Release Kinetics Of Doxorubicin Research Articles

Preclinical evaluation of thermosensitive poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate)-grafted liposomes for cancer thermochemotherapy

Thermosensitive liposomes grafted with cholesterol-conjugated poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate) (chol-pHPMAlac) have been developed for heat-induced release of doxorubicin (DOX). These liposomes release DOX completely during mild hyperthermia, but their interaction with blood cells and cancer cells has not been studied. Following intravenous administration, liposomes may interact with plasma proteins and various types of cells (e.g., endothelial cells, platelets, and macrophages), which would reduce their disposition in the tumor stroma. Interaction between liposomes and platelets may further cause platelet activation and thrombosis, which could lead to vascular occlusion and thromboembolic complications. The aim was to investigate DOX release kinetics in the presence of serum, stability, in vitro uptake by and toxicity to cancer cells and somatic cells, and platelet activating potential of the chol-pHPMAlac liposomes. DOX release was determined spectrofluorometrically. Liposome stability was determined in buffer and serum by dynamic light scattering and nanoparticle tracking analysis. Association with/uptake by and toxicity of empty liposomes to AML-12, HepG2 (both hepatocyte-derived cancer cells), RAW 264.7 (macrophages), and HUVEC (endothelial) cells was assayed in vitro. Platelet activation was determined by analysis of P-selectin expression and fibrinogen binding. DOPE:EPC liposomes (diameter = 135 nm) grafted with 5% chol-pHPMAlac (cloud point (CP) = 16 °C; Mn = 8.5 kDa) released less than 10% DOX at 37 °C in 30 min, whereas complete release took place at 47 °C or higher within 10 min. The size of these liposomes remained stable in buffer and serum during 24 h at 37 °C. Fluorescently labeled but DOX-lacking chol-pHPMAlac-liposomes exhibited poor association with/uptake by all cells under investigation, were not cytotoxic, and did not activate platelets in both buffered solution and whole blood. In conclusion, thermosensitive chol-pHPMAlac-grafted liposomes rapidly release DOX during mild hyperthermia. The liposomes are stable in a physiological milieu, are not taken up by cells that are encountered in an in vivo setting, and are non-antagonistic towards platelets. Chol-pHPMAlac-grafted liposomes are therefore good candidates for DOX delivery to tumors and temperature-triggered release in tumor stroma.

Supramolecular poly(N-acryloylmorpholine)-b-poly(d,l-lactide) pseudo-block copolymer via host-guest interaction for drug delivery

In the present study, a pseudo-block copolymer was prepared from β-cyclodextrin terminated poly(N-acryloylmorpholine) (β-CD-PNAM) and adamantine-terminated linear poly(D,L-lactide) (AD-PDLLA), through host-guest interaction between β-CD and AD groups. Initially, the hydrophilic polymer PNAM was synthesized using reversible addition fragmentation polymerization, which was further linked to N3-β-CD through click reaction. In parallel, an AD terminated hydrophobic polymer, AD-PDLLA was synthesized using ring opening polymerization. The synthesized polymers were characterized by means of 1H NMR, gel permeation chromatography and fourier transform infrared. Subsequently, the formation of a pseudo-block copolymer via inclusion complexation between the β-CD core and AD-moiety was confirmed by 2D-NOESY NMR and self-aggregation of the pseudo-block copolymer was investigated by fluorescence spectroscopy. In addition, doxorubicin (DOX) a hydrophobic drug was loaded into the supramolecular micelles and the release kinetics of DOX from the micelles was studied. The result revealed that DOX release was accelerated as the pH reduced from 7.4 to 6.4.

Combining ultrasound and intratumoral administration of doxorubicin-loaded microspheres to enhance tumor cell killing

