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Abstract
The success of most advanced drug delivery strategies requires development of sophisticated new site-specific carriers. Several new targeting methods use physical and chemical signals such as magnetic fields or changes in pH or temperature as targeting and triggering tools. In addition to site-specificity, the carrier should achieve passive targeting to evade the body's reticulo-endothelial system (RES) and exhibit long blood circulation times in order to efficiently distribute active drug to the site of action (active targeting). To fulfil these requirements, thermo-responsive polymeric micelles have been prepared from amphiphilic block copolymers composed of N-isopropylacrylamide (IPAAm) (a thermo-responsive outer shell) and styrene (St) (hydrophobic inner core). The polymeric micelle which is very stable in aqueous media was formed by the dialyzed method from DMF solution against water. The micelles have a unimodal size distribution (24±4 nm) and CMC was around 10 mg/l (ml→l). These micelles have a small diameter with a low critical micelle concentration, providing a carrier that may have long blood circulation times and a low RES uptake. When the temperature is increased above the transition temperature of the thermo-responsive block chains (32°C), the outer shell chains dehydrate and collapse, allowing aggregation between micelles and favoring binding interactions with cell membrane surfaces. Moreover, these changes are reversible. Hydrophobic molecules are shown to be incorporated into the inner hydrophobic core of the thermo-responsive micelles. Consequently, these micelles are valuable for site-specific delivery of drugs using changes in temperature as a trigger.
... Regulatory concerns have, however, so far restricted their wide use to high added-value applications, conventionally found in biomedical applications. Among these are therapeutic delivery systems, to which nanomaterials have been suggested since the early 90s [99,100], with core-shell nanoparticles following only a few years after [101]. However, as far as it concerns biomedical or pharmaceutical applications, the main advantage of core-shell nanoparticles over other materials ranging in the nano-domain, is affiliated with their biocompatibility [102]. ...
... The acceptance of core-shell nanoparticles from the biomedical sector was driven mainly by their exceptional (shell-based) biocompatibility, combined with their outstanding guidance potential and traceability, based on their magnetic cores. In addition, while some biomedical applications in drug delivery [101] and hyperthermia [107] are decade-old concepts, their research output has escalated to promising clinical trials [110]. The above is valid due to the favorable biocompatibility of core-shell nanoparticles when compared to other nanomaterials [102], usually attributed to the composition of their shell. ...
Several developments have recently emerged for core-shell magnetic nanomaterials, indicating that they are suitable materials for biomedical applications. Their usage in hyperthermia and drug delivery applications has escalated since the use of shell materials and has several beneficial effects for the treatment in question. The shell can protect the magnetic core from oxidation and provide biocompatibility for many materials. Yet, the synthesis of the core-shell materials is a multifaceted challenge as it involves several steps and parallel processes. Although reviews on magnetic core-shell nanoparticles exist, there is a lack of literature that compares the size and shape of magnetic core-shell nanomaterials synthesized via various methods. Therefore, this review outlines the primary synthetic routes for magnetic core-shell nanoparticles, along with the recent advances in magnetic core-shell nanomaterials. As core-shell nanoparticles have been proposed among others as therapeutic nanocarriers, their potential applications in hyperthermia drug delivery are discussed.
... When micelles are diluted below the CMC, disassembly into unimolecular amphiphiles occurs. Copolymerization with hydrophobic monomers, such as polystyrene (Pst) in PIPAAm-PSt [129], butylmethacrylate (PBMA) in PIPAAm-PBMA [130], poly-l-lactide in P-(IPAAm-co-DMAAm)-b-P-(d,l-lactide), and caprolactone (PCL) in P-(NIPAAm-co-NHMAAm)-b-PCL [128] enhanced the micellar formation and stability of the nanoparticle in aqueous media. In contrast to the addition of hydrophilic monomers that increases the LCST, copolymerization of PNIPAAm with hydrophobic blocks showed no [129][130][131] or minor [128] effect on the LCST. ...
... Copolymerization with hydrophobic monomers, such as polystyrene (Pst) in PIPAAm-PSt [129], butylmethacrylate (PBMA) in PIPAAm-PBMA [130], poly-l-lactide in P-(IPAAm-co-DMAAm)-b-P-(d,l-lactide), and caprolactone (PCL) in P-(NIPAAm-co-NHMAAm)-b-PCL [128] enhanced the micellar formation and stability of the nanoparticle in aqueous media. In contrast to the addition of hydrophilic monomers that increases the LCST, copolymerization of PNIPAAm with hydrophobic blocks showed no [129][130][131] or minor [128] effect on the LCST. ...
Nanotechnology has great capability in formulation, reduction of side effects, and enhancing pharmacokinetics of chemotherapeutics by designing stable or long circulating nano-carriers. However, effective drug delivery at the cellular level by means of such carriers is still unsatisfactory. One promising approach is using spatiotemporal drug release by means of nanoparticles with the capacity for content release triggered by internal or external stimuli. Among different stimuli, interests for application of external heat, hyperthermia, is growing. Advanced technology, ease of application and most importantly high level of control over applied heat, and as a result triggered release, and the adjuvant effect of hyperthermia in enhancing therapeutic response of chemotherapeutics, i.e., thermochemotherapy, make hyperthermia a great stimulus for triggered drug release. Therefore, a variety of temperature sensitive nano-carriers, lipid or/and polymeric based, have been fabricated and studied. Importantly, in order to achieve an efficient therapeutic outcome, and taking the advantages of thermochemotherapy into consideration, release characteristics from nano-carriers should fit with applicable clinical thermal setting. Here we introduce and discuss the application of the three most studied temperature sensitive nanoparticles with emphasis on release behavior and its importance regarding applicability and therapeutic potentials.
... This thermoresponsive polymer has been widely utilized in biomedical applications because of its relatively low LCST, which is close to the human body temperature. Examples of these applications include temperature-controlled drug and gene delivery systems [37][38][39][40][41][42][43][44], biosensors and bioimaging systems [45][46][47][48][49][50][51][52], nanoactutors [53][54][55][56][57][58][59], bioseparation tools [60][61][62][63][64][65][66][67][68][69][70][71][72][73][74], cell separation materials [75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90], and cell culture substrates for tissue engineering [91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110]. ...
In recent decades, various bioanalytical technologies have been investigated for appropriate medical treatment and effective therapy. Temperature-responsive chromatography is a promising bioanalytical technology owing to its functional properties. Temperature-responsive chromatography uses a poly( N -isopropylacrylamide)(PNIPAAm) modified stationary phase as the column packing material. The hydrophobic interactions between PNIPAAm and the analyte could be modulated by changing the column temperature because of the temperature-responsive hydrophobicity of PNIPAAm. Thus, the chromatography system does not require organic solvents in the mobile phase, making it suitable for therapeutic drug monitoring in medical settings such as hospitals. This review summarizes recent developments in temperature-responsive chromatography systems for therapeutic drug monitoring applications. In addition, separation methods for antibody drugs using PNIPAAm are also summarized because these methods apply to the therapeutic drug monitoring of biopharmaceutics. The temperature-responsive chromatography systems can also be utilized for clinical diagnosis, as they can assess multiple medicines simultaneously. This highlights the significant potential of temperature-responsive chromatography in medicine and healthcare.
Graphical abstract
... PNI-PAAm is a temperature-responsive polymer that exhibits changes in hydrophobicity with temperature [21][22][23][24][25]. Given this unique property, PNIPAAm has been used in various biomedical applications, such as drug delivery systems [26][27][28][29][30][31][32][33][34], biosensor and bioimaging [35][36][37][38], bioseparation [39][40][41][42][43][44][45][46], and tissue engineering [47,48]. Specifically, PNIPAAm-modified tissue culture dishes have been used to fabricate cell sheets. ...
... Thus, PLL can enhance its cell interactions through electrostatic interactions and promote cell adhesion (17). Besides, PLL contains abundant cations; it can self-assemble into nanoparticles with drugs that contain anions through electrostatic forces (18,19). Studies have also shown that PLL has hemostatic effects (20). ...
Background: Hemorrhage control and anti-infection play a crucial role in promoting wound healing in trauma-related injuries. Objectives: This study aimed to prepare nanoparticles with dual functions of hemostasis and antibacterial properties. Methods: The dual-functional nanoparticles (CDCA-PLL NPs) were developed using a self-assembly method based on the electrostatic forces between Poly-L-lysine (PLL) and Chenodeoxycholic acid (CDCA). The physicochemical properties, hemostatic properties, and antibacterial activities were investigated. Results: The prepared nanoparticles displayed a spherical structure, exhibiting a high drug loading capacity, encapsulation efficiency, and good stability. The CDCA-PLL NPs could reduce the hemolysis caused by PLL and promote the proliferation of human fibroblasts, indicating excellent biosafety. Moreover, CDCA-PLL NPs demonstrated a shorter in vivo hemostasis time and reduced blood loss in mouse tail vein hemorrhage, femoral vein hemorrhage, femoral artery hemorrhage, and liver hemorrhage models. Also, CDCA-PLL NPs showed excellent antibacterial efficacy against E. coli and S. aureus. Conclusions: CDCA-PLL NPs have great potential to be extensively applied as a hemostatic and antibacterial agent in various clinical conditions.
... Fluorescence measurements A Hitachi F-7000 Fluorescence Spectrophotometer was used to determine critical micelle concentration (CMC) by the pyrene fluorescent probe method adapted from the literature (Cammas et al. 1997;Wang et al. 2017Wang et al. , 2020. Ten microliters of pyrene stock solution (0.15 mM) were poured into empty vials, and acetone was evaporated by argon stream. ...
The presented research concerns the preparation of polymer nanoparticles (PNPs) for the delivery of doxorubicin. Several block and statistical copolymers, composed of ketoester derivative, N-isopropylacrylamide, and cholesterol, were synthesized. In the nanoprecipitation process, doxorubicin (DOX) molecules were kept in spatial polymeric systems. DOX-loaded PNPs show high efficacy against estrogen-dependent MCF-7 breast cancer cell lines despite low doses of DOX applied and good compatibility with normal cells. Research confirms the effect of PNPs on the degradation of the biological membrane, and the accumulation of reactive oxygen species (ROS), and the ability to cell cycle arrest are strictly linked to cell death.
