Temperature-dependent Drug Release Research Articles

Tunable self-assembly of lipid-based block polymeric micelles with temperature-sensitive poly(vinylcaprolactam) shell for effective anticancer drug delivery

Lipids, as naturally occurring biomolecules have emerged as promising carriers for delivering various therapeutic agents. However, only a few attempts have been made in terms of their applications as amphiphilic block copolymers for anticancer drug delivery. In this work, a biocompatible micellar drug delivery system with fatty acid-based polymer core and temperature-sensitive shell was developed. A series of amphiphilic block copolymers poly(vinyl stearate)/poly(vinyl laurate)-b-poly(N-vinylcaprolactam) (PVS/PVL-b-PNVCL) were synthesized via microwave-assisted reversible addition-fragmentation chain transfer polymerization in a controlled fashion. By varying the fatty acid type and hydrophilic/hydrophobic block lengths, the self-assembly behaviour of the block copolymer micelles proved to be highly tunable in terms of their morphology and particle size. Nile Red and hydrophobic anticancer drug doxorubicin (DOX) were effectively incorporated into the micelles, demonstrating high drug loading capacity, good serum stability, and temperature-dependent drug release characteristics of the polymeric micelles. In vitro studies using cell models revealed that blank PVS -b-PNVCL micelles are biocompatible with different cell lines, while DOX-loaded micelles were internalized into and accumulated in the cells, showing a high cytotoxic effect against HeLa cells. These findings suggest an opportunity for the development of safe and efficient lipid-based micellar system for smart drug delivery and cancer treatments.

Assessment of Temperature-Dependent Drug Release of Solubilizing Nanoformulations Using the SITUA.

The evaluation of temperature-dependent drug release for solubilizing nanoformulations uses a modification of the stable isotope ultrafiltration assay (SITUA). This method is specific to parenterally administered solubilizing nanomedicines and can be used to assess drug release from the total dosage form for regulatory purposes of lot release. The principle upon which this method is based is the relationship between drug solubility and temperature in a plasma simulating media, 4.5% human serum albumin, that allows for discrimination of passing and failing lots based upon the release characteristics.

Macromolecular carrier with long retention and body-temperature triggered nitric oxide release for corneal alkali burn therapy via leptin-related signaling

Corneal injuries, such as alkali burn, are a common ocular trauma worldwide and usually cause corneal opacification and even loss of sight, if without timely treatments. Eye drops have long been regarded as the best media for treating ocular surface diseases. However, their effectiveness was seriously dampened by natural self-cleaning mechanism of the eye. Herein, we designed and prepared polyamino acid-based poly-S-nitrosothiols (PGlu-TEPA-SNAP) as long-acting eye drops to treat corneal alkali burns. The cationic polymeric NO donor demonstrated good retention on the negatively charged surface of cornea without causing obvious biotoxicity. Meanwhile, the polymer can release NO in a temperature-dependent manner, by remaining relatively stable at 4 ℃ and 25 ℃, while rapidly releasing NO at around 35 ℃. In vivo study proved that the eye-drop with proper concentration effectively mitigated alkali-induced corneal damage in mice, via leptin related STAT3/MAPK/AKT signaling pathway. It selectively promoted epithelium regeneration without inducing neovascularization by utilization of the difference in cell sensitivity towards NO. Overall, the combined strategy of temperature-dependent drug release and strong retention of carriers can indeed fasten the healing of damaged cornea. It may serve as an inspiration for future NO or leptin-based work for ocular surface therapy.

Temperature-responsive and biocompatible nanocarriers based on clay nanotubes for controlled anti-cancer drug release.