Melanoma is an incurable disease for which alternative treatments to chemotherapy alone are sought. Here, using a melanoma model, we investigated the antitumor potential of combining ultrasound (US) with poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with doxorubicin (DOX). The aim was to achieve synergistic tumoricidal activity through direct and indirect US-mediated damage of tumor cells combined with sustained and potentially controllable release (when combined with US) of DOX from microspheres. An in vitro release assay demonstrated an ability of US to affect the release kinetics of DOX from DOX-loaded PLGA microspheres by inducing a 12% increase in the rate of release. In vitro viability assays demonstrated that combining US with DOX-loaded PLGA microspheres resulted in synergistic tumor cell (B16-F10 melanoma cells) killing. Melanoma-bearing mice were treated intratumorally with DOX (8 µg)-loaded microspheres and subjected to US treatment at the tumor site. This treatment could significantly extend survival (mean survival (MS) = 22.1 days) compared to untreated mice (MS = 10.4 days) and most other treatments, such as blank microspheres plus US (MS = 11.5 days) and DOX (8 µg)-loaded microspheres alone (MS = 13 days). The findings that immune checkpoint blockade did not significantly extend survival of mice treated with DOX (8 µg)-loaded microspheres plus US, and that tumor-free (“cured”) mice were not protected from subsequent tumor rechallenge suggests minimal involvement of the adaptive immune response in the observed antitumor activity. Nevertheless, the synergistic increase in survival of melanoma-challenged mice treated with the combination of US and DOX-loaded microspheres implicates such a treatment methodology as a promising additional tool for combatting otherwise currently incurable cancers.

Graphene oxide@gold nanorods for chemo-photothermal treatment and controlled release of doxorubicin in mice Tumor

Graphene oxide (GO) is a close derivative of graphene has unlocked many pivotal steps in drug delivery due to their inherent biocompatibility, excellent drug loading capacity, and shows antibacterial, antifungal properties etc. We used a novel plant material called Gum arabic (GA) to increase the solubility of GO as well as to chemically reduce it in the solution. GA functionalized GO (fGO) exhibited increased absorption in near infra-red region (NIR) which was exploited in photothermal therapy for cancer. In order to understand the shape and size effect of GO which may affect their rheological properties, we have conjugated them with gold nanorods (GNRs) using in situ synthesis of GO@GNRs via seed mediated method. To the above conjugate, Doxorubicin (DOX) was attached at ambient temperature (28±2°C). The release kinetics of DOX with the effect of NIR exposure was also carefully studied via in vitro photothermal killing of A549 cell lines. The enhancement in NIR induced drug release and photothermal property was observed which indicates that the fGO@GNRs-DOX method is an ideal choice for chemotherapy and photothermal therapy simultaneously.

Biodegradable poly(D,L-lactide-co-glycolide)/poly(L-γ-glutamic acid) nanoparticles conjugated to folic acid for targeted delivery of doxorubicin

A novel targeted drug delivery nanoparticle system based on poly(D,L-lactide-co-glycolide) acid (PLGA) for delivery of doxorubicin (DOX) was developed. DOX-PLGA NPs were obtained by the emulsification-solvent evaporation technique. Then, their surface was modified with poly(L-γ-glutamic acid) (γ-PGA) and finally conjugated to modified folic acid (FA) as a targeting ligand. The surface modification and FA conjugation were followed by UV–Vis and FT-IR spectroscopies. Morphology was observed by TEM/SEM. Particle size, PDI and zeta potential were measured using DLS studies. Encapsulation and loading efficiencies, and DOX release kinetics were determined. Specific uptake and cell viability of DOX-PLGA/γ-PGA-FA NPs were tested in HeLa cells. Quasi-spherical nanoparticles with a particle size lower than 600nm (DLS) were obtained. Spectroscopic techniques demonstrated the successful surface modification with γ-PGA and FA conjugation. Release profile of DOX-PLGA/γ-PGA-FA NPs showed a release of 55.4±0.6% after seven days, in an acidic environment. HeLa cells exhibited a decrease in viability when treated with DOX-PLGA/γ-PGA-AF NPs, and cellular uptake was attributed to FA receptor-mediated endocytosis. These results suggest that DOX-PLGA/γ-PGA-FA NPs are a potential targeted drug carrier for further applications in cancer therapy.

