Thermosensitive and photocleavable polyaspartamide derivatives for drug delivery

The development of novel thermo‐ and photo‐dual‐responsive biodegradable polymeric micelles based on amphiphilic polyaspartamide derivatives (NB‐g‐PHPA‐g‐mPEG) for anticancer drug delivery is reported. The obtained polymers containing hydrophobic photocleavable o‐nitrobenzyl groups exhibit thermo‐ and photosensitivity. The micelles and paclitaxel‐loaded micelles based on the thermo‐ and photo‐dual‐sensitive polymers were prepared by a quick heating method without using toxic organic solvent. The paclitaxel release from the drug‐loaded micelles can be triggered under photoirradiation. Enhancement of the anticancer activity against HeLa cells was observed for paclitaxel‐loaded NB‐g‐PHPA‐g‐mPEG micelles after light irradiation, while the empty NB‐g‐PHPA‐g‐mPEG micelles with or without irradiation did not show any toxicity. Therefore, the thermo‐ and photo‐dual‐responsive NB‐g‐PHPA‐g‐mPEG micelles have a promising future applied as a light controlled drug delivery system for anticancer drugs. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2855–2863     

Hybrid alginate beads with thermal‐responsive gates for smart drug delivery

Polysaccharide‐based thermo‐responsive material was prepared by grafting PNIPAAm onto hybrid alginate beads, in which a biomineralized polyelectrolyte layer was constructed aiming to enhance the mechanical strength and ensure higher graft efficiency. XPS results demonstrated that the incorporation of PNIPAAm to the hybrid beads was successful, and the PNIPAAm‐grafted beads were more hydrophilic than the ungrafted ones as indicated by their swelling behavior. The drug release behaviors revealed that the grafted beads were both thermo‐ and pH‐sensitive, and the PNIPAAm existed in the pores of the alginate beads acted as the “on–off” gates: the pores of the beads were covered by the stretched PNIPAAm to delay the drug release at 25°C and opened to accelerate the drug release at 37°C because of the shrinking of PNIPAAm molecules. This paper would be a useful example of grafting thermo‐responsive polymers onto biodegradable natural polymer substrate. The obtained beads provide a new mode of behavior for thermo‐responsive “smart” polysaccharide materials, which is highly attractive for targeting drug delivery system and chemical separation. Copyright © 2010 John Wiley & Sons, Ltd.     

Novel alginate-poly(L-histidine) microcapsules as drug carriers: in vitro protein release and short term stability

Spherical, smooth-surfaced and mechanically stable alginate-poly(L-histidine) (PLHis) microcapsules with narrow particle size distributions were prepared by incubating calcium alginate beads in aqueous solutions of PLHis. The in vitro release characteristics, drug loading and encapsulation efficiency of the microcapsules were investigated using bovine erythrocytes hemoglobin (Hb) as a model drug. The results showed that the concentration of Ca(2+) ions had a considerable effect on the drug loading, encapsulation efficiency and in vitro release behavior of the microcapsules. When the concentration of CaCl(2) in the PLHis solution was increased from 0 to 3.0% (w/v), the drug loading and encapsulation efficiency decreased significantly from 38.0 to 4.3% and from 92.9 to 8.0%, respectively, while the total cumulative release of Hb from microcapsules in phosphate buffered saline solution (PBS, pH 6.8) decreased from 96.2 to 72.8% in 24 h. No significant protein release was observed during 70 h of incubation in hydrochloric acid solution (pH 1.2). However, under neutral conditions (PBS, pH 6.8), the Hb was completely and stably released within 24-70 h. An explosion test showed that the stability of alginate-PLHis microcapsules depended strongly on the concentration of PLHis and the calcium ions in solution. [Diagram: see text] Microscopy photo of Hb-loaded alginate-PLHis microcapsules.     

