Controlled Release Of Paclitaxel Research Articles

The influence of electron beam and gamma irradiation on paclitaxel-loaded nanoparticles of fully randomized copolymers in relation to potential sterilization

The presented report describes the evaluation of the influence of e-beam and γ-radiation on properties of the newly developed anticancer drug delivery systems (DDSs) based on biodegradable polymeric matrices: poly(ɛ-caprolactone) (PCL), poly(l-lactide) (PLA), poly(l-lactide-co-ɛ-caprolactone) (PLACL) and poly(ɛ-caprolactone-co-glycolide) (PCLGA), in relation to potential sterilization process. The physicochemical properties of the pharmaceutical formulations of paclitaxel (PTX)-loaded nanoparticles, as well as the basic polymeric matrices, were studied after irradiation with γ-rays and e-beam at sterilization dose 25 kGy. The structure of the polymers was found to be practically intact after the irradiation. Importantly, no PTX-related degradation products were detected after the irradiation. The results demonstrate, that the polyester based DDSs can realize sustained and controlled release of PTX. The kinetics of drug release were defined as first order with non-Fickian diffusion for all systems. The obtained results demonstrated a great potential of e-beam for the sterilization purposes of polymeric nanoparticles. In comparison, some effect on PTX release from the γ-irradiated copolymeric nanoparticles was observed due to faster polymer degradation.

The Influence of Ionizing Radiation on Paclitaxel-Loaded Nanoparticles Based on PLGA

The effect of ionizing radiation (γ-rays and electron beam) on anticancer drug delivery systems (DDSs) properties was evaluated concerning potential sterilization. For this purpose, paclitaxel (PTX)-loaded nanoparticles were obtained using a biodegradable, self-developed copolymer of l-lactide and glycolide (PLGA), synthesized in the presence of bismuth 2-ethylhexanoate catalyst. The nanoparticles were obtained with a high encapsulation efficiency of PTX (EE = 94.2%). The average size of the nanoparticles was 253.5 nm. The influence of irradiation (sterilization dose, 25 kGy) on the microstructure and the physicochemical and thermal properties of the polymer matrix was investigated, as well as the effect of irradiation on the morphology and physicochemical properties of the pharmaceutical formulations of the nanoparticles. Additionally, an in vitro drug release study was conducted regarding any alterations in the kinetic profiles of drug release. It was confirmed that the irradiation with both types of ionizing radiation, i.e., γ-rays and electron-beam (EB), slightly decreased the average molecular weight of the polymer matrix. While only negligible changes in the microstructure and thermal properties of PLGA were observed after irradiation with EB, the average length of lactidyl blocks (lLL) in the copolymer chains irradiated with γ-rays decreased from 4.33 to 3.35. Moreover, the contribution of crystalline phase (Xc) in γ-irradiated samples decreased significantly from 35.1% to 22.7%, suggesting a dominant mechanism of chain scission over cross-linking in PLGA samples irradiated with γ-rays. In vitro drug release results demonstrate a sustained and controlled release of PTX from the nanoparticles based on PLGA. The kinetics of drug release was defined as first order with non-Fickian diffusion. Only negligible differences in the kinetic profiles of PTX release from PLGA drug carriers were observed after irradiation. The overall results suggest good resistance of PLGA nanoparticles to irradiation within the conditions used and the great potential of EB in the sterilization process of the polymeric DDSs.

Pheophorbide A and Paclitaxel Bioresponsive Nanoparticles as Double-Punch Platform for Cancer Therapy.

