) [P(AA-co-SA)] and poly(ethylene glycol) (PEG) was synthesized, where acrylic acid, stearyl acylate and PEG was employed as the pH-sensitive, hydrophobic and hydrophilic segment, respectively. Polymeric nanoparticles prepared by the dialysis of simulated graft copolymer solution in dimethylformamide against citrate buffer solution with different pH values were characterized by transmission electron microscopy (TEM), fluorescence technique and laser light scattering (LLS). TEM image revealed the spherical shape of the self-aggregates, which was further confirmed by LLS measurements. The critical aggregation concentration increased markedly (10 to 150 mg/L) with increasing pH (4.6 to 7.0), consistent with the de-protonation of carboxylic groups at higher pH. The hydrodynamic radius of polymeric nanoparticles decreased from 118 nm at pH 3.4 to 90 nm at pH 7.0. The controlled release of indomethacin from those nanoparticles was investigated, and the self-assembled nanoparticles exhibited improved performance in controlled drug release.     

Sticky nanoparticles: a platform for siRNA delivery by a bis(zinc(II) dipicolylamine)-functionalized, self-assembled nanoconjugate

Delivering the goods: Multifunctional, self-assembled, polymeric nanoparticles for the simultaneous delivery of small-molecule drugs and siRNA have been synthesized. The nanoparticles are composed of biodegradable hyaluronic acid, for tumor targeting and cellular delivery, and a high siRNA binding affinity is provided by a Zn(II)-dipicolylamine analogue as an artificial phosphate-binding receptor (see scheme).     

Syntheses of amphiphilic biodegradable copolymers of poly(ethyl ethylene phosphate) and poly(3-hydroxybutyrate) for drug delivery

Biodegradable and amphiphilic triblock copolymers poly(ethyl ethylene phosphate)-poly(3-hydroxy-butyrate)-poly(ethyl ethylene phosphate) (PEEP-b-PHB-b-PEEP) have been successfully synthesized through ring-opening polymerization. The structures are confirmed by gel permeation chromatography and NMR analyses. Crystallization investigated by X-ray diffraction reveals that the block copolymer with higher content of poly(ethyl ethylene phosphate) (PEEP) is more amorphous, showing decreased crystallizability. The obtained copolymers self-assemble into biodegradable nanoparticles with a core-shell micellar structure in aqueous solution, verified by the probe-based fluorescence measurements and transmission electronic microscopy (TEM) observation. The hydrophobic poly(3-hydroxybutyrate) (PHB) block serves as the core of the micelles and the micelles are stabilized by the hydrophilic PEEP block. The size and size distribution are related to the compositions of the copolymers. Paclitaxel (PTX) has been encapsulated into the micelles as a model drug and a sustained drug release from the micelles is observed. MTT assay also demonstrates that the block copolymers are biocompatible, rendering these copolymers attractive for drug delivery. Supported by the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No.20060358036)     

Synthesis of poly(ethylene glycol)/polypeptide/poly(D,L‐lactide) copolymers and their nanoparticles

Core‐shell structured nanoparticles of poly(ethylene glycol) (PEG)/polypeptide/poly(D ,L ‐lactide) (PLA) copolymers were prepared and their properties were investigated. The copolymers had a poly(L ‐serine) or poly(L ‐phenylalanine) block as a linker between a hydrophilic PEG and a hydrophobic PLA unit. They formed core‐shell structured nanoparticles, where the polypeptide block resided at the interface between a hydrophilic PEG shell and a hydrophobic PLA core. In the synthesis, poly(ethylene glycol)‐b‐poly(L ‐serine) (PEG‐PSER) was prepared by ring opening polymerization of N‐carboxyanhydride of O‐(tert‐butyl)‐L ‐serine and subsequent removal of tert‐butyl groups. Poly(ethylene glycol)‐b‐poly(L ‐phenylalanine) (PEG‐PPA) was obtained by ring opening polymerization of N‐carboxyanhydride of L ‐phenylalanine. Methoxy‐poly(ethylene glycol)‐amine with a MW of 5000 was used as an initiator for both polymerizations. The polymerization of D ,L ‐lactide by initiation with PEG‐PSER and PEG‐PPA produced a comb‐like copolymer, poly(ethylene glycol)‐b‐[poly(L ‐serine)‐g‐poly(D ,L ‐lactide)] (PEG‐PSER‐PLA) and a linear copolymer, poly(ethylene glycol)‐b‐poly(L ‐phenylalanine)‐b‐poly(D ,L ‐lactide) (PEG‐PPA‐PLA), respectively. The nanoparticles obtained from PEG‐PPA‐PLA showed a negative zeta potential value of ?16.6 mV, while those of PEG‐PSER‐PLA exhibited a positive value of about 19.3 mV. In pH 7.0 phosphate buffer solution at 36 °C, the nanoparticles of PEG/polypeptide/PLA copolymers showed much better stability than those of a linear PEG‐PLA copolymer having a comparable molecular weight. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Well‐Defined Poly(Ortho Ester Amides) for Potential Drug Carriers: Probing the Effect of Extra‐ and Intracellular Drug Release on Chemotherapeutic Efficacy

To compare the chemotherapeutic efficacy determined by extra‐ and intracellular drug release strategies, poly(ortho ester amide)‐based drug carriers (POEAd‐C) with well‐defined main‐chain lengths, are successfully constructed by a facile method. POEAd‐C3‐doxorubicin (DOX) can be rapidly dissolved to release drug at tumoral extracellular pH (6.5–7.2), while POEAd‐C6‐DOX can rapidly release drug following gradual swelling at intracellular pH (5.0–6.0). In vitro cytotoxicity shows that POEAd‐C3‐DOX exhibits more toxic effect on tumor cells than POEAd‐C6‐DOX at extracellular pH, but POEAd‐C6‐DOX has stronger tumor penetration and inhibition in vitro and in vivo tumor models. So, POEAd‐C6‐DOX with the intracellular drug release strategy has stronger overall chemotherapeutic efficacy than POEAd‐C3‐DOX with extracellular drug release strategy. It is envisioned that these poly(ortho ester amides) can have great potential as drug carriers for efficient chemotherapy with further optimization.