Newly designed hydrogel with both sensitive thermoresponse and biodegradability

The synthesis and characterization of thermoresponsive hydrogels on the basis of N‐isopropylacrylamide (IPAAm) copolymers crosslinked with biodegradable poly(amino acids) are described. This hydrogel was prepared with two kinds of reactive IPAAm‐based copolymers containing poly(amino acids) as the side‐chain groups and activated ester groups. We introduced the graft chains by decarboxylation polymerization of amino acid N‐carboxyanhydrides initiated from lateral amino groups in the PIPAAm copolymer. The hydrogels easily crosslinked with degradable poly(amino acid) chains by only mixing the copolymer aqueous solutions. The gelling method in this study would provide some of the following innovative features: (1) no necessary removal of unreacted monomers and so forth, (2) simpler loading of drugs into the hydrogels (only mixing when gelling), and (3) easier insertion into the body. On the basis of the swelling ratio measurement of the hydrogel, large volume changes dependent on temperature changes were observed. Moreover, the enzymatic temperature‐dependent degradation was confirmed. The results suggested that these hydrogels could be used for an injectable or implantable matrix of temperature‐modulated drug release. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 779–787, 2003     

Biodegradable and thermosensitive micelles of amphiphilic polyaspartamide derivatives containing aromatic groups for drug delivery

The preparation, characterization, release, and in vitro cytotoxicity of a biodegradable polymeric micellar formulation of paclictaxel (PTX) were investigated. The micelles based on thermosensitive and degradable amphiphilic polyaspartamide derivatives containing pendant aromatic structures (phe‐g‐PHPA‐g‐mPEG) were prepared by a quick heating method without using toxic organic solvent. Dynamic light‐scattering results show that the micelles are stable upon dilution under physiological conditions and the destabilization of the micelles is pH‐dependent and the phe‐g‐PHPA‐g‐mPEG polymers are biodegradable. PTX was loaded into the phe‐g‐PHPAs‐g‐mPEG micelles with encapsulation efficiency of >90%, resulting in a high drug loading content (up to 29%). PTX‐loaded micelles had a mean size around 70 nm with narrow size distribution (polydispersity index, <0.1). The PTX‐loaded micelles showed sustained drug release and obvious anticancer activity similar to Taxol against HepG2 cells, whereas blank micelles were nontoxic. The present results suggest that the thermosensitive and biodegradable phe‐g‐PHPA‐g‐mPEG micelles are a promising delivery system for the hydrophobic drugs. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3917–3924     

Temperature and pH dual‐sensitive polyaspartamide derivatives for antitumor drug delivery

The pH‐sensitive tertiary amino groups were introduced to synthesize temperature and pH dual‐sensitive degradable polyaspartamide derivatives (phe/DEAE‐g‐PHPA) containing pendant aromatic structures and ionizable tertiary amino groups. The thermo/pH‐responsive behavior of phe/DEAE‐g‐PHPA polymer can be tuned by adjusting the graft copolymer composition. Due to the pH sensitivity of the phe/DEAE‐g‐PHPA‐g‐mPEG polymer with hydrophilic long PEG chain, the micelles and the anticancer drug‐loaded micelles were prepared by a quick pH‐changing method without using toxic organic solvent. The obtained polymeric micelles, paclitaxel‐loaded micelles and doxorubicin‐loaded micelles were stable under physiological conditions. Both the drug‐loaded micelles showed much faster release at pH 5 than at pH 7.4. The doxorubicin‐loaded micelles showed obvious and better anticancer activity against both HepG2 and HeLa cells than free doxorubicin. Thus these nontoxic, dual thermo‐ and pH‐sensitive phe/DEAE‐g‐PHPA‐g‐mPEG micelles may be a promising anticancer drug delivery system. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 879–888     

Formulation characterization and in vitro evaluation of acacia gum–calcium alginate beads for oral drug delivery systems