Graphical Abstract
... At 32 degrees Celsius, the polymer undergoes a temperature-dependent phase transition in the liquid phase, resulting in changes in hydrophobic and hydrophilic characteristics [6]. P-(NIPAAM) has been benefited in a variety of biological applications, including thermally regulated gene and drug delivery systems, due to its lower critical solution temperature (LCST) being closer to body temperature [7,8]. ...
... Despite the significant impact, the self-assembly process and the drug-polymer interaction are little understood. In majority cases in the literature, the out dated perception of like dissolve like or micellar core-shell architecture, where hydrophobic core is responsible for drug encapsulation and hydrophilic shell interacts with solvent molecules providing colloidal stability [110,111], are repetitively discussed. ...
In the past decade, poly(2-oxazoline)s (POx) and very recently poly(2-oxazine)s (POzi) based amphiphiles have shown great potential for medical applications. Therefore, the major aim of this thesis was to further explore the pharmaceutical and biomedical applications of POx/POzi based ABA triblock and AB diblock copolymers, respectively with the special emphasis on structure property relationship (SPR). ABA triblock copolymers (with shorter side chain length in the hydrophobic block) have shown high solubilizing capacity for hydrophobic drugs. The issue of poor aqueous solubility was initially addressed by developing a (micellar) formulation library of 21 highly diverse, hydrophobic drugs with POx/POzi based ABA triblock copolymers. Theoretically, the extent of compatibility between polymers and drug was determined by calculating solubility parameters (SPs). The SPs were thoroughly investigated to check their applicability in present systems. The selected formulations were further characterized by various physico-chemical techniques. For the biomedical applications, a novel thermoresposive diblock copolymer was synthesized which has shown promising properties to be used as hydrogel bioink or can potentially be used as fugitive support material. The most important aspect i.e. SPR, was studied with respect to hydrophilic block in either tri- or di-block copolymers. In triblock copolymer, the hydrophilic block played an important role for ultra high drug loading, while in case of diblock, it has improved the printability of the hydrogels. Apart from the basic research, the therapeutic applications of two formulations i.e. mitotane (commercially available as tablet dosage form for adrenocortical carcinoma) and BT-44 (lead compound for nerve regeneration) were studied in more detail.
... 23 The temperature of tumor tissues is reported to be slightly higher than that of the normal tissues, owing to faster metabolism. [24][25][26][27][28] Moreover, tissues can withstand temperatures of up to 43 1C for long periods of time, without any irreversible consequences. 29 Therefore, micelles of temperature-responsive polymers may have the ability of targeted release at the delivery site. ...
Multi-stimuli-responsive materials may dominate next-generation drug delivery systems. Herein, dual-thermo-responsive micelles were prepared by introducing cholesterol chloroformate to facilitate the spontaneous self-assembly of graft polymers prepared by combining two charged polymers, poly-sulfobetaine and carboxylated ε-poly-l-lysine. This polymerization was controlled by reversible addition fragmentation chain transfer polymerization. Turbidimetry measurements and temperature-dependent ¹H NMR spectroscopy were used to investigate the phase transition behaviors; transmission electron microscopy and atomic force microscopy were used to determine the morphology of the micelles. The dependence of self-assembled structures on temperature was investigated through ultra-small-angle X-ray scattering (USAXS). The micelles formed spherical shapes in water which was confirmed by TEM and AFM. Interestingly, different, temperature-dependent micelle size change behaviors were observed through dynamic light scattering, Ultraviolet-visible (UV-Vis) spectroscopy, and USAXS; this might be due to the concentration-dependent hierarchical phase transition. This study provides crucial information on the mesoscopic structure of the micelles, and will enable greater control over their transition temperatures for numerous biomaterial applications.
... They are self-assembled colloidal particles made up of block copolymers comprising hydrophilic and hydrophobic domains [21]. It is commonly believed that the hydrophobic core is responsible for drug encapsulation and the hydrophilic shell interacts with solvent molecules (representing core-shell morphology) providing colloidal stability [22,23]. Depending on the nature of the hydrophilic domain, cargo and employed (cargo) load, it is becoming more evident that at certain threshold drug concentration, the hydrophilic domain also starts to interact [24][25][26][27][28][29] with the cargo, indicative of much complex morphologies [30][31][32]. ...
BT44 is a novel, second generation glial cell line-derived neurotropic factor (GDNF) mimetic, with improved biological activity and a lead compound for the treatment of neurodegenerative disorders. Like many other small molecules, it suffers from intrinsic poor aqueous solubility, posing significant hurdles at various levels for its preclinical development and clinical translation. Herein, we report a novel poly(2-oxazoline)s (POx) based BT44 micellar nanoformulation with ultra-high drug loading capacity of 47 wt.%. The BT44 nanoformulations were comprehensively characterized by 1H-NMR spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), dynamic light scattering (DLS) and cryo-transmission/scanning electron microscopy (cryo-TEM/SEM). The DSC, XRD and redispersion studies collectively confirmed that the BT44 formulation can be stored as a lyophilized powder and can be redispersed when needed. The DLS further suggested that the redispersed formulation is suitable for parenteral administration (Dh ≈ 70nm). The cryo-TEM analysis revealed the presences of worm like structures. The BT44 formulation retains biological activity in immortalized cells and in cultured dopamine neurons. The micellar formulation of BT44 exhibited improved absorption and blood-brain barrier (BBB) penetration and produced no acute toxic effects in mice. In conclusion, herein, we have developed an ultra-high BT44 loaded aqueous injectable nanoformulation, which can be used to pave way for its preclinical and clinical development for the management of neurodegenerative disorders.
... The use of chemically similar co-monomers with similar reactivity towards radicals is, therefore, advantageous [30]. To date, several hydrophobic segments in the amphiphilic LCST-type diblock copolymers were investigated [31][32][33][34][35][36]. In continuation of the work of Eggers et al. [33] and Lauterbach et al. [37], who investigated the thermoresponsive behavior of amphiphilic poly(N-acryloyl pyrrolidine)-b-polystyrene and poly(N,N-dimethyl acrylamide)-b-poly(N-acryloyl piperidine-co-N-acryloyl pyrrolidine)-b-polystyrene block copolymers, the present work also used polystyrene as a hydrophobic block, which makes the block copolymer water-insoluble. ...
Thermoresponsive poly((N,N-dimethyl acrylamide)-co-(N-isopropyl acrylamide)) (P(DMA-co-NIPAM)) copolymers were synthesized via reversible addition−fragmentation chain transfer (RAFT) polymerization. The monomer reactivity ratios were determined by the Kelen–Tüdős method to be rNIPAM = 0.83 and rDMA = 1.10. The thermoresponsive properties of these copo-lymers with varying molecular weights were characterized by visual turbidimetry and dynamic light scattering (DLS). The copolymers showed a lower critical solution temperature (LCST) in water with a dependence on the molar fraction of DMA in the copolymer. Chaotropic and kosmotropic salt anions of the Hofmeister series, known to affect the LCST of thermoresponsive polymers, were used as additives in the aqueous copolymer solutions and their influence on the LCST was demonstrated. Further on, in order to investigate the thermoresponsive behavior of P(DMA-co-NIPAM) in a confined state, P(DMA-co-NIPAM)-b-PS diblock copolymers were prepared via polymerization induced self-assembly (PISA) through surfactant-free RAFT mediated emulsion polymerization of styrene using P(DMA-co-NIPAM) as the macromolecular chain transfer agent (mCTA) of the polymerization. As confirmed by cryogenic transmission electron microscopy (cryoTEM), this approach yielded stabilized spherical micelles in aqueous dispersions where the PS block formed the hydrophobic core and the P(DMA-co-NIPAM) block formed the hydrophilic corona of the spherical micelle. The temperature-dependent behavior of the LCST-type diblock copolymers was further studied by examining the collapse of the P(DMA-co-NIPAM) minor block of the P(DMA-co-NIPAM)-b-PS diblock copolymers as a function of temperature in aqueous solution. The nanospheres were found to be thermosensitive by changing their hydrodynamic radii almost linearly as a function of temperature between 25 °C and 45 °C. The addition of kosmotropic salt anions, as a potentially useful tuning feature of micellar assemblies, was found to increase the hydrodynamic radius of the micelles and resulted in a faster collapse of the micelle corona upon heating.
... They are self-assembled colloidal particles made up of block copolymers comprising hydrophilic and hydrophobic domains [21]. It is commonly believed that the hydrophobic core is responsible for drug encapsulation and the hydrophilic shell interacts with solvent molecules (representing core-shell morphology) providing colloidal stability [22,23]. Depending on the nature of the hydrophilic domain, cargo and employed (cargo) load, it is becoming more evident that at certain threshold drug concentration, the hydrophilic domain also starts to interact [24][25][26][27][28][29] with the cargo, indicative of much complex morphologies [30][31][32]. ...
BT44 is a novel, second generation glial cell line-derived neurotropic factor (GDNF) mimetic, with improved biological activity and a lead compound for the treatment of neurodegenerative disorders. Like many other small molecules, it suffers from intrinsic poor aqueous solubility, posing significant hurdles at various levels for its preclinical development and clinical translation. Herein, we report a novel poly(2-oxazoline)s (POx) based BT44 micellar nanoformulation with ultra-high drug loading capacity of 47 wt.%. The BT44 nanoformulations were comprehensively characterized by 1H-NMR spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), dynamic light scattering (DLS) and cryo-transmission/scanning electron microscopy (cryo-TEM/SEM). The DSC, XRD and redispersion studies collectively confirmed that the BT44 formulation can be stored as a lyophilized powder and can be redispersed when needed. The DLS further suggested that the redispersed formulation is suitable for parenteral administration (Dh ≈ 70nm). The cryo-TEM analysis revealed the presences of worm like structures. The BT44 formulation retains biological activity in immortalized cells and in cultured dopamine neurons. The micellar formulation of BT44 exhibited improved absorption and blood-brain barrier (BBB) penetration and produced no acute toxic effects in mice. In conclusion, herein, we have developed an ultra-high BT44 loaded aqueous injectable nanoformulation, which can be used to pave way for its preclinical and clinical development for the management of neurodegenerative disorders.
