Paclitaxel-loaded microparticles and implants for the treatment of brain cancer: Preparation and physicochemical characterization

Elkharraz, K.; Faisant, N.; Guse, C.; Siepmann, Florence; Arıca-Yegin, Betül; Oger, Jean-Michel; Gust, Ronald; Goepferich, Achim; Benoit, Jean‐Pierre; Siepmann, Juergen

doi:10.1016/j.ijpharm.2005.07.028

Cited by 73 publications

(62 citation statements)

References 29 publications

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“…The solution was completely removed and replaced at certain time points in an attempt to model the conditions of the cerebral spinal fluid, which has a net turnover of 3.7 times a day [125]. While this is a simplistic model, it is the standard for determining the in vitro release of chemotherapeutics from polymeric microspheres [27,49,51,52].…”

Section: Discussionmentioning

confidence: 99%

“…For hydrophobic chemotherapeutics, the single emulsion or oil in water (O/W) emulsion is commonly used [27][28][29][30]. As shown in Figure 2 For water soluble chemotherapeutics, the double emulsion or water in oil in water (W/O/W) emulsion is utilized [43,46,49,78].…”

Section: Microsphere Formulation and Characterizationmentioning

confidence: 99%

“…[24,27,41,51,52,55,56]. For example, a typical release of 5-FU from PLGA microspheres has a biphasic profile: an initial burst phase in the first day or two followed by a sustained release for 18 days, as shown in Figure 3.1 [36,72].…”

Section: In Vitro Release Of Drugs From Polymeric Microspheresmentioning

confidence: 99%

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Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

Floyd

Galperin

Ratner

2015

J Biomedical Materials Res

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Departments of Bioengineering and Chemical EngineeringThe grim prognosis for patients diagnosed with malignant gliomas necessitates the development of new therapeutic strategies for localized and sustained drug delivery to combat tumor drug resistance and regrowth. Here we introduced the novel formulation of drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy (DREAM BIG Therapy) that is applied post-resection. DREAM BIG Therapy consists of three types of microspheres [poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), and poly(ε-caprolactone) (PCL)] containing various encapsulated chemotherapeutics, suspended in a degradable, aqueous poly(Nisopropylacrylamide) (PNIPAM) solution. The thermoresponsive PNIPAM solution is capable of suspending drug encapsulated microspheres at room temperature which can be "sprayed on" the post-surgical site. The physiological temperature of the treatment site (37°C) would cause PNIPAM solution to solidify and form an adherent gel layer with entrapped microspheres, providing intimate contact with remaining tumor cells. Over time, PLGA (rapid degradation), PLA (medium speed degradation), and then PCL (slow degradation) microspheres would break iv down, releasing their drug payloads in a sequential, multi-drug release directly to the tumor site, addressing cancerous regrowth and tumor drug resistance. This dissertation will address the development of DREAM BIG Therapy, from microsphere formulation to pilot in vivo studies.Initial work focused on developing blank and drug encapsulated microspheres using emulsion techniques. Preliminary studies utilized rhodamine B as a model drug for encapsulation in PLGA, PLA, and PCL particles and optimized formulation parameters to achieve a high encapsulation. Then, gefitinib, IgG, and lomustine were encapsulated in PLGA, PLA, and PCL microspheres, respectively, achieving encapsulation efficiencies greater than 80% and drug loadings greater than 0.3%. The in vitro release of gefitinib and IgG were also studied. Gefitinib released from PLGA microspheres over 40 days while the release of IgG from PLA microspheres was slower, over a year long period.The microsphere-PNIPAM system was tested for aerosolized application ex vivo. The aqueous PNIPAM solution suspended the microspheres and was aerosolized before phase transitioning to an adherent gel layer on the tissue, entrapping the microspheres on the tissue surface. Finally, when tested in vivo, the gefitinib encapsulated PLGA microspheres entrapped in PNIPAM slowed the tumor volume growth of a subcutaneous C6 glioma in comparison to blank PLGA microspheres entrapped in PNIPAM. Overall, this research confirms the potential of DREAM BIG therapy for future use with multiple chemotherapeutics and microsphere types to combat gliomas at a localized site.v

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Section: Discussionmentioning

confidence: 99%

Section: Microsphere Formulation and Characterizationmentioning

confidence: 99%

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Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

Floyd

Galperin

Ratner

2015

J Biomedical Materials Res

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“…6,7 In order to enhance its aqueous solubility and/or achieve controlled/targeted release, a great many polymeric formulations of paclitaxel have been developed, including coatings, [8][9][10] liposomes, [11][12][13] micelles, [14][15][16] and micrometer-and nano-size particles. [17][18][19] In these polymeric formulations, most studies have found that the paclitaxel was amorphous at low concentrations in the polymers. Lee et al 16 investigated the solubilization of paclitaxel into hydrotropic polymeric micelles using diblock copolymers of poly(ethylene glycol) and poly(2-(4-vinylbenzyloxy)-N,N-diethylnicotinamide).…”