In the present work, new matrix bead formulations based on linear and branched polysaccharides have been developed using an ionic gelation technique, and their potential use as oral drug carriers has been evaluated. Using calcium chloride as a cross‐linking agent and sodium diclofenac (SD), as a model drug, acacia gum–calcium alginate matrix beads were formulated. The response surface methodology based on 3² factorial design was used as a statistical method to evaluate and optimize the effects of the biopolymers‐blend ratio and the concentration of calcium chloride on the particle size (mm), density (g/cm³), drug encapsulation efficiency (%), and the cumulative drug release after 8 hours (R_8h,%). The optimized beads with the highest drug encapsulation efficiency were examined for a drug‐excipients compatibility by powder X‐ray diffraction, differential scanning calorimetry, thermo‐gravimetric analysis, and Fourier transform‐infrared spectroscopy analyses. The swelling and degradation of the matrix beads were found to be influenced by the pH of medium. Higher degrees of swelling were observed in intestinal pH than in stomach pH. Accordingly, the drug release study showed that the amount of SD released from the acacia gum–calcium alginate beads was higher in intestinal pH than in stomach pH. Therefore, the in vitro drug release from the SD‐loaded beads appears to follow the controlled‐release (Hixson‐Crowell) pattern involving a case‐2 transport mechanism operated by swelling and relaxation of the polymeric blend matrix.     

Hydrogels obtained by radiation-induced polymerization as delivery systems for peptide and protein drugs

The controlled release of peptides and proteins from hydrogels obtained by radiation-induced polymerization of 2-hydroxyethyl methacrylate at a low temperature was studied. It was found that the extent of release progressively decreased as protein molecular weight increased until no further release occurred above a critical value of the latter. However, an increasing rate of protein release was found if the polymerization was carried out in the presence of poly(ethylene glycol), PEG. Moreover, only with high molecular weight PEGs were large proteins released. The release data as a function of swellability and porosity of polymer matrices were discussed.     

Ionically crosslinked alginate/carboxymethyl chitin beads for oral delivery of protein drugs

Complex beads composed of alginate and carboxymethyl chitin (CMCT) were prepared by dropping aqueous alginate-CMCT into an iron(III) solution. The structure and morphology of the beads were characterized by IR spectroscopy and scanning electron microscopy (SEM). IR confirmed electrostatic interactions between iron(III) and the carboxyl groups of alginate as well as CMCT, and the binding model was suggested as a three-dimensional structure. SEM revealed that CMCT had a porous morphology while alginate and their complex beads had a core-layer structure. The swelling behavior, encapsulation efficiency, and release behavior of bovine serum albumin (BSA) from the beads at different pHs were investigated. The BSA encapsulation efficiency was fairly high (>90%). It was found that CMCT disintegrated at pH 1.2 and alginate eroded at pH 7.4 while the complex beads could effectively retain BSA in acid (>85%) and reduce the BSA release at pH 7.4. The results suggested that the iron(III)-alginate-CMCT bead could be a suitable polymeric carrier for site-specific protein drug delivery in the intestine.     

The behavior of poly(amino acids) containing l‐cysteine and their block copolymers with poly(ethylene glycol) on gold surfaces

Poly(ethylene glycol) (PEG) is often used to biocompatibilize surfaces of implantable biomedical devices. Here, block copolymers consisting of PEG and l ‐cysteine‐containing poly(amino acid)s (PAA's) were synthesized as polymeric multianchor systems for the covalent attachment to gold surfaces or surfaces decorated with gold nanoparticles. Amino‐terminated PEG was used as macroinitiator in the ring‐opening polymerization, (ROP), of respective amino acid N‐carboxyanhydrides (NCA's) of l ‐cysteine (l ‐Cys), l ‐glutamate (l ‐Glu), and l ‐lysine (l ‐Lys). The resulting block copolymers formed either diblock copolymers, PEG‐b‐p(l ‐Glu_x‐co‐l ‐Cys_y) or triblock copolymers, PEG‐b‐p(l ‐Glu)_x‐b‐p(l ‐Cys)_y. The monomer feed ratio matches the actual copolymer composition, which, together with high yields and a low polydispersity, indicates that the NCA ROP follows a living mechanism. The l ‐Cys repeat units act as anchors to the gold surface or the gold nanoparticles and the l ‐Glu repeat units act as spacers for the reactive l ‐Cys units. Surface analysis by atomic force microscopy revealed that all block copolymers formed homogenous and pin‐hole free surface coatings and the phase separation of mutually immiscible PEG and PAA blocks was observed. A different concept for the biocompatibilization of surfaces was followed when thiol‐terminated p(l ‐Lys) homopolymer was first grafted to the surface and then covalently decorated with HOOC‐CH₂‐PEG‐b‐p(Bz‐l ‐Glu) polymeric micelles. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 248–257     

