Nicolas Bertrand - Academia.edu (original) (raw)

Papers by Nicolas Bertrand

Proceedings of the National Academy of Sciences of the United States of America, Jan 15, 2014

Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic c... more Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(D,L-lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA-b-PEG and alendronate-conjugated polymer PLGA-b-PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo bi...

Advanced Drug Delivery Reviews, 2014

Cancer nanotherapeutics are progressing at a steady rate; research and development in the field h... more Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000's. The path to the commercialization of oncology drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnology can meaningfully contribute to create differentiated products and improve clinical outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL® and Abraxane®. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncology, where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential "retention" in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor associated macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers.

Nature Communications, 2015

Nanotechnology may offer fast and effective solutions for environmental clean-up. Herein, amphiph... more Nanotechnology may offer fast and effective solutions for environmental clean-up. Herein, amphiphilic diblock copolymers are used to develop a platform of photosensitive core-shell nanoparticles. Irradiation with ultraviolet light removes the protective layer responsible for colloidal stability; as a result, the nanoparticles are rapidly and irreversibly converted to macroscopic aggregates. The associated phase separation allows measuring the partitioning of small molecules between the aqueous phase and nanoparticles; data suggests that interactions are enhanced by decreasing the particle size. Adsorption onto nanoparticles can be exploited to efficiently remove hydrophobic pollutants from water and contaminated soil. Preliminary in vivo experiments suggest that treatment with photocleavable nanoparticles can significantly reduce the teratogenicity of bisphenol A, triclosan and 17α-ethinyl estradiol without generating obviously toxic byproducts. Small-scale pilot experiments on wastewater, thermal printing paper and contaminated soil demonstrate the applicability of the approach.

Angewandte Chemie (International ed. in English), Jan 26, 2015

Selective tumor targeting and drug delivery are critical for cancer treatment. Stimulus-sensitive... more Selective tumor targeting and drug delivery are critical for cancer treatment. Stimulus-sensitive nanoparticle (NP) systems have been designed to specifically respond to significant abnormalities in the tumor microenvironment, which could dramatically improve therapeutic performance in terms of enhanced efficiency, targetability, and reduced side-effects. We report the development of a novel L-cysteine-based poly (disulfide amide) (Cys-PDSA) family for fabricating redox-triggered NPs, with high hydrophobic drug loading capacity (up to 25 wt % docetaxel) and tunable properties. The polymers are synthesized through one-step rapid polycondensation of two nontoxic building blocks: L-cystine ester and versatile fatty diacids, which make the polymer redox responsive and give it a tunable polymer structure, respectively. Alterations to the diacid structure could rationally tune the physicochemical properties of the polymers and the corresponding NPs, leading to the control of NP size, hydr...

Methods in Molecular Biology, 2009

pH-sensitive liposomes have been designed to deliver active compounds specifically to acidic intr... more pH-sensitive liposomes have been designed to deliver active compounds specifically to acidic intracellular organelles and to augment their cytoplasmic concentrations. These systems combine the protective effects of other liposomal formulations with specific environment-controlled drug release. They are stable at physiological pH, but abruptly discharge their contents when endocytosed into acidic compartments, allowing the drug to be released before it is exposed to the harsh environment of lysosomes.

ACS Symposium Series, 2006

In the last decades, the rapid advances in the understanding of the role of proteins and peptides... more In the last decades, the rapid advances in the understanding of the role of proteins and peptides in several diseases have propelled them as therapeutic entities. Protein delivery is a challenge and one of the new approaches to their administration is to implant cells producing the ...

Monographs in Supramolecular Chemistry, 2013

Trends in Molecular Medicine, 2015

The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of various ... more The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of various diseases, including cancer. The unique properties of nanoparticles (NPs), such as large surface-to-volume ratio, small size, the ability to encapsulate various drugs, and tunable surface chemistry, give them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make NPs a mode of treatment potentially superior to conventional cancer therapies. This review highlights the most recent developments in cancer treatment using NPs as drug delivery vehicles, including promising opportunities in targeted and combination therapy.