Administration of temperature-responsive drug carriers that release anticancer drugs at high temperatures can benefit hyperthermia therapies because of the synergistic effect of anticancer drug molecules and high temperature on killing the cancer cells. In this study, we design and characterize a new temperature-responsive nanocarrier based on a naturally occurring and biocompatible clay mineral, halloysite nanotubes. Poly(N-isopropylacrylamide) brushes were grown on the surface of halloysite nanotubes using a combination of mussel-inspired dopamine polymerization and surface-initiated atom transfer radical polymerization. The chemical structure of the hybrid materials was investigated using X-ray photoelectron spectroscopy, thermogravimetric analysis and energy-dispersive X-ray spectroscopy. The hybrid material was shown to have a phase transition temperature of about 32 °C, corresponding to a 40 nm thick polymer layer surrounding the nanotubes. Cell studies suggested that grafting of poly(N-isopropylacrylamide) brushes on the polydopamine-modified halloysite nanotubes suppresses the cytotoxicity caused by the polydopamine interlayer and drug release studies on nanotubes loaded with doxorubicin showed that thanks to the poly(N-isopropylacrylamide) brushes a temperature-dependent drug release is observed. Finally, a fluorescent dye molecule was covalently attached to the polymer-grafted nanotubes and stimulated emission depletion nanoscopy was used to confirm the internalization of the nanotubes in HeLa cells.

Construction of a pH/Temperature dual-responsive drug delivery platform based on exfoliated MoS2 nanosheets for effective delivery of doxorubicin: Parametric optimization via central composite design

The aim of the current work was to develop drug delivery system for encapsulation and release of doxorubicin using exfoliated molybdenum disulfide nanosheets modified N-isopropyl acrylamide/methyl methacrylate. Here, glutamine was conjugated to the surface of molybdenum disulfide nanosheets. Several techniques such as Fourier transform infrared spectroscopy, X-ray diffraction, thermal gravimetric analysis, field emission scanning electron microscopy, and Zeta potential were applied to characterize the nanoadsorbent. Three important parameters of pH, contact time, and temperature were optimized by the response surface methodology technique. According to the central composite design, the maximum adsorption efficiency of 95% is attained at the pH = 8, contact time of 15 min, and temperature of 30 °C. The non-linear isotherms and kinetics sorption of drug onto nanoadsorbent can be excellently simulated by the Freundlich isotherm model and pseudo-second-order kinetic models, respectively. The dual-responsive nanocarrier indicated a slow release profile in simulated blood fluid at pH = 7.4 (T = 37 °C), whereas 98% of drug was released when nanocarrier were dissolved in pH = 5.6 (T = 50 °C) after 6 h, showing a sustained pH and temperature dependent drug release. The biocompatibility of nanocarrier was evaluated by MTT assay on KB cell line as a breast cancer modal cell.

Injectable in situ intelligent thermo-responsive hydrogel with glycyrrhetinic acid-conjugated nano graphene oxide for chemo-photothermal therapy of malignant hepatocellular tumor.

Malignant tumor is one of the major diseases with high morbidity and mortality. The purpose of this study is to prepare berberine hydrochloride (BH) in situ thermo-sensitive hydrogel based on glycyrrhetinic acid (GA) modified nano graphene oxide (NGO) (GA-BH-NGO-gel). NGO was taken as the photosensitizer, GA was taken as the target molecule, and BH was taken as the model drug. The physicochemical properties and anti-tumor activity in vivo and in vitro were also studied. This subject could provide a certain theoretical basis for the chemo-photothermal therapy combined treatment of malignant tumor. The release behavior of GA-BH-NGO-gel in vitro presented sustained and temperature-dependent drug release effect. The anti-tumor activity studies in vivo and in vitro had shown that GA-BH-NGO-gel had stronger anti-tumor activity, which could be targeting distributed to the tumor tissues. Moreover, the inhibitory effect of GA-BH-NGO-gel was enhanced when combined with 808nm of laser irradiation. In this research, the chemo-photothermal combination therapy was applied into the tumor treatment, which may provide certain research ideas for the clinical treatment of malignant tumor.