     

Poly(glycoamidoamine)s: Cationic glycopolymers for DNA delivery

Polymer science is playing an exciting role in inspiring and advancing novel discoveries in the area of genetic drug delivery. Polymeric materials can be synthesized and chemically tailored to bind and compact nucleic acids into viral‐like nanoparticles termed polyplexes that can deliver genetic materials into cells. This article highlights our work in this area to synthesize and study a novel class of cationic glycopolymers that we have termed poly(glycoamidoamine)s (PGAAs). The design of these materials has been inspired by many previous works in the literature. Carbohydrate comonomers have been incorporated into these structures to lower the toxicity of the delivery vehicle, and oligoamine moieties have been added to yield a cationic backbone that facilitates strong DNA binding, compaction, cellular uptake, and delivery of genetic material. PGAAs have been designed to vary in the carbohydrate size, the hydroxyl number and stereochemistry, the amine number, and the presence or absence of heterocyclic groups. Through structure–bioactivity studies, we have discovered that these materials are highly biocompatible, and each specific feature plays a large role in the observed delivery efficacy. Such structure–property studies are important for increasing our understanding of how the polymer chemistry affects the biological activity for the clinical development of polymer‐based therapeutics. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6895–6908, 2006     

In vitro enzymatic degradation of nanoparticles prepared from hydrophobically-modified poly(gamma-glutamic acid)

Amphiphilic poly(gamma-glutamic acid) (gamma-PGA) was prepared by the introduction of L-phenylalanine ethylester (L-PAE) as a side chain. This gamma-PGA-graft-L-PAE formed monodispersed nanoparticles in water. The particle size of the gamma-PGA nanoparticles could be controlled by the degree of L-PAE grafting. The hydrolytic degradation and enzymatic degradation by gamma-glutamyl transpeptidase (gamma-GTP) of these gamma-PGA nanoparticles was studied by gel permeation chromatography (GPC) and scanning electron microscopy (SEM). The hydrolysis ratio of gamma-PGA was found to decrease upon increasing the hydrophilicity of the gamma-PGA. The degradation of the gamma-PGA backbone by gamma-GTP resulted in a dramatic change in nanoparticle morphology. With increasing time, the gamma-PGA nanoparticles reduced in size and finally disappeared completely.Time-course of the changes in the morphology of the gamma-PGA nanoparticles following incubation with gamma-glutamyl transpeptidase.     

Salt Effects in the Cononsolvency of Poly(N‐isopropylacrylamide) Microgels

Poly(N‐isopropylacrylamide) (PNIPAM) is well known to exhibit reentrant behavior or cononsolvency in response to the composition of a mixed solvent consisting of water and a low‐chain alcohol. Since the solvent structure plays an important role in this phenomenon, the presence of structure‐breaking/structure‐making ions in solution is expected to have a dramatic effect on the cononsolvency of PNIPAM. The present work examines the way that the presence of different salts can modify the reentrant‐phase diagram displayed by a cationic PNIPAM microgel in the mixed ethanol/water solvent. The effects of four Hofmeister anions—SO₄^2?_, Cl^?, NO₃^? and SCN^?—with different abilities to modify the solvent structure are analyzed. The species with kosmotropic or structure‐making character show a clear competition with ethanol for the water molecules, intensifying the nonsolvency of the PNIPAM with the EtOH volume fraction (?_e). However, striking results are found with the most chaotropic or structure‐breaking anion, SCN^?. In contrast to what happens in water‐rich solutions, the presence of SCN^? in alcohol‐rich solvents enhances the solubility of the polymer, which macroscopically results in the microgel swelling. Moreover, this ion displays great stabilizing properties when ?_e> is 0.2. These results have been explained by considering how chaotropic or structure‐breaking ions interact with water and ethanol molecules.     

Synthesis of Poly(acyclic orthoester)s: Acid‐Sensitive Biomaterials for Enhancing Immune Responses of Protein Vaccine

While poly(acyclic orthoester)s (PAOEs) have many appealing features for drug delivery, their application is significantly hindered by a lack of facile synthetic methods. Reported here is a simple method for synthesizing acyclic diketene acetal monomers from diols and vinyl ether, and their polymerization with a diol to first synthesize PAOEs. The PAOEs rapidly hydrolyze at lysosomal pH. With the help of a cationic lipid, ovalbumin, a model vaccine antigen was efficiently loaded into PAOEs nanoparticles using a double emulsion method. These nanoparticles efficiently delivered ovalbumin into the cytosol of dendritic cells and demonstrated enhanced antigen presentation over poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles. PAOEs are promising vehicles for intracellular delivery of biopharmaceuticals and could increase the utility of poly(orthoesters) in biomedical research.