Mathematical modeling of drug release from biodegradable microspheres is designed to improve unde... more Mathematical modeling of drug release from biodegradable microspheres is designed to improve understanding of phenomena involved in this complex process. In spite of the considerable information obtained from conventional models, their use of equation curve fitting often limits the possibility to generalize their results. The objective of the presented study is to develop a model involving a three-dimensional cellular automaton to simulate both polymer erosion and drug diffusion independently. The model involves millions of independent cells in different states representing the components present in microspheres. The different states allow representation of polymer, drug, pores and solvent. For erosion, each cell is defined with a life expectancy and its chance of being eroded evolves according to the number of direct neighbours containing solvent. For diffusion, drug-containing cells are allowed to randomly diffuse their content in their neighbouring solvent-containing cells. Good correlations are obtained between simulations and two sets of experimental data obtained from release study at different pH. The model offers some insights about important drug release phases, like burst and subsequent release. Graphical representations obtained from the cellular automaton are also compared to SEM images. Cellular automaton proves to be an interesting tool for drug release modeling offering insights on the phenomena involved.

Journal of Controlled Release, 2011

Macromolecular binders consist of polymers, dendrimers, and oligomers with binding properties for... more Macromolecular binders consist of polymers, dendrimers, and oligomers with binding properties for endogenous or exogenous substrates. This field, at the frontier of host/guest chemistry and pharmacology, has met a renewed interest in the past decade due to the clinical success of several sequestrants, like sevelamer hydrochloride (Renagel®) or sugammadex (Bridion®). In many instances, multivalent binding by the macromolecular drugs can modify the properties of the substrate, and may prevent it from reaching its site of action and/or trigger a biological response. From small (e.g., ions) to larger substrates (e.g., bacteria and cells), this review presents the state-of-the-art of macromolecular binders and provides detailed illustrative examples of recent developments bearing much promise for future pharmaceutical applications.

Journal of Controlled Release, 2012

Recent advances in chemistry and material sciences have witnessed the emergence of an increasing ... more Recent advances in chemistry and material sciences have witnessed the emergence of an increasing number of novel and complex nanosized carriers for the delivery of drugs and imaging agents. Nevertheless, this raise in complexity does not necessarily offer more efficient systems. The lack of performance experienced by several colloidal drug carriers during the preclinical and clinical development processes can be explained by inadequate pharmacokinetic/biodistribution profiles and/or unacceptable toxicities. A comprehensive understanding of the body characteristics is necessary to predict and prevent these problems from the early stages of nanomaterial conception. In this manuscript, we review and discuss the anatomical and physiological elements which must be taken into account when designing new carriers for delivery or imaging purposes. This article gives a general overview of the main organs involved in the elimination of nanosized materials and briefly summarizes the knowledge acquired over more than 30 years of research and development in the field of drug targeting.

Biomaterials, 2009

The purpose of this work was to characterize the pharmacokinetics (PK) and biodistribution of pHr... more The purpose of this work was to characterize the pharmacokinetics (PK) and biodistribution of pHresponsive N-isopropylacrylamide (NIPAAm) copolymers, and to determine the impact of some physicochemical parameters on their biological profiles. Radiolabeled copolymers of NIPAAm and methacrylic acid (MAA) of different molecular weight, amphiphilicity and lower critical solution temperature (LCST) were synthesized and injected intravenously to rats. The PK and excretion profiles were monitored over 48 h. It was found that elimination occurred mainly through urinary excretion, which was principally governed by molecular weight. Above a threshold of 32,000, the polymer chains avoided glomerular filtration and presented prolonged circulation times. Moreover, the presence of alkyl moieties at the chain extremity influenced circulation time and tissue distribution of polymer chains, hypothetically through formation of micellar structures. The polymers with an LCST situated below the physiological temperature did not circulate for prolonged periods in the bloodstream and were highly captured by the organs of the mononuclear phagocyte system. Finally, the complexation of an alkylated pH-sensitive polymer with a molecular weight of 10,000 to the bilayer of PEGylated liposomes produced a drastic change in the PK parameters, indicating that the polymer remained anchored in the phospholipid bilayer in the bloodstream. These data indicate that stable pH-sensitive liposomes can be produced using excretable NIPAAm copolymers.