Novel mucoadhesive carriers based on alginate-acrylamide hydrogels for drug delivery

New mucoadhesive two-component carriers for drug delivery based on synthetic acrylamide/diethylacrylamide and natural alginate hydrogels have been synthesized. The introduction of sodium alginate into polyacrylamide/ poly(diethylacrylamide) gels, followed by their crosslinking with metal ions, significantly changed structure and properties of hydrogels, such as swelling degree, drug capacity and drug release rate in physiological solution. The structure of the gels was characterized by FTIR spectroscopy and scanning electron microscopy.     

Sugar-containing polyanions as a self-assembled coating of plasmid/polycation complexes for receptor-mediated gene delivery

Novel poly(ethylene glycol) (PEG) derivatives having both carboxylic acid, and sugar side chains were synthesized. These polymers were used to coat DNA/poly(ethyleneimine) complexes, and effectively protected them against albumin-induced aggregation. They presented carbohydrate moieties on the DNA complex surfaces as a cell-binding ligand, and the galactose-bearing polymer remarkably enhanced the poly(ethyleneimine)-mediated gene transfection on HepG2 cells.

Synthesis of poly(ethylene glycol) derivatives having both carboxylic acid and sugar pendant groups.     

Thermosensitive polylactide‐glycolide delivery systems for treatment of narcotic addictions

Environmental switches may be fabricated for the controlled release of pharmaceutical drug using a thermally responsive polymer with the intrinsic chemical and physical nature of stimuli‐sensitive smart materials. Particularly, much attention has been paid to the biomedical applications of poly(N‐isopropyl acrylamide) (PNIPAAm) because of its unique reversible transition at a specific lower critical solution temperature (LCST).Thermally sensitive block copolymers, poly(N‐isopropyl acrylamide‐b‐poly(L ‐lactide‐co‐glycolide) (PNIPAAm‐b‐PLGA), and polyethylene glycol‐poly (lactide‐co‐glycolide) (PEG‐PLGA) triblock copolymers with different compositions and length of PLGA block were synthesized via ring‐opening polymerization of lactide and glycolide in the presence of OH‐terminated PNIPAAm or PEG. The composition and structure of the polymer were determined by NMR and FTIR. The effect of important factors, such as ionic strength, pH, and polymer concentration on the phase transition behavior of temperature‐sensitive polymers, were investigated by cloud point measurements. The resulting thermosensitive polymers were used for the entrapment of a narcotic antagonist drug, naltrexone, as the model drug. The loading efficiency and drug release behavior of naltrexone‐loaded hydrogels were investigated. The naltrexone loaded thermosensitive polymers were able to sustain the release of naltrexone for different periods of time, depending on the polymer composition, and concentration. In vitro release studies showed that these thermosensitive polymers are able to deliver naltrexone in biologically active forms at a controlled rate for 3–8 weeks. Copyright © 2009 John Wiley & Sons, Ltd.     

