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Dive into the research topics where Marina Talelli is active.

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Featured researches published by Marina Talelli.


Biomaterials | 2010

Core-crosslinked polymeric micelles with controlled release of covalently entrapped doxorubicin

Marina Talelli; Maryam Iman; Amir K. Varkouhi; Cristianne J.F. Rijcken; Raymond M. Schiffelers; Tomáš Etrych; Karel Ulbrich; Cornelus F. van Nostrum; Twan Lammers; Gert Storm; Wim E. Hennink

Doxorubicin (DOX) is clinically applied in cancer therapy, but its use is associated with dose limiting severe side effects. Core-crosslinked biodegradable polymeric micelles composed of poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAm-Lac(n))) diblock copolymers have shown prolonged circulation in the blood stream upon intravenous administration and enhanced tumor accumulation through the enhanced permeation and retention (EPR) effect. However a (physically) entrapped anticancer drug (paclitaxel) was previously shown to be rapidly eliminated from the circulation, likely because the drug was insufficiently retained in the micelles. To fully exploit the EPR effect for drug targeting, a DOX methacrylamide derivative (DOX-MA) was covalently incorporated into the micellar core by free radical polymerization. The structure of the doxorubicin derivative is susceptible to pH-sensitive hydrolysis, enabling controlled release of the drug in acidic conditions (in either the intratumoral environment and/or the endosomal vesicles). 30-40% w/w of the added drug was covalently entrapped, and the micelles with covalently entrapped DOX had an average diameter of 80 nm. The entire drug payload was released within 24 h incubation at pH 5 and 37 degrees C, whereas only around 5% release was observed at pH 7.4. DOX micelles showed higher cytotoxicity in B16F10 and OVCAR-3 cells compared to DOX-MA, likely due to cellular uptake of the micelles via endocytosis and intracellular drug release in the acidic organelles. The micelles showed better anti-tumor activity than free DOX in mice bearing B16F10 melanoma carcinoma. The results presented in this paper show that mPEG-b-p(HPMAm-Lac(n)) polymeric micelles with covalently entrapped doxorubicin is a system highly promising for the targeted delivery of cytostatic agents.


Advanced Drug Delivery Reviews | 2010

Micelles based on HPMA copolymers

Marina Talelli; Cristianne J.F. Rijcken; C.F. van Nostrum; Gert Storm; Wim E. Hennink

Polymeric micelles have been under extensive investigation during the past years as drug delivery systems, particularly for anticancer drugs. They are formed by the self-assembly of amphiphilic block copolymers in aqueous solutions and have a spherical shape and a size in the nano-range (<200nm). Tumor accumulation of polymeric micelles upon intravenous administration can occur as a result of the leaky vasculature of tumor tissue (called the enhanced permeation and retention (EPR) effect).To benefit from the EPR effect, polymeric micelles need to have prolonged circulation times as well as high and stable drug loadings. Poly[N-(2-hydroxypropyl) methacrylamide] (pHPMA) is a hydrophilic polymer currently under investigation for its use in polymer-drug conjugates. Its biocompatibility, non-immunogenicity and the possibility for functionalization are properties that resulted in broad pharmaceutical and biomedical applications, also in the micelle technology research. Being hydrophilic, it can serve as a micellar stealth corona, while it can also be modified with hydrophobic moieties to serve as a micellar core in which hydrophobic drugs can be solubilized and retained. HPMA-based polymeric micelles have been showing very promising in vitro and in vivo results. This review summarizes the applications of pHPMA in the field of polymeric micelles, either serving as a micellar stealth corona, or, if hydrophobically rendered by derivatization, as a micellar core.