Biomacromolecules, 2007

Poly(ethylene oxide)-block-poly(styrene oxide) (PEO-b-PSO) and PEO-b-poly(butylene oxide) (PEO-b-... more Poly(ethylene oxide)-block-poly(styrene oxide) (PEO-b-PSO) and PEO-b-poly(butylene oxide) (PEO-b-PBO) of different chain lengths were synthesized and characterized for their self-assembling properties in water by dynamic/static light scattering, spectrofluorimetry, and transmission electron microscopy. The resulting polymeric micelles were evaluated for their ability to solubilize and protect the anticancer drug docetaxel (DCTX) from degradation. The drug release kinetics as well as the cytotoxicity of the loaded micelles were assessed in vitro. All polymers formed micelles with a highly viscous core at low critical association concentrations (<10 mg/L). Micelle morphology depended on the nature of the hydrophobic block, with PBO- and PSO-based micelles yielding monodisperse spherical and cylindrical nanosized aggregates, respectively. The maximum solubilization capacity for DCTX ranged from 0.7 to 4.2% and was the highest for PSO micelles exhibiting the longest hydrophobic segment. Despite their high affinity for DCTX, PEO-b-PSO micelles were not able to efficiently protect DCTX against hydrolysis under accelerated stability testing conditions. Only PEO-b-PBO bearing 24 BO units afforded significant protection against degradation. In vitro, DCTX was released slower from the latter micelles, but all formulations possessed a similar cytotoxic effect against PC-3 prostate cancer cells. These data suggest that PEO-b-P(SO/BO) micelles could be used as alternatives to conventional surfactants for the solubilization of taxanes.

American Journal of Health-System Pharmacy, 2012

Physical compatibility of calcium gluconate and magnesium sulfate injections and magnesium (Ca/Mg... more Physical compatibility of calcium gluconate and magnesium sulfate injections and magnesium (Ca/Mg) versus placebo on response to FOLFOX + bevacizumab (BEV) in the CONcePT trial. J Clin Oncol. 2008; 26(suppl):abstract 4010. 5. Particulate matter in injections (general information chapter 788). In: The United States pharmacopeia, 33rd rev., and The national formulary, 28th ed. Rockville, MD: United States Pharmacopeial Convention; 2010. 6. Chan P, Bishop A, Kupiec TC et al. Compatibility of ceftobiprole medocaril with selected drugs during simulated Y-site administration. Am J Health-Syst Pharm. 2008; 65:1545-51.

Advanced Drug Delivery Reviews, 2012

The application of nanotechnology to personalized medicine provides an unprecedented opportunity ... more The application of nanotechnology to personalized medicine provides an unprecedented opportunity to improve the treatment of many diseases. Nanomaterials offer several advantages as therapeutic and diagnostic tools due to design flexibility, small sizes, large surface-to-volume ratio, and ease of surface modification with multivalent ligands to increase avidity for target molecules. Nanomaterials can be engineered to interact with specific biological components, allowing them to benefit from the insights provided by personalized medicine techniques. To tailor these interactions, a comprehensive knowledge of how nanomaterials interact with biological systems is critical. Herein, we discuss how the interactions of nanomaterials with biological systems can guide their design for diagnostic, imaging and drug delivery purposes. A general overview of nanomaterials under investigation is provided with an emphasis on systems that have reached clinical trials. Finally, considerations for the development of personalized nanomedicines are summarized such as the potential toxicity, scientific and technical challenges in fabricating them, and regulatory and ethical issues raised by the utilization of nanomaterials.