Cancer therapy is still a challenging issue. To address this, the combination of anticancer drugs with other therapeutic modalities, such as light-triggered therapies, has emerged as a promising approach, primarily when both active ingredients are provided within a single nanosystem. Herein, we describe the unprecedented preparation of tumor microenvironment (TME) responsive nanoparticles exclusively composed of a paclitaxel (PTX) prodrug and the photosensitizer pheophorbide A (PheoA), e.g., PheoA≅PTX2S. This system aimed to achieve both the TME-triggered and controlled release of PTX and the synergistic/additive effect by PheoA-mediated photodynamic therapy. PheoA≅PTX2S were produced in a simple one-pot process, exhibiting excellent reproducibility, stability, and the ability to load up to 100% PTX and 40% of PheoA. Exposure of PheoA≅PTX2S nanoparticles to TME-mimicked environment provided fast disassembly compared to normal conditions, leading to PTX and PheoA release and consequently elevated cytotoxicity. Our data indicate that PheoA incorporation into nanoparticles prevents its aggregation, thus providing a greater extent of ROS and singlet oxygen production. Importantly, in SK-OV-3 cells, PheoA≅PTX2S allowed a 30-fold PTX dose reduction and a 3-fold dose reduction of PheoA. Our data confirm that prodrug-based nanocarriers represent valuable and sustainable drug delivery systems, possibly reducing toxicity and expediting preclinical and clinical translation.

Stimulus-responsive tea polyphenols as nanocarrier for selective intracellular drug delivery.

Nanodrug delivery systems have been widely researched to achieve efficient antitumor drug delivery. However, the controlled drug delivery at tumor cells remains the main challenge for antitumor therapy. Herein, a pH and reduction-responsive nanocarrier based on green tea polyphenols was employed as a smart excipient for chemotherapy drug delivery. Paclitaxel, as a chemotherapy drug, was loaded in the nanocarrier, noted as green tea polyphenol/paclitaxel. The green tea polyphenol/paclitaxel kept constant diameter at physiological condition (i.e. pH 7.4), while gradually enlarged at acid environment (pH = 5.5) and the reductive environment. The in vitro paclitaxel release results indicated that the release of paclitaxel from the green tea polyphenol/paclitaxel at pH 7.4 was slow, whereas obviously accelerated at the acid environment (pH = 5.5) and the reductive environment. The in vitro antitumor assay showed more efficient tumor cells inhibition of green tea polyphenol/paclitaxel than free paclitaxel. Meanwhile, due to the proper size (∼100 nm), green tea polyphenol/paclitaxel could effectively accumulate at tumor sites. In the in vivo mice bearing A549 xenograft mouse models, green tea polyphenol/paclitaxel exhibited satisfactory antitumor effect and depressed system toxicity when compared with free paclitaxel, owing to the enhanced paclitaxel accumulation and controlled paclitaxel release in the tumor cells. With simple compositions and satisfactory antitumor effects, this green tea polyphenol-based nanocarrier can be a promising nanodrug delivery system for the therapy of cancers.

Stem cell membrane vesicle–coated nanoparticles for efficient tumor‐targeted therapy of orthotopic breast cancer

Nanoparticles‐based drug delivery strategies have been widely researched for cancer therapy. However, most of them are expected to accumulate in tumor sites via the enhanced permeability and retention (EPR) effect, which is insufficient to deliver the loaded drug into tumors. Cell membrane–camouflaged nanoparticles have obtained much attention for their excellent stability and long blood circulation and reduced the macrophage cells uptake in drug delivery. Herein, bone marrow–derived mesenchymal stem cell membrane vesicle (SCV)–coated paclitaxel (PTX)–loaded poly (lactide‐co‐glycolide) (PLGA) nanoparticles (SCV/PLGA/PTX) were fabricated as the efficient orthotopic breast cancer–targeted drug delivery system. The SCV/PLGA/PTX showed excellent stability, more controlled PTX release, and more effective antitumor effect in vitro. After administration in vivo, SCV/PLGA/PTX exhibited the long‐term retention and enhanced accumulation at tumor sites due to the immune escape and mesenchymal stem cell–mimicking cancer‐targeting capacity. As expected, the SCV/PLGA/PTX could significantly suppress the primary tumor growth by increased apoptosis and necrosis areas within tumor tissues and attenuated the toxic side effects of PTX in 4T1 orthotopic breast cancer model. The study indicated the mesenchymal stem cell membrane coating strategy was highly efficient for targeted drug delivery, which provided a new insight for precise and effective breast cancer treatment.