Journal of Controlled Release | 2011

Nanobody — Shell functionalized thermosensitive core-crosslinked polymeric micelles for active drug targeting

Marina Talelli; Cristianne J.F. Rijcken; Sabrina Oliveira; Roy van der Meel; Paul M.P. van Bergen en Henegouwen; Twan Lammers; Cornelus F. van Nostrum; Gert Storm; Wim E. Hennink

The aim of this study was to develop poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAm-Lac(n))) core-crosslinked thermosensitive biodegradable polymeric micelles suitable for active tumor targeting, by coupling the anti-EGFR (epidermal growth factor receptor) EGa1 nanobody to their surface. To this end, PEG was functionalized with N-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP) to yield a PDP-PEG-b-p(HPMAm-Lac(n)) block copolymer. Micelles composed of 80% mPEG-b-p(HPMAm-Lac(n)) and 20% PDP-PEG-b-p(HPMAm-Lac(n)) were prepared and lysozyme (as a model protein) was modified with N-succinimidyl-S-acetylthioacetate, deprotected with hydroxylamine hydrochloride and subsequently coupled to the micellar surface. The micellar conjugates were characterized using SDS-PAGE and gel permeation chromatography (GPC). Using the knowledge obtained with lysozyme conjugation, the EGa1 nanobody was coupled to mPEG/PDP-PEG micelles and the conjugation was successful as demonstrated by western blot and dot blot analysis. Rhodamine labeled EGa1-micelles showed substantially higher binding as well as uptake by EGFR over-expressing cancer cells (A431 and UM-SCC-14C) than untargeted rhodamine labeled micelles. Interestingly, no binding of the nanobody micelles was observed to EGFR negative cells (3T3) as well as to14C cells in the presence of an excess of free nanobody. This demonstrates that the binding of the nanobody micelles is indeed by interaction with the EGF receptor. In conclusion, EGa1 decorated (mPEG/PDP-PEG)-b-(pHPMAm-Lac(n)) polymeric micelles are highly promising systems for active drug targeting.


Nanomedicine: Nanotechnology, Biology and Medicine | 2011

Thermosensitive polymeric micelles for targeted drug delivery

Marina Talelli; Wim E. Hennink

Thermosensitive polymers are characterized by temperature-dependent aqueous solution properties. Below their lower critical solution temperature they are in an expanded state and fully dissolved, while above it they are dehydrated and insoluble. This has been exploited for the development of polymeric micelles that can be formed or destabilized depending on the solution temperature. Many micelle forming thermosensitive polymers have been described in literature, among which poly(N-isopropylacrylamide) (pNIPAAm), Pluronics (triblock copolymers of polypropylene oxide middle block flanked by two polyethylene oxide blocks) and poly(hydroxypropyl methacrylamide-lactate) (p(HPMAm-Lac(n))) are the most frequently studied and some drug-loaded formulations based on thermosensitive polymers have reached clinical trials. The first generation of micelles composed of thermosensitive polymers was based on mere hydrophobic interactions between polymer blocks, while more recently shell or core crosslinking was introduced, in order to improve their stability in the circulation after intravenous administration and therefore, the accumulation of their depot in diseased areas. Various formulations of drug-loaded micelles based on thermosensitive polymers have shown promising results in vitro, as well as in vivo. This review gives an overview of the most important recent developments regarding the design and synthesis of various types of thermosensitve polymers for drug delivery.


Biomaterials | 2013

Intrinsically active nanobody-modified polymeric micelles for tumor-targeted combination therapy

Marina Talelli; Sabrina Oliveira; Cristianne J.F. Rijcken; Ebel H.E. Pieters; Tomáš Etrych; Karel Ulbrich; C.F. van Nostrum; Gerrit Storm; Wim E. Hennink; Twan Lammers

Various different passively and actively targeted nanomedicines have been designed and evaluated over the years, in particular for the treatment of cancer. Reasoning that the potential of ligand-modified nanomedicines can be substantially improved if intrinsically active targeting moieties are used, we have here set out to assess the in vivo efficacy of nanobody-modified core-crosslinked polymeric micelles containing covalently entrapped doxorubicin. Nanobody-modified polymeric micelles were found to inhibit tumor growth even in the absence of a drug, and nanobody-modified micelles containing doxorubicin were significantly more effective than nanobody-free micelles containing doxorubicin. Based on these findings, we propose that the combination of two therapeutic strategies within one nanomedicine formulation, i.e. the intrinsic pharmacological activity of ligand-modified carrier materials with the cytostatic activity of the incorporated chemotherapeutic agents, is a highly promising approach for improving the efficacy of tumor-targeted combination therapy.