... Therefore, at this point we will only refer to published reviews on this topic. Table 1 summarizes the work on micellar PNIPAAm-based micelles P4VP-PNIPAAm catalysis, synthesis [166] PNIPAAm-PDMAAm drug delivery, synthesis [167] PNIPAAm-DNA synthesis/analysis [168] PNIPAAm-PHPMA-PEG synthesis/analysis [169] PNIPAAm-PBMA drug delivery, synthesis [170] PNIPAAm-PS synthesis/analysis [171,172] PNIPAAm-HPG [173] POX-based micelles [174,175] PEtOX-PPropOX synthesis/analysis [176] PIPOX-PAMPT radionuclide delivery, synthesis [177] PMeOX-PIPOX-PBuO synthesis/analysis [178] PBOX-PEtOX drug delivery, synthesis [153] PMeOX-PBuOX synthesis/analysis [179] other polymers PDMAEMA-PCL drug delivery, synthesis [180] PEGMA-PMMA-PDEAEMA synthesis/analysis [181] PHPMA-PDEGMA drug delivery, synthesis [182] polymers grafted on nanoparticles [4,115,117,164,[183][184][185] ...
In the last decades, numerous stimuli-responsive polymers have been developed and investigated regarding their switching properties. In particular, thermoresponsive polymers, which form a miscibility gap with the ambient solvent with a lower or upper critical demixing point depending on the temperature, have been intensively studied in solution. For the application of such polymers in novel sensors, drug delivery systems or as multifunctional coatings, they typically have to be transferred into specific arrangements, such as micelles, polymer films or grafted nanoparticles. However, it turns out that the thermodynamic concept for the phase transition of free polymer chains fails, when thermoresponsive polymers are assembled into such sterically confined architectures. Whereas many published studies focus on synthetic aspects as well as individual applications of thermoresponsive polymers, the underlying structure–property relationships governing the thermoresponse of sterically constrained assemblies, are still poorly understood. Furthermore, the clear majority of publications deals with polymers that exhibit a lower critical solution temperature (LCST) behavior, with PNIPAAM as their main representative. In contrast, for polymer arrangements with an upper critical solution temperature (UCST), there is only limited knowledge about preparation, application and precise physical understanding of the phase transition. This review article provides an overview about the current knowledge of thermoresponsive polymers with limited mobility focusing on UCST behavior and the possibilities for influencing their thermoresponsive switching characteristics. It comprises star polymers, micelles as well as polymer chains grafted to flat substrates and particulate inorganic surfaces. The elaboration of the physicochemical interplay between the architecture of the polymer assembly and the resulting thermoresponsive switching behavior will be in the foreground of this consideration.
... The phase transition temperature of PNIPAAm is ~32 • C, close to the body temperature, and can be modulated by incorporating hydrophobic and hydrophilic monomers [11]. Thus, PNIPAAm is used in numerous biomedical applications; for example, PNIPAAm is used in thermally modulated drug delivery systems [12][13][14][15][16][17][18][19][20][21], bioseparation and analysis systems [22][23][24][25][26][27][28], cell culture microcarriers [29][30][31], and cell culture substrates used in tissue engineering and regenerative medicine [32][33][34][35][36][37][38]. Furthermore, PNIPAAm-conjugated proteins are used to induce changes in the thermally modulated reaction properties of PNIPAAm-modified interfaces [39][40][41]. ...
Poly(N-isopropylacrylamide) (PNIPAAm) is the most well-known and widely used stimuli-responsive polymer in the biomedical field owing to its ability to undergo temperature-dependent hydration and dehydration with temperature variations, causing hydrophilic and hydrophobic alterations. This temperature-dependent property of PNIPAAm provides functionality to interfaces containing PNIPAAm. Notably, the hydrophilic and hydrophobic alterations caused by the change in the temperature-responsive property of PNIPAAm-modified interfaces induce temperature-modulated interactions with biomolecules, proteins, and cells. This intrinsic property of PNIPAAm can be effectively used in various biomedical applications, particularly in bioseparation and tissue engineering applications, owing to the functionality of PNIPAAm-modified interfaces based on the temperature modulation of the interaction between PNIPAAm-modified interfaces and biomolecules and cells. This review focuses on PNIPAAm-modified interfaces in terms of preparation method, properties, and their applications. Advances in PNIPAAm-modified interfaces for existing and developing applications are also summarized.
... For example, it was shown that the truncated triangular AgNPs exhibited better antibac-terial efficiency than that of spherical and rod-shaped silver particles [44,45]. In same way, it is also described that the silver nanoplates demonstrated higher antibacterial effectiveness than silver nanorods or nanospheres [46][47][48]. One of the explanations for the great antibacterial activity of these anisotropic-shaped AgNPs was the basal plane with highatom-density (111) facets which acted as the maximum reactivity sites leading to the strongest antibacterial activity [5]. ...
According to the literature data, metal nanoparticles can be synthesized by various methods but the chemical reduction methods are mostly applied getting more advantageous comparing with the other methods. This work emphasizes also that the combination of synthetized methods could lead to the spectacular results depending on the application. Among the chemical methods, this work analyzed the polyol method, radiolytic process, microemulsion method, solvo-thermal method, microwave-assisted synthesis, and electrochemical synthesis. It also presents the main application of metal nanoparticles in biomedical fields, empathizing on their antimicrobial potential.
... LCSTs of the PNIPAM and its copolymers are nearly 32°C, which is close to the physiological temperatures of the human body. PNIPAM has been utilized in various biomedical applications such as biosensors [101,102], thermally modulated drug and gene delivery systems [103][104][105][106][107], PNIPAM conjugated proteins for thermally modulated enzyme function [ 1 0 8 -1 1 0 ] , e t c . A p p l i c a t i o n o f t h e p o l y ( Nisopropylacrylamide)-grafted brush coatings have at least two advantages: First, a sharp phase transition around 32°C leading to essential changes in wettability, thickness, and coating morphology. ...
Temperature responsivity of polymer brushes may be driven by different mechanisms, from which the lower critical solution temperature (LCST) is the most famous one. The using of the grafted temperature-responsive polymer brushes based on LCST opens numerous opportunities for fabrication of “smart” or responsive surfaces. In this review, we try to join information on thermoresponsive and multi-responsive grafted polymer brushes with transitions based on LCST. The overwhelming majority of previously reported temperature-responsive grafted polymer brush coatings were based on PNIPAM and POEGMA, despite the fact that a wide range of other thermoresponsive polymers demonstrate similar properties. In this work, we not only give the detailed account for fabrication, mechanisms of action, and applications of well-known PNIPAM- and POEGMA-grafted brush coatings but also point to other types of thermoresponsive grafted brushes.
Graphical abstract
... Hitachi F-7000 Fluorescence Spectrophotometer was used to determine critical micelle concentration (CMC) by pyrene fluorescent probe method adapted from literature. [20][21][22] Ten microliters of pyrene stock solution (0.15 mM) were poured into empty vials and acetone was evaporated by argon stream. Then, 3 mL of polymer aqueous solutions of various concentrations (10 −4 to 2 mg/mL) were added into vials and shaken vigorously. ...
Purpose
Efficient intracellular delivery of a therapeutic compound is an important feature of smart drug delivery systems (SDDS). Modification of a carrier structure with a cell-penetrating ligand, ie, cholesterol moiety, is a strategy to improve cellular uptake. Cholesterol end-capped poly(N-isopropylacrylamide)s offer a promising foundation for the design of efficient thermoresponsive drug delivery systems.
Methods
A series of cholesterol end-capped poly(N-isopropylacrylamide)s (PNIPAAm) with number-average molar masses ranging from 3200 to 11000 g·mol–1 were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization from original xanthate-functionalized cholesterol and self-assembled into micelles. The physicochemical characteristics and cytotoxicity of cholesterol end-capped poly(N-isopropylacrylamide)s have been thoroughly investigated.
Results
Phase transition temperature dependence on the molecular weight and hydrophilic/hydrophobic ratio in the polymers were observed in water. Biological test results showed that the obtained materials, both in disordered and micellar form, are non-hemolytic, highly compatible with fibroblasts, and toxic to glioblastoma cells. It was found that the polymer termini dictates the mode of action of the system.
Conclusion
The cholesteryl moiety acts as a cell-penetrating agent, which enables disruption of the plasma membrane and in effect leads to the restriction of the tumor growth. Cholesterol end-capped PNIPAAm showing in vitro anticancer efficacy can be developed not only as drug carriers but also as components of combined/synergistic therapy.
... In past decades, stimuli-responsive polymer micelles that could respond to temperature [9][10][11][12], light [13][14][15][16][17], ultrasound [18][19][20][21], and pH [22][23][24][25][26][27] have emerged as effective drug carriers, improving the performance of a controlled drug release. Among the various types of external stimuli, photo irradiation is of particular interest because the on-off switching of drug release from photo-responsive polymer micelles can be expected. ...
Polymer micelles with a tunable drug release would be suitable for the concept of drug delivery system. We constructed photo-responsive polymer micelles from amphiphilic block copolymers. The polymer micelles were synthesized by mechanochemical solid-state copolymerization of poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) and 4,5-dimethoxy-2-nitrobenzyl methacrylate as a photosensitive moiety. The above mechanochemical solid-state copolymerization was performed by vibratory-ball milling at 30 Hz in a nitrogen atmosphere with the use of an agate vessel and an agate ball to yield amphiphilic block copolymers (PHPMA-b-PDNMA). Spherical polymer micelles were formed by the self-assembly of PHPMA-b-PDNMA. The diameter of the PHPMA-b-PDNMA micelles was in the range of 130-200 nm. The PHPMA-b-PDNMA micelles loaded with the antitumor drug 5-fluorouracil (5-FU) showed photo irradiation induced time-dependent release of 5-FU with an associated decrease of micellar size. The drug release profile of the PHPMA-b-PDNMA micelles followed a clear sigmoid curve. Our approach provides a controlled drug release system through the use of photo-responsive polymer micelles, accompanied by the gradual decrease of micellar size. Polymer micelles with a tunable drug release are promising carriers for drug delivery system. It is very important to clarify the correlation between micellar dissociation kinetics and drug release profile on a stimuli-induced deformation of polymer micelles. In this study, photo-cleavable o-nitrobenzyl ester-based amphiphilic block copolymer was successfully designed and prepared by mechanochemical solid-state copolymerization without any solvents and initiators. The self-assembled block copolymer micelles containing anticancer drugs showed sigmoidal decrease of micellar size and released the corresponding drugs depending on the photo-irradiation time.