Fibrous CaF2:Yb,Er@SiO2-PAA ‘tumor patch’ with NIR-triggered and trackable DOX release

Smart localized drug delivery systems (LDDSs), with stimuli-responsive properties, offer tremendous opportunity for personalized cancer chemotherapy. In our work, an implantable ‘tumor patch’, consisting of upconversion (UC) photoluminescent CaF2:Yb,Er nanoparticles embedded within silica nanofibers (CaF2:Yb,Er@SiO2), was designed and synthesized for doxorubicin (DOX) delivery. DOX loading capacity of the fiber mesh was remarkably enhanced with assist of polyacrylic acid (PAA) functionalization. PAA modified CaF2:Yb,Er@SiO2 nanofibers presented highly corresponding optical response to DOX release kinetics. Accelerated drug release in acidic condition induced more rapid increase in the spectral intensity ratio of green to red emission (I550/I660), and vice versa. More importantly, under the irradiation of NIR (808nm) laser, DOX release kinetics and consequently the in-vitro anti-cancer efficacy were enhanced. This study has thus offered another new implantable LDDS with NIR-triggered and monitored DOX delivery for personalized protocols in tumor chemotherapy.

Optimization of Formulation and Process Variables for the Preparation of Novel Doxorubicin-Loaded Sonosensitive Nanodroplets

In the present study the effect of process (homogenization speed) and formulation (polymer concentration, surfactant concentration, drug amount, perfluorohexane volume fraction and co-surfactant inclusion) variables on particle size, entrapment efficiency, and drug release kinetics of doxorubicin-loaded alginate stabilized perfluorohexane nanodroplets were evaluated. Particle size and doxorubicin entrapment efficiency were highly affected by formulation and process variables. In vitro release profile of doxorubicin from all formulations was an apparently biphasic release process and 7–13 % of drug released from nanodroplets after 24 h incubation in PBS, pH 7.4, depending on the nanodroplets composition but ultrasound exposure for 10 min resulted in triggered release of 85.95 % of doxorubicin fromoptimal formulation (G). The inclusion of Span 60 (0.15 %), Poloxamer 188 (0.15 %) as co-surfactants reduced the particle size of nanodroplets from 51.8 to 42.3 and 35.6 nm, respectively. The entrapment efficiency decreased for span 60, while it did not changed in the case of Poloxamer 188. Comparison of drug release kinetics demonstrated that drug release was delayed for both Span 60 and Poloxamer 188. Thus, it was concluded that the particle size, entrapment efficiency and the doxorubicin release kinetics could easily be adjusted by taking advantage of process and formulation variables.

Nanoparticle loaded coatings and patches on live cells

Event Abstract Back to Event Nanoparticle loaded coatings and patches on live cells Brad Berron1, Pei-Jung Wu1, Jacob L. Lilly1 and Roberto Arreaza1 1 University ofKentucky, Chemical and Materials Engineering, United States Introduction: Cells possess biodistribution characteristics which are unique from all traditional modes of drug delivery. For example, a red blood cell can carry large payloads of oxygen and remain in circulation for weeks. Other cells actively defeat natural barriers to which are difficult to drug delivery (blood-brain barrier, blood-retinal barrier). The present work develops the fabrication techniques for loading cells with drug-eluting nanoparticles for cell-directed drug delivery using nanoscale coatings. For prolonged systemic delivery, we develop techniques for depositing a nanoparticle loaded coating on the surface of red blood cells. For cell-directed drug delivery, we develop techniques for restricting the drug-loaded coating to a small area on the cell. Methods: For uniform coatings, cell surfaces are first labeled with an eosin photoinitiator through immunolabeling with a biotinylated antibody and subsequent immersion in a streptavidin eosin conjugate. Cells are then immersed in a pH buffered solution of the desired nanoparticles, PEG diacrylate, triethanol amine, and vinyl pyrollidinone. Irradiation with 530 nm light (20 mW/cm2 for 20 minutes) results in the conformal coating of the cell. Cell patches are prepared similarly, with the additional use of a photomask to restrict polymer formation to irradiated regions. Results Discussion: Conformal cell coatings were deposited on human red cells, Jurkats, A549, and H358 cells. Diffusion of drugs through the coatings was limited to materials <10 kDa. Transport of low MW materials was rapid; equilibrium release rates are established within seconds. The release kinetics of doxorubicin from nanoparticles from the coatings is consistent with that of the doxorubicin from the nanoparticles, again supporting the minimal mass transfer resistance of the coatings for small molecules. >80% cell viability was confirmed by calcein, ethidium, and caspase assays. The coated cells are able to deform to traverse <10 micron openings. Patterned coatings are formed on cells with photomasks to limit the area of light exposure. The parameter space was evaluated to determine their influence on gelation kinetics and the associated quality of the pattern. Additionally, the influence of the parameter space on cell viability was evaluated. Key findings include: 1) Rapid gelation kinetics promote accuracy of patterning, 2) High light doses negatively impact viability, 3) The presence of oxygen during polymerization promotes redox damage of cells. Conclusion: Photopolymerization offers a convenient route to load nanoparticles into coatings on cells. The cells retain viability during the coating process. The coatings offer minimal resistance to mass transfer of small molecules, while large species are trapped in the coatings. Photopatterning of these coatings is simple. The polymerization design is focused on cell-compatible conditions while encouraging rapid gelation for accurate patterning on the micron scale. Keywords: Drug delivery, material design, Cell modulation, bioinerface Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: General Session Oral Topic: Biomaterials for therapeutic delivery Citation: Berron B, Wu P, Lilly JL and Arreaza R (2016). Nanoparticle loaded coatings and patches on live cells. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02101 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Brad Berron Pei-Jung Wu Jacob L Lilly Roberto Arreaza Google Brad Berron Pei-Jung Wu Jacob L Lilly Roberto Arreaza Google Scholar Brad Berron Pei-Jung Wu Jacob L Lilly Roberto Arreaza PubMed Brad Berron Pei-Jung Wu Jacob L Lilly Roberto Arreaza Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Thermoresponsive Random Poly(ether urethanes) with Tailorable LCSTs for Anticancer Drug Delivery.