Journal of Controlled Release | 2009

The influence of bile acids on the oral bioavailability of vitamin K encapsulated in polymeric micelles.

P.M. van Hasselt; G.E.P.J. Janssens; T.K. Slot; M. van der Ham; T.C. Minderhoud; Marina Talelli; L.M. Akkermans; Cristianne J.F. Rijcken; C.F. van Nostrum

The purpose of this study was to assess the ability of polymeric micelles to enable gastrointestinal absorption of the extremely hydrophobic compound vitamin K, by comparison of its absorption in bile duct ligated and sham operated rats. Hereto, vitamin K was encapsulated in micelles composed of mPEG(5000)-b-p(HPMAm-lac(2)), a thermosensitive block copolymer. Vitamin K plasma levels rose significantly upon gastric administration of 1 mg vitamin K encapsulated in polymeric micelles in sham operated rats, but not after bile duct ligation (AUC 4543 and 1.64 ng/mL/h respectively, p<0.01). Duodenal administration of polymeric micelles together with bile acids in bile duct ligated rats fully restored absorption. Dynamic light scattering time series showed a significant and dose dependent rise in micellar size in the presence of bile acids in vitro, indicating the gradual formation of mixed micelles during the first 3 h of incubation. The highest bile acid amounts (11 mM deoxycholic acid and 41 mM taurocholic acid) eventually caused aggregation of the loaded micelles after the formation of mixed micelles. These data suggest that the gastrointestinal absorption of encapsulated vitamin K from polymeric micelles is mediated by free bile and that uptake of intact micelles through pinocytosis is insignificant.


Bioconjugate Chemistry | 2011

Synthesis and Characterization of Biodegradable and Thermosensitive Polymeric Micelles with Covalently Bound Doxorubicin-Glucuronide Prodrug via Click Chemistry

Marina Talelli; K. Morita; Cristianne J.F. Rijcken; R. W. M. Aben; Twan Lammers; Hans W. Scheeren; C.F. van Nostrum; Gert Storm; Wim E. Hennink

Doxorubicin is an anthracycline anticancer agent that is commonly used in the treatment of a variety of cancers, but its application is associated with severe side effects. Biodegradable and thermosensitive polymeric micelles based on poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAmLac(n))) have been studied as drug delivery systems for therapeutic and imaging agents and have shown promising in vitro and in vivo results. The purpose of this study was to investigate the covalent coupling of a doxorubicin-glucuronide prodrug (DOX-propGA3) to the core of mPEG-b-p(HPMAmLac(2)) micelles. This prodrug is specifically activated by human β-glucuronidase, an enzyme that is overexpressed in necrotic tumor areas. To this end, an azide modified block copolymer (mPEG(5000)-b-p(HPMAmLac(2)-r-AzEMA)) was synthesized and characterized, and DOX-propGA3 was coupled to the polymer via click chemistry with a high (95%) coupling efficiency. Micelles formed by this DOX containing polymer were small (50 nm) and monodisperse and released 40% of the drug payload after 5 days incubation at 37 °C in the presence of β-glucuronidase, but less than 5% in the absence of the enzyme. In vitro cytotoxicity experiments demonstrated that DOX micelles incubated with 14C cells showed the same cytotoxicity as free DOX only in the presence of β-glucuronidase, indicating full conversion of the polymer-bound DOX into the parent drug. Overall, this novel system is very promising for enzymatically responsive anticancer therapy.


Langmuir | 2015

Magnetic-Responsive Release Controlled by Hot Spot Effect

Eduardo Guisasola; Alejandro Baeza; Marina Talelli; Daniel Arcos; María Moros; Jesús M. de la Fuente; María Vallet-Regí

Magnetically triggered drug delivery nanodevices have attracted great attention in nanomedicine, as they can feature as smart carriers releasing their payload at clinicians will. The key principle of these devices is based on the properties of magnetic cores to generate thermal energy in the presence of an alternating magnetic field. Then, the temperature increase triggers the drug release. Despite this potential, the rapid heat dissipation in living tissues is a serious hindrance for their clinical application. It is hypothesized that magnetic cores could act as hot spots, this is, produce enough heat to trigger the release without the necessity to increase the global temperature. Herein, a nanocarrier has been designed to respond when the temperature reaches 43 °C. This material has been able to release its payload under an alternating magnetic field without the need of increasing the global temperature of the environment, proving the efficacy of the hot spot mechanism in magnetic-responsive drug delivery devices.