... There are different well-studied thermoresponsive nanomedicines such as liposomes [183][184][185][186][187][188] , nanogels [189][190][191][192] , hydrogel coated metal nanoparticles [193] , polymeric nanoparticles [194][195][196][197] and elastin-like peptide-drug conjugates [179] . Thermodox® is a doxorubicin loaded thermoresponsive liposome, approved for the treatment of liver cancer. ...
The tumour vasculature plays an important role in tumour growth and metastasis. Tumour angiogenesis provides more oxygen and nutrients to growing tumour cells, is not as tightly regulated as embryonic angiogenesis, and do not follow any hierarchically ordered pattern. The heterogeneity of the vasculature, high interstitial fluid pressure, poor extravasation due to sluggish blood flow, and larger distances between exchange vessels are potential barriers to the delivery of therapeutic agents to tumours. The prevention of angiogenesis, normalization of tumour vasculature, and enhancement of blood perfusion through the use of monoclonal antibodies against receptor proteins that are overexpressed on proangiogenic tumour cells, and improved, tumour-targeted delivery of therapeutic agents can all be achieved using nanocarriers of appropriate size. Nanomedicines such as polymeric nanoparticles, lipid nanoparticles, micelles, mesoporous silica particles, metal nanoparticles, noisomes, and liposomes have been developed for the delivery of anticancer drugs in combination with antiangiogenic agents. Amongst them, liposomal delivery systems are mostly approved by the FDA for clinical use. In this review, the molecular pathways of tumour angiogenesis, the physiology of tumour vasculature, barriers to tumour-targeted delivery of therapeutic agents, and the different strategies to overcome these barriers are discussed.
... The examples of LCST polymers include poly(N-isopropyl acrylamide) (PNIPAM), [41,42] p o l y ( 2 -o x a z o l i n e ) s ( P O x s ) , [ 5 4 ] p o l y ( N , Ndimethylaminoethyl methacrylate)(PDMAEMA), [55] poly(acrylic acid) (PAA)/poly(acrylamide) (PAm), [56] poly(vinyl methyl ether)(PVME), [57] poly(methacrylamide) (PMAAm), [58] etc., which are extensively researched for last two decades. For example, PNIPAM is known to show a reversible LCST-type soluble-to-insoluble phase transition in aqueous solution with a cloud point (T cL ) at 32°C, [59] and such inherent thermoresponsive property can be intelligently used in various applications such as in therapeutics as controlled drug and gene delivery agents, [60,61] enzyme bioconjugates, [62] temperature-responsive surfaces [63] etc. The other thermoresponsive non-ionic polymers have also been reviewed by many research groups. ...
The current challenge is to focus on the fundamental understanding of ion-containing polymers. Poly(ionic liquid)s (PILs) belong to an important subclass of ionic polyelectrolyte with broad range of structural and functional properties. This review outlines the different kinds of stimuli-responsive PILs those are recently developed, specifically highlighting our own work and their materialistic applications. A brief introduction is also been provided to describe the advancement of PILs over their monomeric ionic liquids’ (ILs) moiety and their smart responsive behaviour towards different chemical, physical and biochemical stimuli such as pH, redox, CO2, temperature, light, enzyme etc. The thermoresponsive PILs with lower critical solution temperature (LCST)- or upper critical solution temperature (UCST)-type phase transition behaviours are discussed in a generalized way. The pH-responsive PILs also prove themselves as a potent candidate for potential applications in the biomedical area including therapy, drug delivery, diagnostics, etc. and the synthetic developments of those are also described here briefly. The rise of atmospheric CO2 level is now a matter of worldwide concern. Thus, in particular, CO2 responsive materials have attracted much attention and in this regards, PILs are much familiar and are found to be sorptive in nature both physically and chemically. Therefore, it is indeed important to describe the role and potential applications of PILs those are responsive to CO2. Polymerized ionic liquids (PILs), those are responsive to other different stimuli such as photo, redox etc., are also described in this review.
... PMO-G and PMO-H also turned blue indicating that the polymeric micelles consisted of an oil phase inner core and aqueous phase outer shell. In other words, an amphiphilic polymer, poloxamer 407 in compositions G and H, serves as an outer shell and helps to successfully form polymeric micelles of oleanolic acid by encapsulating the inner core of Capryol® 90 containing oleanolic acid [31]. Particle size, size distribution, and shape can be good indicators for predicting the physical stability of micelle formulations. ...
Oleanolic acid has been used only as a subsidiary agent in cosmetic products. The aim of the study is to show the effect of oleanolic acid as an active ingredient for the alleviation of wrinkles in humans and to develop a polymeric micelle formulation that enables poorly soluble oleanolic acid to be used as a main ingredient in cosmetic products for reducing wrinkles. The solubility of oleanolic acid was evaluated in solubilizers, surfactants, and polymers. The particle sizes and shapes of polymeric micelles containing oleanolic acid were evaluated by electrophoretic light scattering spectrophotometer and scanning electron cryomicroscopy. Encapsulation efficiency and skin permeation were measured by HPLC. Stability of the polymeric micelles stored at 40 °C for 3 months was evaluated by visual observation, particle size measurement, and oleanolic acid content measurement. Polymeric micelles in final product ampoule form were applied around the eyes of 23 female subjects for 8 weeks. Five skin parameters were evaluated by optical profilometry every 4 weeks for 8 weeks. In addition, professionals made visual observations of the skin and a human skin irritation study was conducted. Polymeric micelles of oleanolic acid with a particle size of less than 100 nm were prepared using Capryol 90® and poloxamer. The skin permeation rate of the oleanolic acid in the polymeric micelles was higher than that in the other solutions made of oleanolic acid dispersed in 2 different surfactants. No significant changes in particle size, color, or oleanolic acid content were observed, and the polymeric micelles stored at 40 °C for 3 months did not undergo phase separation. After 8 weeks of application, skin irritation had not developed and all five parameters evaluated by optical profilometry as well as the visual evaluation scores were significantly improved. This study showed that the polymeric micelles of oleanolic acid prepared in this study were stable and effective at alleviating wrinkles in humans as the principal active ingredient. Based on these findings, it is expected that polymeric micelles of oleanolic acid can be widely used in cosmetic applications.
... Thermo-responsive polymers have been extensively studied over the past few decades owing to their industrial and biomedical applications [1][2][3][4][5][6][7]. Among them, thermo-thickening has received much attention from academic and industrial fields because of its huge application potential in many fields [3,[7][8][9][10][11][12], especially in oil recovery [9,11]. ...
In this work, the transformation of chitosan-grafted-polyacrylamide (GPAM) aggregates in aqueous solution upon heating was explored by cryo-electron microscope (cryo-TEM) and dynamic light scattering (DLS), and larger aggregates were formed in GPAM aqueous solution upon heating, which were responsible for the thermo-thickening behavior of GPAM aqueous solution during the heating process. The heating initiates a transformation from H-bonding aggregates to a large-sized cluster formed by self-assembled hydrophobic chitosan backbones. The acetic acid (HAc) concentration has a significant effect on the thermo-thickening behavior of GPAM aqueous solution; there is a critical value of the concentration (>0.005 M) for the thermo-thickening of 10 mg/mL GPAM solution. The concentration of HAc will affect the protonation degree of GPAM, and affect the strength of the electrostatic repulsion between GPAM molecular segments, which will have a significant effect on the state of the aggregates in solution. Other factors that have an influence on the thermo-thickening behavior of GPAM aqueous solution upon heating were investigated and discussed in detail, including the heating rate and shear rate.
... Nanoparticles which are fabricated from a unique hydrophobic polymer like poly (1,4-phenyleneacetone dimethyleneketal) readily undergo acid hydrolysis into low molecular weight, hydrophilic components and can potentially deliver encapsulated therapeutics at a more improved rate in acidic environments like tumors or endosomes (Heffernan and Murthy 2005). Recently, it has been observed that thermosensitive and photosensitive polymers are used extensively by the researchers (Sershen et al. 2000;Cammas et al. 1997). ...
Biomedical applications of green synthesized metallic nanoparticles have the most significant advantage nowadays due to these unique magnetic and mechanical properties along with specific characteristics like heat, melting point, and surface area which make them suitable for biomedical applications like imaging, gene targeting, drug delivery, and biosensor development. The nanoparticles should have some qualities to be efficient carriers of drug, like magnetic properties; and the capability to function at the cellular and molecular levels of biological interactions makes the nanoparticles excellent agents to improve the contrast in magnetic resonance imaging (MRI). For biomedical applications, these days nanotechnology has enhanced the features and designs, explicitly the essential requirements and properties of magnetic nanoparticles (MNPs). Magnetic nanoparticles with magnetic properties have been used with higher magnetic moments and antifouling surfaces, and increased functionalities are developed for application in suitable clinical needs like detection, diagnosis, and treatment of malignant tumors and cardiovascular and neurological diseases. Development of a new generation of targeted drug delivery systems, diagnoses, and treatment of a range of life-threatening diseases through green synthesized nanoparticles is considered to be the most efficient treatment method. Because the synthesis of nanoparticles is from a natural source and is high-speed, eco-friendly, cost-effective, nontoxic, and biocompatible, the nanoparticles are applied in biomedical sectors. Passive dissemination mechanisms to target, the release of therapeutically active molecules, poor specificity, and dose-limited toxicity are the major problems associated with the conventional or traditional delivery system. However, delivery specificity has always been a challenge. But due to the avenues of nanotechnology, the synthesized nanoparticles have found that toxicity problem can be easily overcome in the development of new, improved, and efficient drug delivery systems like targeted tissue methods. Biologically synthesized nanoparticles are used to treat many dreadful diseases like cancer and cardiovascular disease, and are used in other disease detection and diagnosis. Moreover, bioconjugation of nanoparticles makes the poorly soluble anticancer drugs more effective. The advanced nontoxic nanomaterial drug delivery technique can be used to diagnose different types of cancer, and moreover, bionanomaterials can be potential nanocarriers for the delivery of drug and many critical therapeutic uses. The role of nanoparticles and nanomaterials in drug delivery is broadly discussed in this chapter.
... Actually, temperatureresponsive polymeric micelles can be easily derived from poly(N-isopropylacrylamide) (PNIP AAm) -based block copolymers with hydrophobic segment. 6 They can form micellar structure below Lower Critical Solution Temperature (LCST). Under heated condition, the thermo-responsive shell layers surrounding the hydrophobic cores effectively dehydrate and the micelles would turn into hydrophobic aggregates. ...