Poly(PEGDMA‐MAA) copolymeric micro and nanoparticles for oral insulin delivery

Poly(ethylene glycol) dimethacrylate (PEGDMA) and methacrylic acid (MAA) based micro and nanoparticles were prepared and evaluated as a carrier for oral delivery of insulin. PEGDMA was synthesized by esterification reaction of the PEG4000 with MAA in the presence of an acid catalyst. Particles of different size were prepared by emulsion polymerization reaction using different concentration of sodium lauryl sulphate (SLS) as an emulsifying agent. Synthesized copolymeric particle were characterized by attenuated total reflectance‐Fourier transform infrared spectroscopy (ATR‐FTIR), scanning electron microscopy, and acid value. The mean particle diameter of the polymeric micro and nanoparticles at various physiologically relevant pH values was measured using dynamic light scattering. Insulin loading efficiency of the particles was found to be directly proportional to the particle size and inversely proportional to the acid value of the particles. In vitro insulin release studies from various insulin loaded particles were performed by simulating the gastrointestinal tract conditions using HPLC. At pH 2.5, the release of insulin from polymeric particles was observed in the range of 5–8% while a significant higher release (20–35%) was observed at pH 7.4 during first 15 min of in vitro release. Largest size copolymeric particles of 8.3 µm also showed the highest efficiency to reduce the blood glucose level in diabetic rabbits. Copyright © 2010 John Wiley & Sons, Ltd.     

Design and optimization of a new self-nanoemulsifying drug delivery system

To improve the dissolution rate of ibuprofen, a model poorly water soluble drug, self-nanoemulsifying drug delivery systems (SNEDDS) were developed. Various surfactants and oils were screened as candidates for SNEDDS on the basis of droplet size of the resulting emulsions. The influence of the constituent structure, concentration and the composition of SNEDDS formulations, and the emulsifier HLB value, on the properties of the resulting emulsions was systematically investigated. Several SNEDDS formulations were employed to study the relationship between the emulsion droplet size and the dissolution rate of ibuprofen. The dissolution rate was accelerated by decreasing the nanoemulsion droplet size, and was significantly faster than that from a conventional tablet. The optimal SNEDDS formulation had a mean nanoemulsion droplet diameters of 58 nm in phosphate buffer, pH 6.8 (simulated intestinal fluid), and released ibuprofen more than 95% within 30 min. Therefore, these novel SNEDDS carriers appear to be useful for controlling the release rate of poorly water soluble drugs.     

Design,Synthesis and Characterization of A Novel Cationic Polymer Poly(lactic acid-b-L-lysine)

A novel biodegradable block copolymer poly(lactic acid-b-lysine) (PLA-b-PLL) has been synthesized and characterized in this study. This product was synthesized via a five-step reaction: Synthesis of hydroxyl-tailed poly(lactic acid) (PLA) by the ring-opening polymerization (ROP) of D,L-lactide in the presence of stannous octoate (Sn(OCt)₂) as initiator; coupling N-t-butoxycarbonyl-L-phenylalanine to hydroxyl-tailed PLA using dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP); the amino-tailed PLA was obtained through de-protection of the Boc-protective group in trifluoroacetic acid (TFA) solution; and then ring-opening polymerization of N ^ε -(Z)-lysine-N-carboxyanhydride (NCA) using the amino-tailed PLA as macro-initiator; finally removal of the Cbz-protective group of PLA-b-poly(N ^ε -(Z)-L-lysine) (PLA-b-PLL(Z) in a mixed hydrobromic acid/acetic acid solution to give the target copolymer. The characterization of this copolymer and its precursors were performed by ¹H-NMR, FTIR and GPC. The block copolymer PLA-b-PLL, combining the characteristics of an aliphatic polyester and poly(amino acids), could be of potential interest in a variety of medical applications, such as the fields of targeted drug delivery and gene delivery systems.     

Polyaspartamide-graft-polymethacrylate nanoparticles for doxorubicin delivery

A new PHEA‐IB‐PMANa⁺ copolymer has been synthesized and its pH‐induced self‐assembly has been investigated in an aqueous medium. PHEA‐IB‐PMANa⁺ formed nanoparticles with diameters from 25 to 50 nm upon protonation of the carboxylic acid moieties dislocated along the grafted polymethacrylate sodium salt side chains. The physico‐chemical characterization of the nanoparticles was performed using light scattering, zeta‐potential measurements, SEM, and AFM. Doxorubicin‐loaded nanoparticles were prepared and drug release profiles were evaluated under conditions mimicking physiological media. A biological characterization was carried out by testing the cytotoxicity on Caco‐2 cells, and cellular uptake on mouse monocyte macrophage (J774 A.1) and Caco‐2 cells.

     

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)