Development and bioevaluation of controlled release 5-aminoisoquinoline nanocomposite: a synergistic anticancer activity against human colon cancer

<abstract> <p>The current study presents a bimodal therapeutic platform for cancer treatment. Bimodal implies that the presented drug loaded core-shell structure is capable of elevating the tumor tissue temperature (hyperthermia) through the superparamagnetic iron oxide core and simultaneously release a Poly (ADP-ribose) polymerase-1(PARP-1)-modifying agent from the thermoresponsive shell. Magnetic thermoresponsive nanocomposite MTN was synthesized via an in situ free radical polymerization of thermo-responsive (N-isopropylacrylamide) (NIPAAm) monomer in the presence of 11-nm monodisperse SPIONs. The composite was allowed to swell in various concentrations of the PARP inhibitor: 5-aminoisoquinoline (5-AIQ) forming drug-loaded magnetic thermoresponsive nanocomposite (MTN-5.AIQ). Structural characterization of the formed composite is studied via various experimental tools. To assess the coil to globule transition temperature, the lower critical solution temperature (LCST) is determined by differential scanning calorimetry (DSC) method and the cloud point (Tp) is determined by turbidometry. Magnetic thermoresponsive nanocomposite (MTN) is formed with excellent potential for hyperthermia. A high drug loading efficiency (85.72%) is obtained with convenient temperature dependent drug release kinetics. Biocompatibility and cytotoxic efficacy are tested on an in vivo and in vitro colorectal-adenocarcinoma model, respectively. MTN.5-AIQ administration exhibits normal hepatic and renal functions as well as lower toxic effect on normal tissue. In addition, the composite effectively inhibits Caco-2 cells viability upon incubation. Based on the obtained results, the proposed therapeutic platform can be considered as a novel, promising candidate for dual therapy of colorectal adenocarcinoma exhibiting a PARP-1 overexpression. as well as increased the inhabiting efficacy of 5-AIQ.</p> </abstract>

Controlled drug release of levofloxacin from poly (acrylamide) hydrogel

Hydrogels are 3D polymer networks capable to absorb and release water or biological fluids. They are stimuli-responsive materials, which can show rapid volume changes with response to small changes in environmental parameters such as ionic strength, pH, and temperature. In this work, we performed a synthesis of Poly(acrylamide) hydrogel and tested for controlled release of levofloxacin hemihydrate as a model drug. We used sodium metabisulfite and potassium persulphate as free radical initiators to prepare hydrogel with methylenebisacrylamide as a crosslinker. Characterization of hydrogel was performed by TGA, SEM, and FT-IR. Swelling study and drug release were performed at pH 1.2 and 7.4 solutions, identical to the gastrointestinal fluid at 37°C (human body temperature) to examine possible site-specific drug delivery. UV-Visible spectrophotometer was used to measure the concentration of drug release. Results exhibited the pH and temperature-dependent drug release. The amount of drug release was found to be 17% and 99% in acidic and alkaline pH of 1.2 and 7.4, respectively, after 6 hours.

Preparation and pharmacodynamics in vivo of nano graphene oxide-based matrine in situ gel