A new class of thermoresponsive random polyurethanes is successfully synthesized and characterized. Poly(ethylene glycol) diol (Mn = 1500 Da) and 2,2-dimethylolpropionic acid are reacted with isophorone diisocyanate in the presence of methane sulfonic acid catalyst. It is found that these polyurethanes are thermoresponsive in aqueous media and manifest a lower critical solution temperature (LCST) that can be easily tuned from 30 °C to 70 °C by increasing the poly(ethylene glycol) content. Their sharp LCST transitions make these random polyurethanes ideal candidates for stimuli-responsive drug delivery applications. To that end, the ability of these systems to efficiently sequester doxorubicin (up to 36 wt%) by means of a sonication/dialysis method is successfully demonstrated. Additionally, it is also demonstrated that accelerated doxorubicin release kinetics from the nanoparticles can be attained above the LCST.

Amphiphilic poly(ethylene glycol)-b-poly(ethylene brassylate) copolymers: One-pot synthesis, self-assembly, and controlled drug release

A set of amphiphilic poly(ethylene glycol)-b-poly(ethylene brassylate) (PEG-b-PEB) copolymers based on the PEB hydrophobic block was first synthesized by ring-opening polymerization of ethylene brassylate with an organic catalyst. The EB/PEG molar ratios and reaction times were adjusted to achieve different chain lengths of PEB. Block copolymers that were characterized by 1H NMR and GPC could self-assemble into multimorphological aggregates in aqueous solution, which were characterized by DLS and TEM. The hydrophobic doxorubicin (DOX) was chosen as a drug model and successfully encapsulated into the nanoparticles. The release kinetics of DOX were investigated.

Redox-responsive nanoreservoirs: The effect of different types of mesoporous silica on the controlled release of doxorubicin in solution and in vitro

Controlled release systems based on SBA-15 and MCM-41 have been obtained by grafting the surfaces of these mesoporous silica nanoparticles with the host–guest pair ferrocenyl group (–Fc)@β-cyclodextrin attached to Au nanoparticles (β-CDS-AuNPs). Investigation of doxorubicin (DOX) release from the FcSBA-15/β-CDS-AuNPs and FcMCM-41/β-CDS-AuNPs nanoreservoirs, triggered by oxidation of the –Fc group in weakly acidic medium, was monitored by fluorescence spectroscopy. The results have evidenced that DOX release depends not only on [O2] and pH, but most importantly, on the type of support. Indeed, the kinetics of DOX delivery from the SBA-15 based nanoreservoir at pH 6.5 and ambient [O2] was about 10times slower than from the analogous reservoir based on MCM-41, however, no appreciable effect on the DOX release kinetics was observed upon changing the β-CDS-AuNPs cap of the latter nanoreservoir for β-CD (i.e., from FcMCM-41/β-CD). These systems were used to deliver DOX to B16F10 mouse melanoma cancer cells. Cell viability results determined by MTT assays have shown that DOX loaded-nanoreservoirs were more toxic to the B16F10 cells than both free DOX and empty nanoreservoirs, at [DOX] of 22nmolL−1, thus suggesting that the nanoreservoirs have improved internalization of DOX in tumor cells.