Section: Introductionmentioning

confidence: 99%

Blends of Paclitaxel with POSS-Based Biodegradable Polyurethanes: Morphology, Miscibility, and Specific Interactions

Guo

Knight

Wu³

et al. 2010

Macromolecules

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The morphology, miscibility, and specific interactions of paclitaxel (PTx) with a family of polyhedral oligosilsesquioxane (POSS)-based biodegradable thermoplastic polyurethanes (POSS TPUs) were investigated systematically using wide-angle X-ray diffraction (WAXD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). These POSS TPUs incorporate an alternating multiblock structure formed by POSS hard segments and the soft segments composed of polylactide/caprolactone copolymer (P(DLLA-co-CL)). They feature variable poly(ethylene glycol) (PEG) content from 0 to 14 wt % through adjusting the poly(ethylene glycol) (PEG) molecular weight in P(DLLA-co-CL) soft segments of fixed molar mass of M _ n = 12 kg/mol and further to 52 wt % utilizing pure PEG M _ n = 1 kg/mol in the soft segments. Using WAXD, it was found that PTx is amorphous in all proportions in the PTx/POSS TPU blends prepared using a solutioncasting method. Interestingly, the PTx not only exhibits excellent miscibility in all of these PTx/POSS TPU blends over the whole range of the drug concentration, but also serves as an antiplasticizer by increasing the blend T g gradually from the polymer T g up to the T g of amorphous PTx. The T g -composition dependences in these blends were well fitted by the Gordon-Taylor equation. The glass transition breadth of the blends increases significantly only for drug concentrations higher than 50 wt % for most of the POSS TPUs, suggesting some spatial heterogeneity at these high drug concentrations. On the other hand, the slight increment of the blend melting temperature, T m , and latent heat, ΔH, indicates enhanced phase separation between the POSS hard segments and the TPU soft segments upon drug incorporation. Gordon-Taylor analysis and FTIR results confirm that the PEG incorporated in the POSS TPUs exhibits strong H-bonding interactions with the PTx. Although PEG can promote the favorable interactions in the PTx/POSS TPU blends, we showed that the more hydrophobic LA/CL repeat units are still required in the soft segments in order to achieve molecular-level miscibility. This systematic investigation of the PTx/POSS TPU systems may be of great value to design plasticizer/antiplasticizer for new polymer materials with controlled and tailored properties, especially for those PLA-or PCL-based biodegradable polymer systems.

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“…associated with oral administration [18]. However, hydrophobic drugs, proteins, and peptides often exhibit a multi-phasic release profile from PLGA-based matrices [20][21][22][23]. To achieve a steady release, various formulation strategies have been employed [20,[24][25][26][27][28][29][30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Effect of formulation parameters on 2-methoxyestradiol release from injectable cylindrical poly(dl-lactide-co-glycolide) implants

Desai

Mallery

Schwendeman

2008

European Journal of Pharmaceutics and Biopharmaceutics

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The objective of this study was to investigate the potential of various formulation strategies to achieve 1-month continuous (improved) release of the novel anti-cancer drug, 2-methoxyestradiol (2-ME), from injectable cylindrical poly(DL-lactide-co-glycolide) (PLGA) implants. PLGA implants were prepared by a solvent extrusion method. PLGA 50:50 (M w = 51 kDa, end group = lauryl ester) (PLGA-lauryl ester) implants loaded with 3-30 wt% 2-ME exhibited a pronounced lag phase (i.e., corresponding to induction time to polymer mass loss) and triphasic release profile. Incorporation of 5 wt% hydroxypropyl-β-cyclodextrin (HP-β-CD) (~57% release after 28 days) or Pluronic ® F127 (~42% release after 28 days) in PLGA-lauryl ester implants reduced the lag-phase and improved the drug release moderately over a period of 28 days. The formation and the incorporation of a 2-ME/ polyethylene glycol (PEG) 8000 solid dispersion in PLGA-lauryl ester implants further increased drug release (~21% and 73% release after 1 and 28 days, respectively), attributable to improved drug solubility/dissolution, higher matrix porosity, and accelerated polymer degradation. Blending of PLGA 50:50 (M w = 24 kDa, end group = COOH) (PLGA-COOH) with the PLGA-lauryl ester also provided moderate enhancement of 2-ME release over a period of 28 days. PLGA-COOH (M w = 24 kDa) implants with 3-5% w/w pore-forming MgCO 3 exhibited the most desirable drug release among all the formulations tested, and, demonstrated 1-month slow and continuous in vitro release of ~80% 2-ME after a minimal initial burst. Hence, these formulation approaches provide several possible avenues to improve release rates of the hydrophobic drug, 2-ME, from PLGA for future application in regional anti-cancer therapy.

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Paclitaxel-loaded microparticles and implants for the treatment of brain cancer: Preparation and physicochemical characterization

Cited by 73 publications

References 29 publications

Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy

Blends of Paclitaxel with POSS-Based Biodegradable Polyurethanes: Morphology, Miscibility, and Specific Interactions

Effect of formulation parameters on 2-methoxyestradiol release from injectable cylindrical poly(dl-lactide-co-glycolide) implants

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