With matrine(MAT) as the model drug, to prepare nano graphene oxide(NGO)-based MAT in situ gel(MAT-NGO-gel), a kind of drug for tumor treatment in combination with phototheraphy, and investigate the physicochemical properties and anti-tumor effects in vivo of MAT-NGO-gel. First, HPLC method was established to measure the content of MAT in the gel. The ultrasonic method was used to load MAT onto the surface of NGO, and then poloxamer 188 and poloxamer 407 were chosen as the main materials to prepare MAT-NGO-gel. The optimum prescription was selected with the gelation temperature as the index. Finally, the drug loading rate, micromorphology, phototherrmal conversion characteristics and drug release in vitro of MAT-NGO-gel were characterized. In the optimized prescription, the concentration of poloxamer 188 and poloxamer 407 was 2% and 20% respectively, and the mass ratio of NGO and MAT was 1∶1. The gelation temperature and drug loading rate of MAT-NGO-gel prepared by the optimal prescription process was 37.5 ℃ and 16.7%. Under 808 nm laser irradiation, MAT-NGO-gel showed obvious concentration-and time-dependent photothermal conversion characteristics. In vitro release experiments showed that MAT-NGO-gel had temperature-dependent release characteristics. The pharmacodynamics of MAT solution, NGO-gel and MAT-NGO-gel were studied by using S180 tumor-bearing mice and 808 nm laser. The relative tumor volume and body weight of the tumor-bearing mice were plotted over time. After the experiment, the tumor tissues of each group were taken and the histopathological changes were observed by HE staining. The results of pharmacodynamic studies demonstrated that when compared with NS group and NGO-gel group, the body weights of mice in MAT-NGO-gel group and MAT-NGO-gel + laser group were higher, and the relative tumor volume growth was slower. The results of HE stained pathological sections showed that the tumor cells count for the mice in MAT-NGO-gel group and MAT-NGO-gel + laser group was significantly reduced, with obvious nuclear fragmentation and nucleolysis in these two groups. These results suggested that MAT-NGO-gel, especially combined with 808 nm laser, had stronger anti-tumor activity in vivo. The prescription process of MAT-NGO-gel in this experiment was stable and feasible. As compared with MAT solution, MAT-NGO-gel showed obvious sustained and temperature-dependent drug release characteristics. MAT-NGO-gel had much more obvious anti-tumor activity in vivo when combined with 808 nm laser irradiation. This study could provide certain theoretical basis for the therapy of malignant tumor with multiple mechanisms.

Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation.

Liposomes containing copper and the copper ionophore neocuproine were prepared and characterized for in vitro and in vivo anticancer activity. Thermosensitive PEGylated liposomes were prepared with different molar ratios of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and hydrogenated soybean phosphatidylcholine (HSPC) in the presence of copper(II) ions. Optimal, temperature dependent drug release was obtained at 70:30 DPPC to HSPC weight ratio. Neocuproine (applied at 0.2 mol to 1 mol phospholipid) was encapsulated through a pH gradient while using unbuffered solution at pH 4.5 inside the liposomes, and 100 mM HEPES buffer pH 7.8 outside the liposomes. Copper ions were present in excess, yielding 0.5 mM copper-(neocuproine)2 complex and 0.5 mM free copper. Pre-heating to 45 °C increased the toxicity of the heat-sensitive liposomes in short-term in vitro experiments, whereas at 72 h all investigated liposomes exhibited similar in vitro toxicity to the copper(II)-neocuproine complex (1:1 ratio). Thermosensitive liposomes were found to be more effective in reducing tumor growth in BALB/c mice engrafted with C26 cancer cells, regardless of the mild hyperthermic treatment. Copper uptake of the tumor was verified by PET/CT imaging following treatment with [64Cu]Cu-neocuproine liposomes. Taken together, our results demonstrate the feasibility of targeting a copper nanotoxin that was encapsulated in thermosensitive liposomes containing an excess of copper.

Ammonium Bisphosphonate Polymeric Magnetic Nanocomplexes for Platinum Anticancer Drug Delivery and Imaging with Potential Hyperthermia and Temperature-Dependent Drug Release

Novel magnetite-ammonium bisphosphonate graft ionic copolymer nanocomplexes (MGICs) have been developed for potential drug delivery, magnetic resonance imaging, and hyperthermia applications. The complexes displayed relatively uniform sizes with narrow size distributions upon self-assembly in aqueous media, and their sizes were stable under simulated physiological conditions for at least 7 days. The anticancer drugs, cisplatin and carboplatin, were loaded into the complexes, and sustained release of both drugs was observed. The transverse NMR relaxivities (r2s) of the complexes were 244 s−1 (mM Fe)−1 which is fast compared to either the commercial T2-weighted MRI agent Feridex IV® or our previously reported magnetite-block ionomer complexes. Phantom MRI images of the complexes demonstrated excellent negative contrast effects of such complexes. Thus, the bisphosphonate-bearing MGICs could be promising candidates for dual drug delivery and magnetic resonance imaging. Moreover, the bisphosphonate MGICs generate heat under an alternating magnetic field of 30 kA·m−1 at 206 kHz. The temperature of the MGIC dispersion in deionized water increased from 37 to 41°C after exposure to the magnetic field for 10 minutes, corresponding to a specific absorption rate of 77.0 W·g−1. This suggests their potential as hyperthermia treatment agents as well as the possibility of temperature-dependent drug release, making MGICs more versatile in potential drug delivery applications.