We have studied the preparations and characterizations of nano-sized complexes derived from stimuli-responsive AB- or ABA-type block copolymers and G3 poly(amidoamine) dendrimers. The block copolymers consisted of thermo-responsive poly(N-isopropylacrylamide) and poly(methacrylic acid), respectively. The nano-sized complexes were consequent on the electrostatic interactions between carboxyl groups of the block copolymers and amino groups of dendrimers in aqueous solutions. We confirmed the effective nano-sized complex formation by dynamic light scattering measurement and transmission electron microscope. Interestingly, the nano-sized complex derived from ABA-type triblock copolymer had smaller size than that from AB-type diblock copolymer. The condensation reactions between the block copolymers and the dendrimers effectively improved the stability of the nano-sized complexes in aqueous solutions. Furthermore, we also confirmed the sensitive response in temperature change.
... Introduction of more hydrophilic residues by copolymerization of PNIPAAm with hydrophilic monomers [207,208] successfully increased the LCST. Copolymerization with hydrophobic monomers [208][209][210] enhances micellar formation, incorporation yield of hydrophobic chemotherapeutics and stability of nanoparticles in aqueous media. Importantly, almost all these thermosensitive polymeric nanoparticles exhibit a release at temperature below the LSCT and require long duration of hyperthermia, up to few hours, to release a significant amount of their payload, which is difficult to translate to the clinical setting and which limits successful testing in preclinical investigations. ...
Chemotherapy is a cornerstone of cancer therapy. Irrespective of the administered drug, it is crucial that adequate drug amounts reach all cancer cells. To achieve this, drugs first need to be absorbed, then enter the blood circulation, diffuse into the tumor interstitial space and finally reach the tumor cells. Next to chemoresistance, one of the most important factors for effective chemotherapy is adequate tumor drug uptake and penetration. Unfortunately, most chemotherapeutic agents do not have favorable properties. These compounds are cleared rapidly, distribute throughout all tissues in the body, with only low tumor drug uptake that is heterogeneously distributed within the tumor. Moreover, the typical microenvironment of solid cancers provides additional hurdles for drug delivery, such as heterogeneous vascular density and perfusion, high interstitial fluid pressure, and abundant stroma. The hope was that nanotechnology will solve most, if not all, of these drug delivery barriers. However, in spite of advances and decades of nanoparticle development, results are unsatisfactory. One promising recent development are nanoparticles which can be steered, and release content triggered by internal or external signals. Here we discuss these so-called smart drug delivery systems in cancer therapy with emphasis on mild hyperthermia as a trigger signal for drug delivery.
Low back pain stands as a pervasive global health concern, afflicting almost 80% of adults at some point in their lives with nearly 40% attributable to intervertebral disc degeneration (IVDD). As only symptomatic relief can be offered to patients there is a dire need for innovative treatments. Given the accumulating evidence that multiple microRNAs (miRs) are dysregulated during IVDD, they could have a huge potential against this debilitating condition. The way miRs can profoundly modulate signaling pathways and influence several cellular processes at once is particularly exciting to tackle this multifaceted disorder. However, miR delivery encounters extracellular and intracellular biological barriers. A promising technology to address this challenge is the vectorization of miRs within nanoparticles, providing both protection and enhancing their uptake within the scarce target cells of the degenerated IVD. This comprehensive review presents the diverse spectrum of miRs’ connection with IVDD and demonstrates their therapeutic potential when vectorized in nanomedicines.
https://authors.elsevier.com/c/1iexC_,OflnfMa
PNIPAAm‐grafted thermoresponsive hollow nano‐holed polymeric‐shell (HHPS) particles were fabricated from surface‐modified colloidal silica (CS) with poly(ethylene glycol) methyl ether‐3‐(triethoxysilyl)propyl isocyanate (PEGME‐IPTES) and 3‐(trimethoxysilyl) propyl methacrylate (MPS) as templates. The polymeric shells were then synthesized through a “grafting‐through” approach via surface‐initiated polymerization of N‐isopropyl acrylamide (PNIPAAm) using potassium persulfate (KPS) as an initiator, followed by the etching of CS with hydrofluoric acid to remove the CS core templates. CS nanoparticles and PEGME‐IPTES were presynthesized using tetraethoxysilane (TEOS) and distilled water in methanol with ammonia solution as a catalyst by the sol–gel method and using 3‐(triethoxysilyl) propyl isocyanate (IPTES) with poly(ethylene glycol) methyl ether (PEGME) in the presence of dibutyltin dilaurate. The chemical structures of bare and modified CS, PNIPAAm, PNIPAAm‐CS, and HHPS particles were characterized by FT‐IR and NMR spectroscopies. SEM and TEM images confirmed that the resulting HHPS particles had a significant number of interconnected nanoholes. To evaluate the LCST behaviors of HHPS particles, the transition of transmittance and the changes in particle diameter according to the temperature change were measured through UV‐vis spectroscopy, DLS, and microscopy.
Combining existing drug therapy is essential in developing new therapeutic agents in disease prevention and treatment. In preclinical investigations, combined effect of certain known drugs has been well established in treating extensive human diseases. Attributed to synergistic effects by targeting various disease pathways and advantages, such as reduced administration dose, decreased toxicity, and alleviated drug resistance, combinatorial treatment is now being pursued by delivering therapeutic agents to combat major clinical illnesses, such as cancer, atherosclerosis, pulmonary hypertension, myocarditis, rheumatoid arthritis, inflammatory bowel disease, metabolic disorders and neurodegenerative diseases. Combinatorial therapy involves combining or co-delivering two or more drugs for treating a specific disease. Nanoparticle (NP)-mediated drug delivery systems, i.e., liposomal NPs, polymeric NPs and nanocrystals, are of great interest in combinatorial therapy for a wide range of disorders due to targeted drug delivery, extended drug release, and higher drug stability to avoid rapid clearance at infected areas. This review summarizes various targets of diseases, preclinical or clinically approved drug combinations and the development of multifunctional NPs for combining therapy and emphasizes combinatorial therapeutic strategies based on drug delivery for treating severe clinical diseases. Ultimately, we discuss the challenging of developing NP-codelivery and translation and provide potential approaches to address the limitations. This review offers a comprehensive overview for recent cutting-edge and challenging in developing NP-mediated combination therapy for human diseases.
The 3D bioprinting can controllably deposit bioink containing cells and fabricate complex bionic tissue structures in a fast and scalable way, which is expected to completely change the scenario of clinical organ transplantation. Bioprinting holds broad application prospect in tissue engineering, life sciences, and clinical medicine. In the process of 3D bioprinting, bioink, as the carrier of cells and bioactive substances, influences cell activity and accuracy of organ structure after printing. To better understand and design bioink, in this review, the concept, development, and basic composition of bioink are introduced, while focusing on the advantages and disadvantages of various biomaterials, and the use of common cells and biomolecules that constitute bioink. In addition, the properties and applications of various stimuli‐responsive smart materials for 4D bioprinting are mentioned. The challenges and development trends of bioink are also summarized.
In this work, the reversible addition‐fragmentation chain transfer (RAFT) emulsion polymerization of poly( N,N ‐dimethylacrylamide‐ co ‐ N ‐isopropylacrylamide)‐ b ‐polystyrene is developed with the aim of scale‐up of the polymer synthesis. Influences on the stability of the emulsion, reaction kinetics, and product quality are examined, compared between small‐scale and bench‐scale syntheses, and discussed in detail. The block copolymer lattices are studied via temperature‐dependent dynamic light scattering measurements in order to investigate the effects of the scale‐up on the thermosensitive behavior of the block copolymer and on emulsion stability. Conversion determination and polymer characterization are attained through ¹ H nuclear magnetic resonance (NMR) spectroscopy and gel permeation chromatography, respectively. The emulsion polymerization is successfully scaled up after several changes in the reaction composition and shows promising results regarding desired properties of the polymer.
Nanoparticles are attractive for many biomedical applications such as imaging, therapeutics and diagnostics. This new book looks at different soft nanoparticles and their current and potential uses in medicine and health including magnetoliposomes, micro/nanogels, polymeric micelles, DNA particles, dendrimers and bicelles.
Each chapter provides a description of the synthesis of the particles and focus on the techniques used to characterize the size, shape, surface charge, internal structure, and surface microstructure of the nanoparticles together with modeling and simulation methods. By giving a strong physical-chemical approach to the topic, readers will gain a good background into the subject and an overview of recent developments.
The multidisciplinary point of view makes the book suitable for postgraduate students and researchers in physics, chemistry, and biology interested in soft matter and its uses.
Synthetic polymer materials have been surged to the forefront of research in the fields of tissue engineering, drug delivery, and biomonitoring in recent years. Biodegradable synthetic polymers are increasingly needed as transient substrates for tissue regeneration and medicine delivery. In contrast to commonly used polymers including polyesters, polylactones, polyanhydrides, poly(propylene fumarates), polyorthoesters, and polyurethanes, biodegradable polyphosphazenes (PPZs) hold great potential for the purposes indicated above. PPZ's versatility in the synthetic process has enabled the production of a variety of polymers with various physico‐chemical, and biological properties have been produced, making them appropriate for biomedical applications. Biocompatible PPZs are often used as scaffolds in the regeneration of skeleton, bones, and other tissues. PPZs have also received special attention as potential drug vehicles of high‐value biopharmaceuticals such as anticancer drugs. Additionally, by incorporating fluorophores into the PPZ backbone to produce photoluminescent biodegradable PPZs, the utility of polyphosphazenes is further expanded as they are used in tracking the regeneration of the target tissue as well as the fate of PPZ based scaffolds or drug delivery vehicles. This review provides a summary of the evolution of PPZ applications in the fields of tissue engineering, drug delivery, and bioimaging in recent 5 years.