Paclitaxel‐Loaded PLA/PEG/Magnetite Anticancer and Hyperthermic Agent Prepared From Materials Obtained by the Ugi's Multicomponent Reaction

In this study, Magnetic microspheres formed by Magnetite, Paclitaxel (PCT), poly(lactic acid) (PLA), and poly(ethylene glycol) (PEG) diblock copolymers material, synthesized by the Ugi four‐component condensation reaction (UFCC), are prepared by single emulsion and solvent evaporation procedure. Prepared PCT‐loaded magnetic microspheres (PCTMMS) are characterized by magnetic induction hyperthermia (MIH), SEM, and LDS techniques. Microencapsulation process yielded PCT encapsulation efficiency (Ee) between 70 and 80%, determined by HPLC analysis of the resulting supernatant after the microencapsulation process. A kinetic study of drug release in vitro using HPLC showed a sustained and controlled release of PCT. Also, the presence of an external magnetic field speeds up the kinetic release profile of PCT. Anticancer activity of release medium against intestine cancer cell line (Caco2) is determined using the cell viability assay. PCTMMSs are able to inhibit cancer cell growth and colony formation. The main contribution of these results is to propose a new application for UFCC in the preparation of one anticancer and hyperthermic drug delivery systems (DDS) able to improve the cancer treatment and even the welfare of the patients.

Synthesis and characterization of paclitaxel-imprinted microparticles for controlled release of an anticancer drug

In this study, novel molecularly imprinted polymer (MIP) microparticles containing methacryl polyhedral oligomeric silsesquioxane (M-POSS) were synthesized through the RAFT precipitation polymerization (RAFTPP) method using paclitaxel (PTX) as the templates. During the course of this investigation, methacrylic acid (MAA) was used as the functional monomer, while ethylene glycol dimethacrylate (EGDMA) was utilized as a cross-linker. The effects of different molar ratios of M-POSS on the microparticles were characterized. The obtained MIP microparticles were confirmed by FT-IR and TGA-DSC. The results of SEM showed regular spherical-shaped MIP microparticles with diameters around 170–490 nm. The PTX loading quantity was closely correlated with the content of M-POSS, and the MIP microparticles showed a satisfactory affinity to PTX with high drug loading (17.1%) and encapsulation efficiency (85.5%). Moreover, these MIP microparticles were sensitive to pH, and consequently the release rates of PTX at pH 5 were much faster than those at pH 7 due to the acid cleavage of the hydrogen bonds. In addition, the results from release experiments of the MIP microparticles showed a very slow and controlled release of PTX, which heralded promising potential as a carrier for PTX delivery in cancer therapy.

Paclitaxel-loaded PLA/PEG/fluorescein anticancer agent prepared by Ugi reaction

ABSTRACTTwo different fluorescent block copolymers of poly(lactic acid) (PLA) and polyethylene glycol (PEG) containing fluorescein grafted to the polymer chain were synthesized by Ugi four-component condensation (UFCC). The structure of these PEG–PLA copolymers was confirmed by 1H-NMR and fluorescence spectroscopy. Paclitaxel-loaded fluorescent microspheres (PCT-FMS1 and PCT-FMS2) were prepared from them by the single-emulsion solvent evaporation method. A kinetic study of drug release in vitro using high-performance liquid chromatography showed a prolonged and controlled release of paclitaxel. Anticancer activity of release medium against colorectal cancer cell line (Caco-2) was determined using the cell viability assay. Paclitaxel-loaded microspheres were able to inhibit cancer cell growth and colony formation. The main contribution of this work is to propose a new application for UFCC in the preparation of biomasked fluorescent drug delivery systems able to improve cancer treatment.