Triggered release of paclitaxel from magnetic solid lipid nanoparticles by magnetic hyperthermia

We developed a magnetic solid lipid nanoparticles formulation of paclitaxel (PTX-loaded MSLNs) via emulsification-diffusion method. The physicochemical characterization of PTX-loaded MSLNs was performed by AFM, DLS, determination of entrapment efficiency (EE) and drug loading (DL), DSC, VSM, and physical stability. The in vitro effect of temperature and pulsed magnetic hyperthermia on drug release were studied. PTX-loaded MSLNs had a particle diameter around 250 nm with a narrow size distribution, spherical morphology, EE of 67.3 ± 1.2% and a DL of 17.1 ± 0.4 μg/mg. A decrease of the melting point of the lipid was observed following the preparation of the MSLNs. A threefold increase in the in vitro drug release rate was seen when temperature was raised from 25 to 43 °C. The lipid coating of MPs confer a temperature-dependent drug release and magnetic hyperthermia was used to trigger controlled PTX release from MSLNs.

Multifunctional stimuli responsive polymer-gated iron and gold-embedded silica nano golf balls: Nanoshuttles for targeted on-demand theranostics

Multi-functional nanoshuttles for remotely targeted and on-demand delivery of therapeutic molecules and imaging to defined tissues and organs hold great potentials in personalized medicine, including precise early diagnosis, efficient prevention and therapy without toxicity. Yet, in spite of 25 years of research, there are still no such shuttles available. To this end, we have designed magnetic and gold nanoparticles (NP)-embedded silica nanoshuttles (MGNSs) with nanopores on their surface. Fluorescently labeled Doxorubicin (DOX), a cancer drug, was loaded in the MGNSs as a payload. DOX loaded MGNSs were encapsulated in heat and pH sensitive polymer P(NIPAM-co-MAA) to enable controlled release of the payload. Magnetically-guided transport of MGNSs was examined in: (a) a glass capillary tube to simulate their delivery via blood vessels; and (b) porous hydrogels to simulate their transport in composite human tissues, including bone, cartilage, tendon, muscles and blood–brain barrier (BBB). The viscoelastic properties of hydrogels were examined by atomic force microscopy (AFM). Cellular uptake of DOX-loaded MGNSs and the subsequent pH and temperature-mediated release were demonstrated in differentiated human neurons derived from induced pluripotent stem cells (iPSCs) as well as epithelial HeLa cells. The presence of embedded iron and gold NPs in silica shells and polymer-coating are supported by SEM and TEM. Fluorescence spectroscopy and microscopy documented DOX loading in the MGNSs. Time-dependent transport of MGNSs guided by an external magnetic field was observed in both glass capillary tubes and in the porous hydrogel. AFM results affirmed that the stiffness of the hydrogels model the rigidity range from soft tissues to bone. pH and temperature-dependent drug release analysis showed stimuli responsive and gradual drug release. Cells’ viability MTT assays showed that MGNSs are non-toxic. The cell death from on-demand DOX release was observed in both neurons and epithelial cells even though the drug release efficiency was higher in neurons. Therefore, development of smart nanoshuttles have significant translational potential for controlled delivery of theranostics’ payloads and precisely guided transport in specified tissues and organs (for example, bone, cartilage, tendon, bone marrow, heart, lung, liver, kidney, and brain) for highly efficient personalized medicine applications.

Tumor-penetrating Peptide-integrated Thermally Sensitive Liposomal Doxorubicin Enhances Efficacy of Radiofrequency Ablation in Liver Tumors.