Colloids and Surfaces B: Biointerfaces | 2012

Cytostatic effect of xanthone-loaded mPEG-b-p(HPMAm-Lac2) micelles towards doxorubicin sensitive and resistant cancer cells.

Ruttiros Khonkarn; Samlee Mankhetkorn; Marina Talelli; Wim E. Hennink; Siriporn Okonogi

Xanthone exhibits several medicinal activities and especially it inhibits the growth of cancer cells. However, the use of xanthone is limited because of its low aqueous solubility and systemic toxicity. In the present study xanthone was loaded into poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-dilactate] mPEG-b-p(HPMAm-Lac(2)) micelles in order to overcome these drawbacks. It was shown that xanthone could be loaded in these micelles up to 2 mg/mL with ~100% entrapment efficiency and ~20% loading capacity. The average particle diameter of the xanthone loaded mPEG-b-p(HPMAm-Lac(2)) micelles as determined by dynamic light scattering ranged from 84 to 112 nm. In vitro assays showed that xanthone in its free form as well as loaded in polymeric micelles had a high cytotoxicity towards both doxorubicin sensitive and, importantly, resistant cancer cells. On the other hand empty mPEG-b-p(HPMAm-Lac(2)) micelles did not show any cytotoxicity towards normal cells (PBMCs). Interestingly, the cytostatic effect of xanthone towards normal cells was masked when loaded in the micelles. The mechanism of cell growth inhibition by xanthone-loaded polymeric micelles was mediated through induction of apoptosis, as evidenced from a subdiploid peak of propidium iodide stained cells using flow cytometric analysis. From the results of this study it can be concluded that xanthone has potent anticancer activity not only on sensitive but also on doxorubicin resistant cancer cell lines. mPEG-b-p(HPMAm-Lac(2)) micelles are therefore attractive delivery systems of xanthone for the treatment of cancer.


Journal of Controlled Release | 2010

Targeted core-crosslinked polymeric micelles with controlled release of covalently entrapped doxorubicin

Marina Talelli; Maryam Iman; Cristianne J.F. Rijcken; C.F. van Nostrum; W.E. Hennink

Doxorubicin (DOX) is clinically applied in cancer therapy, but its use is associated with dose limiting severe side effects. Core-crosslinked biodegradable polymeric micelles composed of poly(ethylene glycol)-b-poly(N-(2-hydroxypropyl) methacrylamide-lactate) (mPEG-b-p(HPMAm-Lacn)) diblock copolymers have shown prolonged circulation in the blood stream upon intravenous administration and enhanced tumor accumulation through the enhanced permeation and retention (EPR) effect. However a (physically) entrapped anticancer drug (paclitaxel) was previously shown to be rapidly eliminated from the circulation, likely because the drug was insufficiently retained in the micelles. To fully exploit the EPR effect for drug targeting, a DOX methacrylamide derivative (DOX-MA) was covalently incorporated into the micellar core by free radical polymerization. The structure of the doxorubicin derivative is susceptible to pH-sensitive hydrolysis, enabling controlled release of the drug in acidic conditions (in either the intratumoral environment and/or the endosomal vesicles). 30e40% w/w of the added drug was cova- lently entrapped, and the micelles with covalently entrapped DOX had an average diameter of 80 nm. The entire drug payload was released within 24 h incubation at pH 5 and 37 � C, whereas only around 5% release was observed at pH 7.4. DOX micelles showed higher cytotoxicity in B16F10 and OVCAR-3 cells compared to DOX-MA, likely due to cellular uptake of the micelles via endocytosis and intracellular drug release in the acidic organelles. The micelles showed better anti-tumor activity than free DOX in mice bearing B16F10 melanoma carcinoma. The results presented in this paper show that mPEG-b-p(HPMAm- Lacn) polymeric micelles with covalently entrapped doxorubicin is a system highly promising for the targeted delivery of cytostatic agents.

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Hans W. Scheeren

Radboud University Nijmegen

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