Inhalable stimuli-sensitive drug delivery system for controlled drug delivery to lungs

Event Abstract Back to Event Inhalable stimuli-sensitive drug delivery system for controlled drug delivery to lungs Elżbieta Pamuła1, Katarzyna Reczyńska1 and Wojciech Chrzanowski2 1 AGH University of Science and Technology, Department of Biomaterials, Faculrty of Materials Science and Ceramics, Poland 2 The University of Sydney, Faculty of Pharmacy, Australia Introduction: Currently the treatment of lung cancer lacks non-invasively targetable and controlled release topical inhalation therapy. Passive targeting using iron-oxide nanoparticles and magnetic field and their ability to induce localised hyperthermia under oscillating magnetic field could potentially enable both goals in one system. This study developed temperature sensitive lipid-based drug carriers containing superparamagnetic iron-oxide nanoparticles (SPIONs) that are: inhalable, targetable and temperature-sensitive. This system exploits combined effects of pharmaceutics and hyperthermia to enhance synergistically efficacy of the cancer therapy. Materials and Methods: Fatty acids (lauric, palmitic and stearic as well as their mixtures) with melting temperature of 40 - 45oC (hyperthermia conditions) were chosen. Paclitaxel (PAX) and SPIONs were dissolved/dispersed in a melted lipid phase at different SPION/lipid ratios and solid lipid particles were produced using oil in water emulsification. The particle size, thermal properties, chemical composition were assessed using Raman spectroscopy, SEM,EDX, AFM, DSC and drug release tests. Results and Discussion: Developed particles were spherical shape, with an average diameter of 2-6 μm. Thermal and chemical analyses confirmed the presence of PAX and SPIONs inside the lipid matrix. Thermal properties of lipid microparticles, thus their ability to release the drug at specific temperature, were tuned by the formation of eutectic composition obtained by mixing different types of fatty acids. The lipid formulations were shown to have slow release profile at body temperature, but fast release at hyperthermic conditions (45°C), suggesting a potentially powerful controlled release therapy of lung cancer. Conclusion: (i) PAX and SPIONs loaded lipid microparticles of desired size and physical-chemical characteristics were fabricated using oil in water emulsification technique; (ii) the lipid system was thermo-sensitive, allowing controlled release of PAX; (iii) the system holds a promise as an effective drug vehicle in targeted and controlled inhalation therapy. This study was supported by Polish National Science Center (No 2014/14/M/ST5/00649). Keywords: Drug delivery, stimuli-response, targeting delivery, Nano/micro particle Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: Poster Topic: Biomaterials for therapeutic delivery Citation: Pamuła E, Reczyńska K and Chrzanowski W (2016). Inhalable stimuli-sensitive drug delivery system for controlled drug delivery to lungs. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02822 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 Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski Google Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski Google Scholar Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski PubMed Elżbieta Pamuła Katarzyna Reczyńska Wojciech Chrzanowski 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.

Synthesis and characterization of paclitaxel-imprinted nanoparticles for recognition and controlled release of an anticancer drug

Imprinted nanoparticles as drug delivery carriers have been considered because owing to their cross-linked network, they act as the drug reservoir for controlled release. In this study, selective MIPs nanoparticles of paclitaxel (PTX) were successfully developed for application in the biological molecular recognition and in the design of new anticancer drug delivery systems. The MIPs nanoparticles prepared by miniemulsion polymerization technique using methacrylic acid (MAA) and methyl methacrylate as non-covalent functional monomer, ethylene glycol dimethacrylate and trimethylolpropane trimethacrylate (TRIM) as cross-linker agent, azobisisobutyronitrile as initiator, and hexadecane as hydrophobic agent. In order to prepare of MIP nanoparticles, the synthesis conditions and effective parameters, such as: cross-linker agent, different molar ratios of template–functional monomer–cross-linker agent, were investigated. In addition, the effect of different molar ratios of template and monomers on polymers binding and morphology were characterized. Structure and thermal properties of MIPs were confirmed by FT-IR spectroscopy and thermogravimetric analysis. Imprinted nanoparticles showed significant drug loading and encapsulation efficiency, 17.8 and 100 %, respectively. The particle size of MIP nanoparticles varies between 187 and 726 nm, according the SEM images and laser light scattering data. The imprinted nanoparticles showed satisfactory affinity (84 %) to PTX with a binding of 12 times higher than non-imprinted nanoparticles in biological samples when MAA and TRIM were used as functional and cross-linker monomer, respectively. Results from release experiments of MIPs showed a very slow and controlled release of PTX which would be helpful for sustained drug delivery.