Purpose To investigate the role of a tumor-penetrating peptide (internalizing CRGDRGPDC [iRGD])-integrated thermally sensitive liposomal (TSL) doxorubicin (DOX) in combination with radiofrequency (RF) ablation of liver tumors in an animal model. Materials and Methods Approval from the institutional animal care and use committee was obtained. Characterization of iRGD-TSL-DOX was performed in vitro. Next, H22 liver adenocarcinomas were implanted in 138 mice in vivo. The DOX accumulation and cell apoptosis of iRGD-TSL-DOX and TSL-DOX with or without RF were evaluated (n = 5) at different time points after treatment with quantitative analysis or pathologic staining. Mice bearing tumors were randomized into the following six groups (each group, eight mice): no treatment, iRGD-TSL-DOX, TSL-DOX, RF alone, RF ablation followed by TSL-DOX at 30 minutes (TSL-DOX combined with RF), and RF ablation followed by iRGD-TSL-DOX (iRGD-TSL-DOX combined with RF). Kaplan-Meier method was used to estimate the survival curves and log-rank test was used for comparison with statistical software. Results DOX encapsulation efficiency in iRGD-TSL-DOX was 97.5% ± 1.3 (standard deviation) with temperature-dependent drug release capability confirmed in vitro. In vivo, the iRGD-TSL-DOX group had overall higher DOX concentration in the tumor and had maximal difference at 24 hours compared with TSL-DOX group (2.7-fold). RF caused more intense cell apoptosis at 24 hours (median, 65% vs 21%, respectively; P < .001). For end-point survival, the iRGD-TSL-DOX combined with RF group had better survival (median, 32 days) than TSL-DOX combined with RF (median, 27 days; P = .035) or RF alone (median, 21 days; P < .001). Conclusion Conjugation to iRGD helped to improve intratumoral DOX accumulation and further enhanced the activity of TSL-DOX in RF ablation of liver tumors. © RSNA, 2017 Online supplemental material is available for this article.

Effect of Moisture on the Thermoresponsive Properties of Binary Mixtures of Monoglycerides for Triggerable Drug Delivery Systems.

The crystallization behavior and temperature-dependent phase transition of monoglycerides have been utilized to develop thermal-sensitive drug delivery systems. The presence of excess water has been reported to influence the phase transition. The present study investigates the effect of moisture on the thermal behavior of binary blends of monoglycerides. Various compositions (0-100wt%) of glyceryl monooleate (GMO) and glyceryl monostearate (GMS) were prepared by fusion method, and exposed to varying relative humidity (RH) levels (0-100%). The moisture uptakes, sorption isotherm, and the thermal behavior of GMO-GMS samples were analyzed using differential scanning calorimeter (DSC), scanning electron microscopy (SEM), and X-ray diffraction (XRD). The in vitro nifedipine (NF) release was studied at 37 and 42°C. Samples of GMO-GMS (25:75, 50:50, and 75:25wt%) stored at 97%RH at 25°C for 3weeks increased in weight by 14.0, 14.7, and 15.8%, respectively. Despite such high moisture uptake, the GMO-GMS matrices maintained crystalline structure. The melting point (T m) and heat of fusion (ΔH f) of the samples were reduced as the amount of moisture in the matrices increased. However, the heat of fusion calculated on dry basis remained constant at 139.4 ± 1.25, 102.7 ± 1.14, and 46.7 ± 1.16J/g for GMO-GMS 25:75, 50:50, and 75:25wt%, respectively. The comparison of the XRD measurements of the dry samples with those containing 30% water confirmed the preserved crystalline arrangement in the matrices. This study indicates that despite the high moisture uptakes, the GMO-GMS matrices retained their crystalline properties and provided temperature-dependent drug release indicating the potential application for thermoresponsive local drug delivery systems.

Herceptin-conjugated temperature-sensitive immunoliposomes encapsulating gemcitabine for breast cancer.