Synthesis of mesoporous SiO2–ZnO nanocapsules: encapsulation of small biomolecules for drugs and “SiOZO-plex” for gene delivery

This work presents a new synthesis of mesoporous SiO2–ZnO composite nanocapsules with sizes of 90–150 nm and represents their applications in encapsulation of small biomolecules (fluorescent molecules, drugs, and DNA) for uses in medical biotechnology (e.g., drug and gene delivery) for the first time. The nanocapsule size and morphology have been confirmed through the HRSEM and HRTEM. The mesoporous structure of the novel materials has been confirmed through both BET and HRTEM, and the pore diameter observed to be ca. 2–8 nm with an average diameter of 5.1 nm. The BET surface area of mesoporous SiO2–ZnO was found to be ~230 m2 g−1. Three different types of pores were detected through HRTEM: type-I, normal pores in silica matrix, pore with ZnO nanoparticles at the boundary (type-II) and type-III, the pores with tiny ZnO nanoparticles (~5–7 nm) inside them. To demonstrate the biocompatibility and cell viability of the nanocapsules, normal and cancerous lymphocyte cells have been chosen and investigated in a systematic way. Fluorescent dye (Rhodamine 6G), anticancer drug e.g., Doxorubicin (DOX) were loaded in all types of pores, and EtBr-labeled DNA molecules were loaded efficiently into the mesopores of second and third types of the composite nanocapsules to manifest the characteristic of mesoporous, and to find out its loading efficacy. The release kinetics of Rhodamine 6G and DOX were studied. The results highlight the potential of novel functional mesoporous SiO2–ZnO nanoparticles for using as the carrier of drugs and formation of “SiOZO-plex”, a complex of mesoporous SiO2–ZnO with DNA for gene delivery applications.

Investigation of the mechanisms governing doxorubicin and irinotecan release from drug-eluting beads: mathematical modeling and experimental verification

Drug-eluting beads (DEBs) are embolising devices in clinical use for the treatment of liver cancer by transarterial chemoembolisation. In this study, release kinetics of doxorubicin (DOX) and irinotecan (IRI) were investigated by experimental evaluations and mathematical modeling, based on Langmuir isotherm and two phenomenological models (Boyd/Bhaskar) developed to determine the actual mechanisms controlling drug release rate. The model was validated through release studies, in particular by assessing how drug loading, ionic strength of the release medium and device swelling during release influence drug release kinetics. Results demonstrated that IRI is released much faster than DOX, and that DEB volume strongly depends upon drug loading and fractional release. This effect was properly taken into account in developing the mathematical model. Experimental results were well fit by numerical simulations, and two different rate-controlling mechanisms were found to govern DOX and IRI delivery.

Magnetic field triggered drug release from polymersomes for cancer therapeutics

Local and temporal control of drug release has for long been a main focus in the development of novel drug carriers. Polymersomes, which can load both hydrophilic and hydrophobic species and, at the same time, be tailored to respond to a desired stimulus, have drawn much attention over the last decade. Here we describe polymersomes able to encapsulate up to 6% (w/w) of doxorubicin (DOX) together with 30% (w/w) of superparamagnetic iron oxide nanoparticles (USPIO; γ-Fe2O3). Upon internalization in HeLa cells and when a high frequency AC magnetic field (14mT at 750kHz) was applied, the developed delivery system elicited an 18% increase in cell toxicity, associated with augmented DOX release kinetics. In order to ensure that the observed cytotoxicity arose from the increased doxorubicin release and not from a pure magnetic hyperthermia effect, polymersomes loaded with magnetic nanoparticles alone were also tested. In this case, no increased toxicity was observed. We hypothesize that the magnetic field is inducing a very local hyperthermia effect at the level of the polymersome membrane, increasing drug release. This approach opens new perspectives in the development of smart delivery systems able to release drug upon demand and therefore, improving treatment control.

Folic acid mediated synaphic delivery of doxorubicin using biogenic gold nanoparticles anchored to biological linkers.