The synthesis and application of stimuli-responsive polymer materials have been extensively studied. Among stimuli-responsive polymers, thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) is the most widely investigated. PNIPAAm-based polymers undergo a reversible hydrophilic/hydrophobic phase transition in response to temperature. In addition, by introducing sites that are responsive to physical and chemical stimuli into PNIPAAm-based polymers, they also undergo phase transitions in response to stimuli, such as light, pH, oxidation/reduction, and enzyme activity. In this focus review, recent advancements in the applications of stimuli-responsive polymers based on PNIPAAm in biomedical fields are summarized, with an emphasis on our own research. In particular, a summary of the design of polymers for application in the separation and purification of (bio)pharmaceutical products and controlled cellular uptake is provided. First, temperature-responsive chromatography with PNIPAAm-modified silica beads is introduced. Thereafter, temperature- and pH-responsive polymers based on PNIPAAm used in imaging and drug delivery applications are discussed. Finally, the conclusions are presented, and future perspectives for the biomedical applications of stimuli-responsive polymers are discussed. Among stimuli-responsive polymers, thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) is the most widely investigated. PNIPAAm-based polymers can undergo appropriate changes in response to their external environment. In this focus review, recent advancements in the applications of stimuli-responsive polymers based on PNIPAAm in biomedical fields are summarized, with an emphasis on our own research. In particular, a summary of the design of polymers for application in the separation and purification of (bio)pharmaceutical products and controlled cellular uptake is provided.
CMC-SA-12-E2-12 hydrogels were prepared from Carboxymethylcellulose (CMC), succinic acid (SA) (biocompatible cross-linker) and Ethane-1,2-diyl-bis(N, N-dimethyl-N-dodecylammoniumacetoxy) (referred as 12-E2-12) (0.0006, 0.0015, 0.003, 0.0045 mMoles) by thermal treatment with economical and easy solution polymerization strategy. The CMC-SA-12E2-12 hydrogels were characterized for mechanical and viscoelastic properties like self-healing, viscosity and modulus using rheological analysis. Further the structural, morphological and thermal properties were investigated by FTIR, SEM and TGA analysis. The investigation revealed significant modulation in properties like mechanical, viscoelastic, self-healing and drug release behavior with the addition of surfactant. The CMC-SA-12-E2-12 hydrogels were investigated for drug release studies in PBS 7.4 for 48 h using Quercetin dihydrate. The results showed sustained release behavior at optimised concentration values of surfactant. Release data fitted nicely to the Higuchi model and hence the release could be seen to be diffusion controlled phenomenon or Fickian diffusion. The biocompatibility of cross-linker and surfactant may potentially make the hydrogels suitable for drug delivery applications.
Ion pair self-assembly (IPSAM) composed of poly(ethylenimine) (PEI) and (phenylthio)acetic acid (PTA) was prepared to investigate the electric field-responsive release property. PEI/PTA ion pairs were found to have an upper critical solution temperature and were air/water interface-active. IPSAM could release its payload (i.e., nile red) in proportion to the voltage. It was more sensitive to the electric field as PEI/PTA ratio was higher, and more sensitive to temperature change as the voltage was stronger. The electric field-induced protonation and oxidation were thought to be major reasons why IPSAM was responsive to the electric field in terms of release.
Viral vectors have attracted attention as a potential new therapeutic modality for gene therapy. In this study, we developed a temperature-modulated viral vector purification column using a mixed polymer brush composed of thermoresponsive and anionic polymers as packing material ligands. The mixed polymer brushes were modified on silica beads using a combination of reversible addition − fragmentation chain transfer (RAFT) polymerization of 2-acrylamido-2-methylpropanesulfonic acid (AMPS) and subsequent atom transfer radical polymerization (ATRP) of N-isopropylacrylamide (NIPAAm). The temperature-modulated zeta potential change in the prepared mixed polymer brush was attributed to the PNIPAAm shrinking and exposing of PAMPS. The prepared mixed polymer brush modified beads were used as packing materials, and the elution behavior of the adeno associated virus type 2 (AAV2) vector was observed. The AAV2 vector was adsorbed on the mixed polymer brush by electrostatic and hydrophobic interactions at 40 °C. By reducing the temperature to 5 °C, adsorbed AAV2 vector on the mixed polymer brush was desorbed and eluted from the column due to lowering the electrostatic and hydrophobic interactions between the AAV2 vector and mixed polymer brush. The AAV2 vector was separated from bovine serum proteins as a contaminant using the column. The ability to infect cells was maintained by the recovered AAV2 vectors from the column. Thus, the developed column would be beneficial for the simple purification of viral vectors.
Thermo‐responsive monomers were designed to contain a Diels‐Alder (DA) adduct such that cyclo‐reversion would yield either the maleimide or the furan unit attached to the polymer chain. These thermally responsive monomers were then copolymerized with N ‐isopropylacrylamide (NIPAM) via reversible addition‐fragmentation chain‐transfer (RAFT) polymerization to yield linear gradient‐copolymer structures as a comparison to existing nanogel/starlike systems to understand how polymer topology and composition influence solution‐state properties. Using UV–Vis spectroscopy, it was determined that solution‐state properties were thermally dependent and influenced by a number of variables such as comonomer feed ratio, polymer chain end functionality, and polymer backbone length and composition. Manipulation of the feed ratio allowed for control over the cloud point, including the breadth and location of phase separation. Thermal treatment of these copolymers revealed tunable and predictable variations in previously observed transitions, directly correlated to cleavage of the DA adducts and change in polymer backbone composition. Finally, on cooling cycles, a double sigmoid was sometimes observed, indicating a complex globule to random coil transition correlated to polymer chain end composition. These studies help understand how to untie the “monkey's fist.”
Metastasis is a major sign of malignant tumors which plays a vital role in cancer-related death. Suppressing metastasis is an important way to improve the survival rate of cancer patients. Herein, multifunctional PEG-LAM-PPS nanoparticles (nPLPs) are fabricated as both nanocarriers and anti-metastatic agents for tumor treatment. In this system, laminarin sulfate (LAM) suppresses metastasis by reducing heparinase and protecting the extracellular matrix; the ROS-sensitive polypropylene sulfide (PPS) improves the release of the loaded drug in the tumor microenvironment. This is the first time that laminarin sulfate has been used as a carrier to inhibit the expression of heparinase and treat melanoma lung metastasis. The blank nanoparticles are excellently safe and showed high anti-metastatic efficacy in melanoma lung metastatic mouse models, reducing metastatic nodules by 60%. They significantly improved the anti-tumor efficacy of the loaded drug doxorubicin, provided ∼33% further reduction of the tumor volume and 50% further reduction of the metastatic nodule number compared with free doxorubicin. Thus, these simple and versatile micellar nanoparticles composed of biocompatible materials offer a promising vehicle for treating invasive solid tumors and metastases.
We present a temperature-responsive spin column using an all-aqueous eluent. The method is intended as a simple sample preparation method for protein removal from serum, which is required for serum drug analysis. As packing materials for the spin column, we prepared two types of silica beads via surface-initiated radical polymerization. The large beads (diameter, 40–63 μm) were grafted with a temperature-responsive cationic copolymer, poly(N-isopropylacrylamide-co-N,N-dimethylaminopropyl acrylamide-co-n-butyl methacrylate) (P(NIPAAm-co-DMAPAAm-co-BMA)), and the small beads (diameter, 5 μm) were grafted with a temperature-responsive hydrophobic copolymer, P(NIPAAm-co-BMA). The beads were packed into the spin column as a double layer: P(NIPAAm-co-BMA) silica beads on the bottom and P(NIPAAm-co-DMAPAAm-co-BMA) silica beads on the top. The sample purification efficacy of the prepared spin column was evaluated on a model sample analyte (the antifungal drug voriconazole mixed with blood serum proteins). At 40 °C, the serum proteins and voriconazole were adsorbed on the prepared spin column via hydrophobic and electrostatic interactions. When the temperature was decreased to 4 °C, the adsorbed voriconazole was eluted from the column with the pure water eluent, while the serum proteins remained in the column. This temperature-responsive spin column realizes sample preparation simply by changing the temperature.
Core–shell drug-carrier particles are known for their unique features. Due to the combination of superior properties not exhibited by the individual components, core–shell particles have gained a lot of interest. The structures could integrate core and shell characteristics and properties. These particles were designed for controlled drug release in the desired location. Therefore, the side effects would be minimized. So, these particles' advantages have led to the introduction of new methods and ideas for their fabrication. In the past few years, the generation of drug carrier core–shell particles in microfluidic chips has attracted much attention. This method makes it possible to produce particles at nanometer and micrometer levels of the same shape and size; it usually costs less than other methods. The other advantages of using microfluidic techniques compared to conventional bulk methods are integration capability, reproducibility, and higher efficiency. These advantages have created a positive outlook on this approach. This review gives an overview of the various fluidic concepts that are used to generate microparticles or nanoparticles. Also, an overview of traditional and more recent microfluidic devices and their design and structure for the generation of core–shell particles is given. The unique benefits of the microfluidic technique for core–shell drug carrier particle generation are demonstrated.
The biorecognition‐based control of attachment/detachment of MCF‐7 cancer cells from polymer‐coated surfaces is demonstrated. A glass surface is coated with a thermoresponsive statistical copolymer of poly(N‐isopropylacrylamide‐co‐acrylamide) [p(NIPAm‐co‐Am)], which is end‐capped with the Gly‐Arg‐Gly‐Asp‐Ser (GRGDS) peptide, and the hydrophilic polymer poly(ethylene glycol) (PEG). Below the lower critical solution temperature (LCST) of p(NIPAm‐co‐Am) (38 °C), the copolymers are in the extended conformation, allowing for accessibility of the GRGDS peptides to membrane‐associated integrins thus enabling cell attachment. Above the LCST, the p(NIPAm‐co‐Am) polymers collapse into globular conformations, resulting in the shielding of the GRGDS peptides into the PEG brush with consequent inaccessibility to cell‐surface integrins, causing cell detachment. The surface coating is carried out by a multi‐step procedure that included: glass surface amination with 3‐aminopropyltriethoxysilane; reaction of mPEG5kDa‐N‐hydroxysuccinimide (NHS) and p(NIPam‐co‐Am)15.1kDa‐bis‐NHS with the surface aminopropyl groups and conjugation of GRGDS to the carboxylic acid termini of p(NIPam‐co‐Am)15.1kDa‐COOH. A range of spectrophotometric, surface, and microscopy assays confirmed the identity of the polymer‐coated substrates. Competition studies prove that MCF‐7 cancer cells are attached via peptide recognition at the coated surfaces according to the mPEG5kDa/p(NIPam‐co‐Am)15.1kDa‐GRGDS molar ratio. These data suggest the system can be exploited to modulate cell integrin/GRGDS binding for controlled cell capture and release.