Gemcitabine (2',2'-difluorodeoxycytidine, GCT) is an analog of deoxycytidine with cytotoxicity for breast cancer cells. However, because of its hepatotoxicity and other side effects, an efficient drug delivery system is needed for better therapeutic outcomes. A temperature-sensitive PEGylated immunoliposome (TSL) with trastuzumab (or Herceptin) attached encapsulating GCT (Her-PEG-TSL-GCT) was prepared. The mean diameter of the liposome was about 200 nm and the prepared immunoliposome showed the capacity to deliver the payload to the hyperthermic environment. The actual number of antibody molecules attached to one single liposome is about 19, with the GCT encapsulation efficiency of 54.6 ± 3.50 %. This immunoliposome shows a temperature-dependent drug release at around 41-43 °C. Anticancer activity of Her-PEG-TSL-GCT was determined using HER-2 expressing breast cancer cells, SK-BR-3, in vitro and resulted in increased cytotoxicity compared to free GCT (IC20 11.7 nM) or conventional liposome lacking the targeting antibody. In conclusion, these data show that improved delivery of GCT to breast cancer cells can be achieved by Her-PEG-TSL-GCT in vitro, and this strategy could be used for breast cancer therapy with further studies.

Characterization and cytotoxicity studies of DPPC:M2+ novel delivery system for cisplatin thermosensitivity liposome with improving loading efficiency

A novel, metal ion-assisted drug-loading model, in which the metal ion was used to modify the microstructure of DPPC bilayers, has been developed to improve the drug-loading efficiency of cisplatin thermosensitivity liposomes. The reactions of dipalmitoyl phosphatidylcholine (DPPC) with diverse metal ions (Zn2+, Cu2+, Mn2+ and Mg2+) yield four typical liposomes, which have been characterized by FT-IR, Raman and fluorescence techniques; the mechanism for higher drug encapsulation efficiency has also been investigated. In these prepared liposomes, the conformation of DPPC is changed due to the electrostatic interaction between the metal ions and phospholipid acyl group, leading to a closer arrangement of the lipid hydrocarbon chains and higher Tm of DPPC. As a result, the encapsulation efficiency of metal ion-assisted loading liposome is significantly higher than that of metal ion-free state. While for the release time, all four metal ion-assisted liposomes could be released within 10min at 42±0.5°C, which approach to the phase transition temperature, indicating that the introduction of metal ions into the DPPC bilayer membranes has no influence on the thermosensitivity of the liposome. Furthermore, the higher cytotoxicity of metal ion-bounded liposomes than that of free cisplatin solution suggests that high encapsulation efficiency can cause cytotoxicity increase. Hence, this work highlighted that metal ion-assisted loading model increased the encapsulation efficiency and cell cytotoxicity of cisplatin in thermosensitive liposomes with no obvious effects on sustained and temperature-dependent drug release.

Temperature-dependent drug release from DPPC:C12H25-PNIPAM-COOH liposomes: Control of the drug loading/release by modulation of the nanocarriers’ components

Novel polymer-modified thermosensitive liposomes were developed for the delivery of indomethacin in order to control its release profile. When attached to 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes, the end functionalized C12H25-poly(N-isopropylacrylamide)-COOH (C12H25-PNIPAM-COOH) polymer was membrane-disruptive in a temperature-dependent manner. The interest for this polymer is driven by its famous lower critical solution temperature (LCST) behavior, where heating an aqueous solution of PNIPAM above 32°C induces nanophase separation and polymer chain aggregation. The physicochemical/structural behavior of these polymer-modified thermosensitive liposomes was found to depend on the PNIPAM:lipid molar ratio and the composition of the polymeric guest. The incorporation of PNIPAM has caused alterations in the thermotropic behavior of DPPC liposomes, as the differential scanning calorimetry (DSC) experiments revealed. The drug loading and the release were found to be strongly dependent on the thermotropic characteristics of the PNIPAM grafted DPPC liposomes. Namely, the in vitro release is immediate at 37°C (>LCST) (“burst” effect), while the prepared mixed nanocarriers did not release the encapsulated bioactive substance at <32°C (<LCST). Thus, the thermosensitivity and the drug loading/release properties of the prepared formulations can be modulated by varying the ratio of DPPC/PNIPAM components, as well as the molecular characteristics of the polymeric guest.

Dual-responsive polymer-coated iron oxide nanoparticles for drug delivery and imaging applications.