Azadirachta indica as a biological sink for fabrication of gold nanoparticles (GNPs) and its applications in efficient delivery of doxorubicin (DOX) are presented here. Sucrose density gradient centrifugation was used to isolate the spherical GNPs of <50 nm from the mixture (containing both spherical and non-spherical) of nanoparticles synthesized using leaves of A. indica at inherent pH (6.14). The stability of GNPs due to the biological capping agents was scrutinised by measuring the flocculation parameter which was found to be in the range of 0-0.65. On the surface of these capped GNPs, doxorubicin was attached along with activated folic acid (FA) as navigational molecules for targeted drug delivery. Attachments were verified using FTIR which confirmed the formation of non-covalent interactions. The GNPs-FA-DOX complex was found be non-toxic for normal cells and considerably toxic for HeLa cells. The drug loading capacity of the GNPs was found to 93%. Doxorubicin release kinetics using GNPs followed 1st order at pH 5.3 which is ideal for solid tumor targeting.

Poly(ethyleneglycol)-b-Poly(ε-caprolactone-co-γ-hydroxyl-ε- caprolactone) Bearing Pendant Hydroxyl Groups as Nanocarriers for Doxorubicin Delivery

A novel biodegradable amphiphilic diblock copolymer methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-γ-hydroxyl-ε-caprolactone) (mPEG-b-P(CL-co-HCL)) bearing pendant hydroxyl groups on the PCL block was prepared. The hydroxyl groups were formed through the reduction of ketones by sodium borohydride without protection and deprotection. The obtained polymers were well characterized by (1)H NMR, Fourier transform infrared (FT-IR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and contact angle measurement. mPEG-b-P(CL-co-HCL) could self-assemble into stable nanoparticles (NPs) with critical micellar concentrations (CMC) of 6.3 × 10(-4) ∼ 8.1 × 10(-4) mg/mL. The NPs prepared from mPEG-b-P(CL-co-HCL) were spherical in shape with diameters about 100 to 140 nm. The hydrophobic doxorubicin (DOX) was chosen as a drug model and successfully encapsulated into the NPs. The encapsulation efficiency and release kinetics of DOX were investigated. The results indicated that the introduction of hydroxyl groups onto the core-forming block could decrease the hydrophobicity of copolymers, thus improving the storage stability of NPs in aqueous solution. Moreover, higher loading capacity and slower in vitro release of DOX were observed, which was due to the hydrogen-bonding formation between DOX and hydroxyl groups. Meanwhile, the MTT assay demonstrated that the blank NPs were biocompatible to HepG2 cell,s while free DOX and DOX-loaded NPs showed significant cytotoxicity against the cells. Moreover, Compared to the free DOX, the DOX-loaded NPs were more efficiently internalized by HepG2 cells. In sum, the introduction of hydroxyl groups on the polyester block in mPEG-b-P(CL-co-HCL) exhibited great potentials for modifications in the stability, drug solubilization, and release properties of NPs.

Formulation and characterisation of magnetic resonance imageable thermally sensitive liposomes for use with magnetic resonance-guided high intensity focused ultrasound

Purpose: Objectives of this study were to: 1) develop iLTSL, a low temperature sensitive liposome co-loaded with an MRI contrast agent (ProHance® Gd-HP-DO3A) and doxorubicin, 2) characterise doxorubicin and Gd-HP-DO3A release from iLTSL and 3) investigate the ability of magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) to induce and monitor iLTSL content release in phantoms and in vivo.Methods: iLTSL was passively loaded with Gd-HP-DO3A and actively loaded with doxorubicin. Doxorubicin and Gd-HP-DO3A release was quantified by fluorescence and spectroscopic techniques, respectively. Release with MR-HIFU was examined in tissue-mimicking phantoms containing iLTSL and in a VX2 rabbit tumour model.Results: iLTSL demonstrated consistent size and doxorubicin release kinetics after storage at 4°C for 7 days. Release of doxorubicin and Gd-HP-DO3A from iLTSL was minimal at 37°C but fast when heated to 41.3°C. The magnitude of release was not significantly different between doxorubicin and Gd-HP-DO3A over 10 min in HEPES buffer and plasma at 37°, 40° and 41.3°C (p > 0.05). Relaxivity of iLTSL increased significantly (p < 0.0001) from 1.95 ± 0.05 to 4.01 ± 0.1 mMs−1 when heated above the transition temperature. Signal increase corresponded spatially and temporally to MR-HIFU-heated locations in phantoms. Signal increase was also observed in vivo after iLTSL injection and after each 10-min heating (41°C), with greatest increase in the heated tumour region.Conclusion: An MR imageable liposome formulation co-loaded with doxorubicin and an MR contrast agent was developed. Stability, imageability, and MR-HIFU monitoring and control of content release suggest that MR-HIFU combined with iLTSL may enable real-time monitoring and spatial control of content release.