Paclitaxel loaded carrier based biodegradable polymeric implants: Preparation and in vitro characterization

The objective of this study was to develop paclitaxel (PTX) loaded poly(ε-caprolactone) (PCL) based tiny implants. β-Cyclodextrin (β-CD) and polyethylene glycol (PEG 6000) were used to enhance solubility and release of the drug in the phosphate buffer saline pH 7.4. Implants were evaluated in terms of color, shape, thickness, surface area, weight, drug content. Developed implants were characterized for their surface morphology (SEM analysis), drug physical state by thermal analysis (DSC studies), crystalline nature (XRD studies) and drug excipients compatibility (FT-IR spectroscopy). Macroscopically all the tiny implants were white in color and cylindrical in shape with smooth surfaces. PTX was entrapped within implants in the polymeric amorphous form. In vitro drug release studies showed prolonged and controlled release of PTX with zero order and Korsmeyer–Peppas model being exhibited. Excipients and method of preparation did not affect chemical stability of PTX.

Phase 2: a dose-escalation study of OncoGel (ReGel/paclitaxel), a controlled-release formulation of paclitaxel, as adjunctive local therapy to external-beam radiation in patients with inoperable esophageal cancer

OncoGel, a novel injectable formulation of paclitaxel in a biocompatible biodegradable gel (ReGel), provides controlled release of paclitaxel at the injection site, resulting in high intralesional paclitaxel concentrations and continuous radiosensitization without attendant systemic toxicities. This dose-escalation study evaluated the toxicity, pharmacokinetics, and preliminary antitumor activity of OncoGel injected intralesionally in patients with inoperable esophageal cancer who were candidates for palliative external-beam radiotherapy (RT). Eleven patients with inoperable advanced esophageal cancer received a single administration of OncoGel into the primary tumor using conventional endoscopic techniques. Three cohorts received approximately one-third of the tumor volume with increasing paclitaxel concentrations to achieve 0.48, 1.0, and 2.0 mg paclitaxel/cm tumor volume. Subsequent to injection, RT was initiated (50.4 Gy in 1.8 Gy fractions). Pharmacokinetic sampling was performed. All patients completed the study. No dose-limiting toxicities were reported. Dysphagia improved and tumor size decreased in most patients. Biopsies were negative for carcinoma in 4 of 11 patients. Peak paclitaxel plasma concentrations were low (0.53-2.73 ng/ml) and directly related to the absolute amount of paclitaxel administered. Paclitaxel was detectable in plasma for 24 h in all patients and for 3 weeks in six patients. OncoGel given as an adjunct to RT was well tolerated in patients with inoperable esophageal cancer and provided prolonged paclitaxel release with minimal systemic exposure. OncoGel plus RT seemed to reduce tumor burden as evidenced by dysphagia improvement, tumor size reduction, and negative esophageal biopsies. The addition of OncoGel to combined modality therapy merits continued clinical development.