Over the last three decades, polymeric micelles have emerged as a highly promising drug delivery platform for therapeutic compounds. Particularly, poorly soluble small molecules with high potency and significant toxicity were encapsulated in polymeric micelles. Polymeric micelles have shown improved pharmacokinetic profiles in preclinical animal models and enhanced efficacy with a superior safety profile for therapeutic drugs. Several polymeric micelle formulations have reached the clinical stage and are either in clinical trials or are approved for human use. This furthers interest in this field and underscores the need for additional learning of how to best design and apply these micellar carriers to improve the clinical outcomes of many drugs. In this review, we provide detailed information on polymeric micelles for the solubilization of poorly soluble small molecules in topics such as the design of block copolymers, experimental and theoretical analysis of drug encapsulation in polymeric micelles, pharmacokinetics of drugs in polymeric micelles, regulatory approval pathways of nanomedicines, and current outcomes from micelle formulations in clinical trials. We aim to describe the latest information on advanced analytical approaches for elucidating molecular interactions within the core of polymeric micelles for effective solubilization as well as for analyzing nanomedicine's pharmacokinetic profiles. Taking into account the considerations described within, academic and industrial researchers can continue to elucidate novel interactions in polymeric micelles and capitalize on their potential as drug delivery vehicles to help improve therapeutic outcomes in systemic delivery.
Les limites des nanovecteurs commerciaux ou actuellement en développement ont motivé l’élaboration de nouvelles nanoparticules mésoporeuses de silice (MSNP), hybrides et multiphasées, pour le contrôle de la délivrance d’actifs à application théranostique. Ainsi, de nouvelles MSNP ont été conçues pour la pénétration intracellulaire (diamètre entre 30 et 60 nm, taille des pores de 2,8 nm). Afin de les rendre hémocompatibles et de contrôler la cinétique de délivrance de principes actifs encapsulés, ces MSNP ont été enrobées d’une bicouche lipidique (MSNP+@SLB-). La composition lipidique s’inspire des membranes asymétriques des globules rouges ciblés par la présente étude.La technologie MSNP+@SLB- ayant montré des limites avec une cinétique de libération trop élevée de la calcéine et trop lente de la rhodamine B, deux améliorations majeures ont été apportées :1- Le recouvrement des SLB par un nanogel d’alginate, permettant un excellent contrôle de la libération d’actifs.2- L’insertion de nanoparticules magnétiques dans le coeur des MSNP, déclenchant la libération de l’actif par hyperthermie.Ces nouvelles architectures de nanovecteurs permettent de moduler les cinétiques de délivrance d’actifs, renforçant et élargissant ainsi le champ d’applications des vecteurs silicés dans les domaines biomédical ( Voie orale et intraveineuse) et dermato-cosmétique (Voie topique).
In recent decades, in addition to existing small-molecule drug therapies, biomedical technology has also rapidly progressed, leading to the development of various therapies based on biopharmaceuticals and therapeutic cells. However, these materials require effective separation methods for their analysis and production. A representative separation method, which has been extensively studied, is the temperature-responsive chromatography system using poly(N-isopropylacrylamide) and its copolymers. Over the last 20 years, various temperature-responsive chromatographic techniques have been developed for the separation of different types of analytes by changing the copolymer composition, the polymer graft configuration, and the base materials of the stationary phase. The developed methods have been successfully applied for the separation of small-molecule drugs, peptides, and proteins, without affecting their biological activity, simply by changing the column temperature. Furthermore, temperature-modulated cell separation columns have been investigated for the separation of cells without changing their properties. Therefore, the developed methods can serve as effective tools for the current and future bioseparation of various biological compounds, biopharmaceutical proteins, and therapeutic cells that are currently used in therapies.
Antibody drugs play an important role in biopharmaceuticals, because of the specificity for target biomolecules and reduction of side effects. Thus, separation and analysis techniques for these antibody drugs have increased in importance. In the present study, we develop functional chromatography matrices for antibody drug separation and analysis. Three types of polymers, poly(N-isopropylacrylamide (NIPAAm)-co-2-acrylamido-2-methylpropanesulfonic acid (AMPS)-co-N-phenyl acrylamide (PhAAm)), P(NIPAAm-co-AMPS-co-n-butyl methacrylate (BMA)), and P(NIPAAm-co-AMPS-co-tert-butylacrylamide (tBAAm)), were modified on silica beads through atom transfer radical polymerisation. Rituximab elution profiles were observed using the prepared beads-packed column. Rituximab adsorption at high temperature and elution at low temperature from the column were observed, as a result of the temperature-modulated electrostatic and hydrophobic interactions. Using the column, rituximab purification from contaminants was performed simply by changing the temperature. Additionally, three types of antibody drugs were separated using the column through temperature-modulated hydrophobic and electrostatic interactions. These results demonstrate that the temperature-responsive column can be applied for the separation and analysis of biopharmaceuticals through a simple control of the column temperature.
Poly(N-isopropylacrylamide) (PNIPAAm)-based thermally responsive micelles are of great importance as smart materials for a number of applications such as drug delivery and biosensing, owing to their tunable lower critical solution temperature (LCST). Their design and synthesis in the nanoscale size range have been widely studied, and research interest in their structural and physic-chemical properties is continually growing. In this Viewpoint, representative research on the construction of PNIPAAm-based thermally responsive micelles as well as their applications are highlighted and discussed, which would serve as a good start for newcomers in this field and a positive guide for future research.
Toxicity and in vivo antitumor activity against five solid tumors (C 26, C 38, M 5076, MKN-45, MX-1) of Adriamycin (ADR)-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer (PEG-P[Asp(ADR)]) were evaluated, and its pharmacokinetic behavior in blood and biodistribution by i.v. injection were obtained. PEG-P[Asp(ADR)] was revealed to express higher antitumor activity than ADR against all the examined tumors except MKN-45. Especially against C 26, PEG-P[Asp(ADR)] expressed critical suppression of tumor growth and considerably prolonged life span of the treated mice. PEG-P[Asp(ADR)] was observed in blood at much higher concentrations with a longer half-life than ADR after the i.v. injection. PEG-P[Asp(ADR)] was known to form a micellar structure with a diameter of approximately 50 nm and a narrow distribution in phosphate-buffered saline. Therefore, the stabilized circulation of ADR residue in blood by binding to the block copolymer was considered to result from the micellar structure which possesses the hydrated outer shell composed of the poly(ethylene glycol) chains.
Adriamycin (ADR), an anthracycline anticancer drug, was bound to the poly(aspartic acid) chain of poly(ethylene glycol)-poly(aspartic acid) block copolymer by amide bond formation between an amino group of Adriamycin and the carboxyl groups of the poly(aspartic acid) chain. The polymeric drug thus obtained was observed to form a micelle structure possessing diameter of approximately 50 nm, with a narrow distribution, in phosphate-buffered saline and to show excellent water solubility despite a large amount of ADR introduction. Further, it was able to be stored in lyophilized form without losing its water solubility in the redissolving procedure. Increased stability of the bound Adriamycin molecules in phosphate-buffered saline and elimination of binding affinity for bovine serum albumin due to the micelle formation were further advantages of this polymeric drug. In vivo high anticancer activity of this micelle-forming polymeric drug against P 388 mouse leukemia was obtained with less body weight loss than that seen with free ADR, due to low toxicity as compared with free ADR.
Concept and methodology of micelle-forming polymeric drug is reviewed. Drug targeting using drug carriers had been studied with three types of carriers ; liposomes, microspheres, and polymers. Now however, a successful example of drug targeting using any drug carrier has not been obtained because of low performance of drug carriers. A novel type of drug carrier system, micelle-forming polymeric drug is presented here. Polymeric micelles were constructed by amphiphilic structure of drug-polymer conjugate using a block copolymer, Expected superior features of the polymeric micelles as a drug carrier are long half-life in bloodstream, high water solubility, no long term-accumulation, high stability etc. Furthermore, functions which are needed for the ideal drug carrier can be shared by different polymer segments which become outer shell and inner core of the micelle. This separated functionality is favorable to get highly functionalized drug carrier system. Several unique characters and superior performance of the micelle-forming polymeric drug to the conventional drug carrier systems are described by the authors' work which is a conjugate of anticancer drug, adriamycin and poly(ethylene glycol)-poly(aspartic acid)block copolymer.
Micelle-forming block copolymer–drug conjugates, Adriamycin-conjugated polyethylene glycol–poly(aspartic acid) block copolymers (PEG-P[Asp(ADR)]), were synthesized in eight compositions with varying chain lengths of the segments constituting the block co-polymer. The antitumor activity of this micelle-forming polymeric anticancer drug against murine colon adenocarcinoma 26 (C 26) was evaluated by injection into the tail vein. The in vivo activity of the micelle-forming polymeric anticancer drug was revealed to be strongly dependent on the composition, while the in vitro cytotoxic activity was found to be in the same range regard-less of the composition. One composition of PEG–P[Asp(ADR)] was observed to significantly suppress tumor growth and to prolong survival of the treated mice in a wide dose range. These results indicated that selective delivery of the micelle-forming polymeric anti-cancer drug to the tumor was achieved by the appropriate composition of the block copolymer–drug conjugates.
A micelle-forming polymeric drug was synthesized using adriamycin (an anti-cancer drug) and poly(ethylene glycol)-poly(aspartic acid) block copolymers. The micelle had a narrow and unimodal size distribution, and its diameter was observed to be ca. 50 nm, the range corresponding to viruses. This micelle-forming polymeric drug exhibited good water solubility and good stability against precipitation irrespective of the large quantity of incorporated hydrophobie adriamycin. In vivo anti-cancer activity of this polymeric drug against P-388 mouse leukemia was studied by changing the length of the poly(aspartic acid) chain of the block copolymer. The polymeric drug showed excellent in vivo anti-cancer activity, judged from the ratio of the survival period of the treated mice to that of the control (T/C), with lower toxicity than that of adriamycin. These results point to a promising figure of polymeric micelles as novel drug carriers.
MANY polymeric hydrogels undergo abrupt changes in volume in response to external stimuli such as changes in solvent composition1, pH2, electric field3 and temperature4–6. For several of the potential applications of these materials, such as 'smart' actuators, a fast response is needed. The kinetics of swelling and de-swelling in these gels are typically governed by diffusion-limited transport of the polymeric components of the network in water, the rate of which is inversely proportional to the square of the smallest dimension of the gel7–9. Several strategies have been explored for increasing the response dynamics10–14, such as introducing porosity14. Here we show that we can induce rapid de-swelling of a polymer hydrogel by tailoring the gel architecture at the molecular level. We prepare a crosslinked hydrogel in which the polymer chains bear grafted side chains; the latter create hydrophobic regions, aiding the expulsion of water from the network during collapse. Whereas similar gels lacking the grafted side chains can take more than a month to undergo full de-swelling, our materials collapse in about 20 minutes.