A stimuli-responsive hydrogel for doxorubicin delivery

The goal of this study was to develop a polymeric carrier for delivery of anti-tumor drugs and sustained release of these agents in order to optimize anti-tumor activity while minimizing systemic effects. We used oligo(poly(ethylene glycol) fumarate) (OPF) hydrogels modified with small negatively charged molecules, sodium methacrylate (SMA), for delivery of doxorubicin (DOX). SMA at different concentrations was incorporated into the OPF hydrogel with a photo-crosslinking method. The resulting hydrogels exhibited sensitivity to the pH and ionic strength of the surrounding environment. Our results revealed that DOX was bound to the negatively charged hydrogel through electrostatic interaction and was released in a timely fashion with an ion-exchange mechanism. Release kinetics of DOX was directly correlated to the concentration of SMA in the hydrogel formulations. Anti-tumor activity of the released DOX was assessed using a human osteosarcoma cell line. Our data revealed that DOX released from the modified, charged hydrogels remained biologically active and had the capability to kill cancer cells. In contrast, control groups of unmodified OPF hydrogels with or without DOX did not exhibit any cytotoxicity. This study demonstrates the feasibility of using SMA-modified OPF hydrogels as a potential carrier for chemotherapeutic drugs for cancer treatments.

Prediction of kinetics of doxorubicin release from sulfopropyl dextran ion-exchange microspheres using artificial neural networks

The purpose of this work was to develop artificial neural networks (ANN) models to predict in vitro release kinetics of doxorubicin (Dox) delivered by sulfopropyl dextran ion-exchange microspheres. Four ANN models for responses at different time points were developed to describe the release profiles of Dox. Model selection was performed using the Akaike information criterion (AIC). Sixteen data sets were used to train the ANN models and two data sets for the validation. Good correlations were obtained between the observed and predicted release profiles for the two randomly selected validation data sets. The difference factor ( f 1) and similarity factor ( f 2) between the ANN predicted and the observed release profiles indicated good performance of the ANN models. The established models were then applied to predict release kinetics of Dox from the microspheres of various initial loadings in media of different ionic strengths and NaCl/CaCl 2 ratios. The results suggested that ANN offered a flexible and effective approach to predicting the kinetics of Dox release from the ion-exchange microspheres.

Comparison of doxorubicin concentration profiles in radiofrequency-ablated rat livers from sustained- and dual-release PLGA millirods.

To evaluate and compare the local pharmacokinetics of doxorubicin in radiofrequency (rf)-ablated rat livers after interstitial delivery from sustained- and dual-release poly(D,L-lactide-co-glycolide) (PLGA) millirods. PLGA millirods with sustained- and dual-release kinetics (burst followed by sustained release) of doxorubicin were implanted in rf-ablated rat livers. Doxorubicin release kinetics in vivo were measured from explanted millirods by UV-Vis spectrophotometer over 8 days. Spatial distribution of doxorubicin in liver tissues was measured by fluorescence imaging. In the initial 24 h after millirod implantation, dual-release millirods released significantly more doxorubicin into liver tissues than the sustained millirods. Subsequently, both types of millirods provided comparable sustained-release kinetics over 8 days. With dual-release millirods, doxorubicin concentration and penetration distance in liver tissue increased more rapidly. To reach 30 microg/g doxorubicin concentration at the ablation boundary (targeted site of action), the time required was 6 days and 1.5 days for sustained- and dual-release millirods, respectively. Compared with sustained-release millirods, dual-release millirods provide a quick concentration elevation and sustaining of the drug concentration at the ablation boundary. Additionally, the steady-state drug concentration agrees well with model predictions based on previously determined transport parameters, which demonstrates the feasibility of rational design of drug formulations in polymer millirods.