A dose-escalation, Phase I study of a depot formulation of paclitaxel administered intralesionally in end-stage cancer patients with solid malignant tumors

2131 Background: To determine the systemic plasma levels, safety and maximum tolerated dose (MTD) of a depot formulation of paclitaxel, OncoGel (paclitaxel/ReGel). This is a cremophor-free formulation which is liquid at administration temperature and rapidly forms a gel depot upon injection. The depot slowly degrades over several weeks allowing controlled release of paclitaxel within the tumor. Methods: A Phase I, dose-escalation study was conducted in 16 end-stage cancer patients with 18 superficially accessible solid malignant lesions at 6 investigative sites. Four paclitaxel dosages based on tumor volume were administered with 3 patients receiving 0.06 mg/cm3, 3 patients at 0.24 mg/cm3, 6 patients with 8 tumors at 0.48 mg/cm3, and 4 patients at 1.92 mg/cm3. There were 7 females and 9 males, ages 41 to 89, with treated tumors ranging from 0.7 cm3 to 19.0 cm3. The primary diagnoses included lymphoma, melanoma, lung, head and neck, laryngeal, thyroid, and breast cancer. Results: Blood samples were collected at predose, at 3, 6, 24 and 72 hours post-dose and then at weekly intervals for up to 9 weeks after injection in 13 subjects. Nine patients had no detectable paclitaxel and four patients had minimal, <2 ng/mL, levels in 5 of 153 plasma samples analyzed. Of the 103 reported adverse events (AEs), 12 mild or moderate AEs in eight patients were considered related to the drug. 9 of these AEs were pain or erythema at the injection site with the 3 others being bruising, drainage, and muscle spasm. No drug-related serious adverse events were reported in any patient. Although not a primary endpoint, analysis of tumor response showed size regression or stable disease in approximately 50% of the injected tumors. Conclusions: The Phase I study demonstrated the drug was well tolerated, maintained paclitaxel at the injection site, and suggested efficacy in stabilizing or reducing tumor growth. No MTD was reached. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MacroMed, Inc. MacroMed, Inc.

A dose-escalation, Phase I study of a depot formulation of paclitaxel administered intralesionally in end-stage cancer patients with solid malignant tumors

2131 Background: To determine the systemic plasma levels, safety and maximum tolerated dose (MTD) of a depot formulation of paclitaxel, OncoGel (paclitaxel/ReGel). This is a cremophor-free formulation which is liquid at administration temperature and rapidly forms a gel depot upon injection. The depot slowly degrades over several weeks allowing controlled release of paclitaxel within the tumor. Methods: A Phase I, dose-escalation study was conducted in 16 end-stage cancer patients with 18 superficially accessible solid malignant lesions at 6 investigative sites. Four paclitaxel dosages based on tumor volume were administered with 3 patients receiving 0.06 mg/cm3, 3 patients at 0.24 mg/cm3, 6 patients with 8 tumors at 0.48 mg/cm3, and 4 patients at 1.92 mg/cm3. There were 7 females and 9 males, ages 41 to 89, with treated tumors ranging from 0.7 cm3 to 19.0 cm3. The primary diagnoses included lymphoma, melanoma, lung, head and neck, laryngeal, thyroid, and breast cancer. Results: Blood samples were collected at predose, at 3, 6, 24 and 72 hours post-dose and then at weekly intervals for up to 9 weeks after injection in 13 subjects. Nine patients had no detectable paclitaxel and four patients had minimal, <2 ng/mL, levels in 5 of 153 plasma samples analyzed. Of the 103 reported adverse events (AEs), 12 mild or moderate AEs in eight patients were considered related to the drug. 9 of these AEs were pain or erythema at the injection site with the 3 others being bruising, drainage, and muscle spasm. No drug-related serious adverse events were reported in any patient. Although not a primary endpoint, analysis of tumor response showed size regression or stable disease in approximately 50% of the injected tumors. Conclusions: The Phase I study demonstrated the drug was well tolerated, maintained paclitaxel at the injection site, and suggested efficacy in stabilizing or reducing tumor growth. No MTD was reached. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MacroMed, Inc. MacroMed, Inc.