In aqueous systems, polymeric micelles based on AB block copolymers of poly(ethylene oxide) (PEO) and poly(beta-benzyl L-aspartate) (PBLA) were investigated. First, AB block copolymers were synthesized using amino-terminated PEO to initiate the polymerization of beta-benzyl L-aspartate N-carboxy anhydride (BLA-NCA). The composition and molecular weights of the block copolymers were established using H-1 NMR. Micellar solutions of PEO-PBLA block copolymer were characterized by static and dynamic light scattering. Photophysical means were used to study the polymeric micelles. From changes in the fluorescence intensity and shifts in the excitation spectrum of pyrene upon micellization, critical micelle concentrations (cmc) of PEO-PBLA block copolymers were obtained. The vibrational structure of pyrene monomer fluorescence was altered in PEO-PBLA micellar solutions consistent with low polarity within the PBLA core. In PEO-PBLA micellar solutions, 1,3-(1,1'-dipyrenyl)propane intramolecular excimer emission, relative to monomer emission, was very weak; this indicates very low mobility of PBLA segments within the micellar core. Further evidence for the limited motion of the PBLA segments in the core was obtained by H-1 NMR. This limited motion of the PBLA segments in the micellar core is in contrast to low molecular weight surfactants which commonly show a higher degree of motion within their cores.
Temperature dependence of solute transport through aqueously swollen polymeric films and membranes can be altered to show even apparent negative activation energies by the use of polymers exhibiting a lower consolute behavior in solution. The principles by which we constructed a host of such polymers are discussed. A solubility rule is presented which predicts that solutes in water will show a lower critical solution temperature if the proper hydrophilic–hydrophobic balance is achieved.
Polymeric micelles have potential utility as drug carriers. To this end, polymeric micelles based on AB block copolymers of polyethylene oxide (PEG) and poly(aspartic acid) [p(Asp)] with covalently bound Adriamycin (ADR) were prepared. The micelle forming polymer–drug conjugates [PEO-p(Asp(ADR)] were radiolabeled and their biodistribution was investigated after intravenous injection in mice. Long circulation times in blood for some compositions of PEO-p[Asp(ADR)] conjugates were evident, which are usually atypical of colloidal drug carriers. This was attributed to the low interaction of the PEO corona region of the micelles with biocomponents (e.g., proteins, cells). Low uptake of the PEO-p(Asp(ADR)] conjugates in the liver and spleen was determined. The biodistribution of the PEO-p[Asp(ADR)] conjugates was apparently dependent on micelle stability; stable micelles could maintain circulation in blood, while unstable micelles readily formed free polymer chains which rapidly underwent renal excretion. Long circulation times in blood of PEO-p(Asp(ADR)] conjugates are thought to be prerequisite for enhanced uptake at target sites (e.g., tumors).
Hydrogels have been synthesized which exhibit a lower critical solution temperature (LCST). The gels shrink and deswell in aqueous solutions when the temperature is raised through their LCST. This phenomenon is reversible on cooling below the LCST where the gels reswell and expand. An enzyme has been immobilized within a thermally reversible hydrogel for the first time. We have shown that the enzyme activity is “shut off” when the gel is raised above its LCST. This phenomenon is reversible and the enzyme-gel regains activity below its LCST. Such catalytic hydrogels may be used to control reaction rates and temperatures by a thermal feedback mechanism.
Hydrogels have been synthesized which exhibit a lower critical solution temperature (LCST) and which shrink and deswell in aquous solutions when the temperature is raised through their LCST. This phenomenon is reversible on cooling below the LCST, when the gels reswell and expand. In this study we have shown that such gels may be used to absorb and/or release (deliver) a variety of biologically and industrially important substances. This action may be simulated by relatively small temperature changes in the environment. We have also shown how a specific binding ligand may be incorporated into the gel for selective binding (and removal or recovery) of specific solutes in aqueous solutions. Important applications of these novel gel systems are proposed for drug delivery, toxin removal, assay of selected solutes, bioprocess or industrial process product recovery and affinity separations in general.
A number of drug-carrier systems have been considered, so far, for time-controlled delivery, targeting, and decrease of toxicity of biologically active compounds. Many of these drug carriers are based on synthetic polymers. Prerequisites for polymeric drug carriers and the need for polyvalent systems capable of carrying different drugs are examined from the viewpoint of effective pharmaceutical uses. The cases of microcapsules, microspheres, nanoparticles, and emulsions based on polymers are recalled. Of particular interest are copolymers, such as amphiphilic block-copolymers and partially quaternized polytertiary amines, that can form hydrophobic microdomains in aqueous media. Discussions are focused on the capability of the corresponding microphases to solubilize, carry, and release lipophilic drugs. The present state of the art is illustrated by recent examples.
Temperature-responsive semitelechelic poly(N-isopropylacrylamide) (PIPAAm) bearing a carboxyl end group has been chemically immobilized on aminated polystyrene particle surfaces via condensation reaction. PIPAAm-grafted particles were uniformly suspended in aqueous media at lower temperatures. With increasing temperature, PIPAAm-grafted particles aggregated and precipitated. Such reversible changes in particle colloidal behaviour was correlated to temperature-modulated hydrophilic/hydrophobic changes of particle surfaces modified by PIPAAm hydration/dehydration with temperature changes. Interactions between platelets and PIPAAm-grafted surfaces were studied by monitoring cytoplasmic free Ca2+ concentration ([Ca2+]i) changes in platelets using intracellularly-trapped Ca2+ indicator dye, Fura 2, at various temperatures. Although changes in [Ca2+]i in platelets in contact with PIPAAm-grafted particles were not observed below the critical temperature of PIPAAm, significant changes in [Ca2+]i in platelets were induced by contact with particles above this critical temperature. Furthermore, temperature-modulated cell adsorption/desorption control by PIPAAm-grafted particles was investigated using a particle aggregation assay in the presence of lymphocytes. Below the critical temperature of PIPAAm, mixed suspensions were completely homogeneous due to minimal interaction between lymphocytes and hydrated particles. In contrast, aggregated precipitates were observed by increasing the suspension temperature above the critical temperature of PIPAAm resulting from strong hydrophobic interactions between particles with lymphocytes. These precipitates are reversibly resuspended in cold buffer. The feasibility of cell activation/inactivation or cell attachment/detachment control by temperature-modulated surface changes is attractive for suspension cell culture and drug delivery at targeted sites in vivo.
Chemical modification of proteins by use of functional polymers is expected to endow them with new properties without destroying their native functions, thus providing useful materials for application in different fields. We have synthesized poly(N-isopropylacrylamide) [poly(IPAAm)] co-oligomer with N,N-dimethylacrylamide (DMAAm) and reactive end groups by telomerization of IPAAm. This co-oligomer exhibits a lower critical solution temperature (LCST) at 37 degrees C. Using this temperature-responsive semitelechelic co-oligomer, we prepared polymer-enzyme conjugates of lipase by covalent coupling via carboxyl end-groups. This bioconjugate exhibits a LCST at 37 degrees C, having rapid, reversible hydration-dehydration changes due to highly mobile free polymer end groups. The conjugate retained its native enzymatic activity below this critical temperature, above which it precipitated and its catalytic function was shut off. This conjugate can be readily separated from reaction mixtures as a precipitate by simple temperature changes after reaction and reused in cycles without denaturation. Such a modulated system is attractive for application as a novel bioreactor system.
Poly(N-isopropyl acrylamide) (PIPAAm) demonstrated a fully expanded chain conformation below 32 degrees C and a collapsed, compact conformation at high temperatures. This unique temperature responsive polymer was grafted onto surfaces of commercial polystyrene dishes and used as temperature switches for creating hydrophilic surfaces below 32 degrees C and hydrophobic surfaces above 32 degrees C. Cell attachment and the growth of bovine endothelial cells and rat hepatocytes on PIPAAm-grafted surfaces at 37 degrees C demonstrated similar behavior to the commercialized culture dishes. Both cell types were observed to detach from the PIPAAm-grafted surface simply by reducing the temperature below the polymer transition temperature (collapse). Cells recovered by this method maintained substrate adhesivity, growth, and secretion activities nearly identical to those found in primary cultured cells in contrast to the compromised function found in cultured cells damaged by trypsinization. These results provide strong evidence that PIPAAm-grafted surfaces, as thermal switches are very effective for reversing cell attachment and detachment without cell damage. Properties of cell culture surfaces can be readily transformed by this technique reversibly into hydrophilic and hydrophobic coatings of PIPAAm-grafted polymers.
We have synthesized carboxyl semitelechelic oligo(N-isopropylacrylamide) (OIPAAm) using radical telomerization with 3-mercaptopropionic acid. This telomerization is also effective for the synthesis of carboxyl semitelechelic co-oligomers of IPAAm with butyl methacrylate (BMA) as hydrophobic or N,N-dimethylacrylamide (DMAAm) as hydrophilic comonomers. All co-oligomers are highly water-soluble at lower temperatures and exhibit phase separation with increasing temperature. Pure OIPAAm exhibits a lower critical solution temperature (LCST) at 32 degrees C, and the LCST for co-oligomers can be controlled to increase over 32 degrees C with increasing DMAAm composition and to decrease below 32 degrees C with increasing BMA composition. OIPAAm was grafted to bovine serum albumin (BSA) and bovine plasma fibrinogen (BPF) by activated ester-amine coupling. These OIPAAm-biomolecule conjugates maintain their temperature responses, are soluble in cold water, and precipitate over a range of temperatures related to oligomer content. Conjugates could be selectively precipitated and independently separated from conjugate solution mixtures with increasing temperature. In this case, the number of OIPAAm molecules attached to a conjugate affects the aggregate sizes of precipitated conjugates in mixtures. Both conjugate mixture ratios and solution concentrations influence the contamination of oligo(IPAAm-co-DMAAm)-BSA conjugates in precipitated oligo(IPAAm-co-BMA)-BPF conjugates. Furthermore, precipitated conjugates separated using centrifugation and filtration redissolve in water and maintain their biofunctionality, indicating the potential of strategy in reversible bioreactors and protein separations.
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