We reported the synthesis and characterization of dual-responsive poly(N-isopropylacrylamide-acrylamide-chitosan) (PAC)-coated magnetic nanoparticles (MNPs) for controlled and targeted drug delivery and imaging applications. The PAC-MNPs size was about 150nm with 70% iron mass content and excellent superparamagnetic properties. PAC-MNPs loaded with anti-cancer drug doxorubicin showed dual-responsive drug release characteristics with the maximum release of drugs at 40°C (∼78%) than at 37°C (∼33%) and at pH of 6 (∼55%) than at pH of 7.4 (∼28%) after 21 days. Further, the conjugation of prostate cancer-specific R11 peptides increased the uptake of PAC-MNPs by prostate cancer PC3 cells. The dose-dependent cellular uptake of the nanoparticles was also significantly increased with the presence of 1.3T magnetic field. The nanoparticles demonstrated cytocompatibility up to concentrations of 500μg/ml when incubated over a period of 24h with human dermal fibroblasts and normal prostate epithelial cells. Finally, pharmacokinetic studies indicated that doxorubicin-loaded PAC-MNPs caused significant prostate cancer cell death at 40°C than at 37°C, thereby confirming the temperature-dependent drug release kinetics and in vitro therapeutic efficacy. Future evaluation of in vivo therapeutic efficacy of targeted image-guided cancer therapy using R11-PAC-MNPs will reinforce a significant impact of the multifunctional PAC-MNPs on the future drug delivery systems.

Synthesis of Amphiphilic Tadpole-Shaped Linear-Cyclic Diblock Copolymers via Ring-Opening Polymerization Directly Initiating from Cyclic Precursors and Their Application as Drug Nanocarriers

We report on the facile synthesis of well-defined amphiphilic and thermoresponsive tadpole-shaped linear-cyclic diblock copolymers via ring-opening polymerization (ROP) directly initiating from cyclic precursors, their self-assembling behavior in aqueous solution, and the application of micellar assemblies as controlled release drug nanocarriers. Starting from a trifunctional core molecule containing alkynyl, hydroxyl, and bromine moieties, alkynyl-(OH)-Br, macrocyclic poly(N-isopropylacrylamide) (c-PNIPAM) bearing a single hydroxyl functionality was prepared by atom transfer radical polymerization (ATRP), the subsequent end group transformation into azide functionality, and finally the intramacromolecular ring closure reaction via click chemistry. The target amphiphilic tadpole-shaped linear-cyclic diblock copolymer, (c-PNIPAM)-b-PCL, was then synthesized via the ROP of ε-caprolactone (CL) by directly initiating from the cyclic precursor. In aqueous solution at 20 °C, (c-PNIPAM)-b-PCL self-assembles into spherical micelles consisting of hydrophobic PCL cores and well-solvated coronas of cyclic PNIPAM segments. For comparison, linear diblock copolymer with comparable molecular weight and composition, (l-PNIPAM)-b-PCL, was also synthesized. It was found that the thermoresponsive coronas of micelles self-assembled from (c-PNIPAM)-b-PCL exhibit thermoinduced collapse and aggregation at a lower critical thermal phase transition temperature (T(c)) compared with those of (l-PNIPAM)-b-PCL. Temperature-dependent drug release profiles from the two types of micelles of (c-PNIPAM)-b-PCL and (l-PNIPAM)-b-PCL loaded with doxorubicin (Dox) were measured, and the underlying mechanism for the observed difference in releasing properties was proposed. Moreover, MTT assays revealed that micelles of (c-PNIPAM)-b-PCL are almost noncytotoxic up to a concentration of 1.0 g/L, whereas at the same polymer concentration, micelles loaded with Dox lead to ∼60% cell death. Overall, chain topologies of thermoresponsive block copolymers, that is, (c-PNIPAM)-b-PCL versus (l-PNIPAM)-b-PCL, play considerable effects on the self-assembling and thermal phase transition properties and their functions as controlled release drug nanocarriers.