ACS Nano, 2010

Injectable scavenging nanocarriers have been proposed as detoxifying agents when there are no spe... more Injectable scavenging nanocarriers have been proposed as detoxifying agents when there are no specific antidotes to treat pharmacological overdoses. They act by capturing the drug in situ, thereby restricting distribution in tissues. In the clinic, the only systems used for that purpose are parenteral lipid emulsions, which are relatively inefficient in terms of uptake capacity. In this study, we investigated long-circulating liposomes with a transmembrane pH gradient as treatment for diltiazem intoxication. The unique ion-trapping properties of the vesicles toward ionizable compounds were exploited to sequester the drug in the bloodstream and limit its pharmacological effect. After in vitro optimization of the formulation, the in vivo scavenging properties of the liposomes were demonstrated by examining the drug's pharmacokinetics. The reduced volume of distribution and increased area under the plasma concentration versus time curve in animals treated with liposomes indicated limited tissue distribution. The vesicles exerted a similar but more pronounced effect on deacetyl-diltiazem, the principal active metabolite of the drug. This in vivo uptake of both drug and metabolite altered the overall pharmacological outcome. In rats receiving an intravenous bolus of diltiazem, the liposomes tempered the hypotensive decline and maintained higher average blood pressure for 1 h. The detoxifying action of liposomes was even stronger when the rats received higher doses of the drug via perfusion. In conclusion, the present work provided clear evidence that liposomes with a transmembrane pH gradient are able to change the pharmacokinetics and pharmacodynamics of diltiazem and its metabolite and confirmed their potential as efficient detoxifying nanocarriers.

Nanomedicine: Nanotechnology, Biology and Medicine, 2014

Microfluidic synthesis of nanoparticles (NPs) can enhance the controllability and reproducibility... more Microfluidic synthesis of nanoparticles (NPs) can enhance the controllability and reproducibility in physicochemical properties of NPs compared to bulk synthesis methods. However, applications of microfluidic synthesis are typically limited to in vitro studies due to low production rates. Herein, we report the parallelization of NP synthesis by 3D hydrodynamic flow focusing (HFF) using a multilayer microfluidic system to enhance the production rate without losing the advantages of reproducibility, controllability, and robustness. Using parallel 3D HFF, polymeric poly(lactide-co-glycolide)-b-polyethyleneglycol (PLGA-PEG) NPs with sizes tunable in the range of 13-150 nm could be synthesized reproducibly with high production rate. As a proof of concept, we used this system to perform in vivo pharmacokinetic and biodistribution study of small (20 nm diameter) PLGA-PEG NPs that are otherwise difficult to synthesize. Microfluidic parallelization thus enables synthesis of NPs with tunable properties with production rates suitable for both in vitro and in vivo studies.

Proceedings of the National Academy of Sciences of the United States of America, Jan 15, 2014

Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic c... more Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(D,L-lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA-b-PEG and alendronate-conjugated polymer PLGA-b-PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo bi...

Advanced Drug Delivery Reviews, 2014

Cancer nanotherapeutics are progressing at a steady rate; research and development in the field h... more Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000's. The path to the commercialization of oncology drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnology can meaningfully contribute to create differentiated products and improve clinical outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL® and Abraxane®. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncology, where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential "retention" in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor associated macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers.

Nature Communications, 2015

Nanotechnology may offer fast and effective solutions for environmental clean-up. Herein, amphiph... more Nanotechnology may offer fast and effective solutions for environmental clean-up. Herein, amphiphilic diblock copolymers are used to develop a platform of photosensitive core-shell nanoparticles. Irradiation with ultraviolet light removes the protective layer responsible for colloidal stability; as a result, the nanoparticles are rapidly and irreversibly converted to macroscopic aggregates. The associated phase separation allows measuring the partitioning of small molecules between the aqueous phase and nanoparticles; data suggests that interactions are enhanced by decreasing the particle size. Adsorption onto nanoparticles can be exploited to efficiently remove hydrophobic pollutants from water and contaminated soil. Preliminary in vivo experiments suggest that treatment with photocleavable nanoparticles can significantly reduce the teratogenicity of bisphenol A, triclosan and 17α-ethinyl estradiol without generating obviously toxic byproducts. Small-scale pilot experiments on wastewater, thermal printing paper and contaminated soil demonstrate the applicability of the approach.

Angewandte Chemie (International ed. in English), Jan 26, 2015

Selective tumor targeting and drug delivery are critical for cancer treatment. Stimulus-sensitive... more Selective tumor targeting and drug delivery are critical for cancer treatment. Stimulus-sensitive nanoparticle (NP) systems have been designed to specifically respond to significant abnormalities in the tumor microenvironment, which could dramatically improve therapeutic performance in terms of enhanced efficiency, targetability, and reduced side-effects. We report the development of a novel L-cysteine-based poly (disulfide amide) (Cys-PDSA) family for fabricating redox-triggered NPs, with high hydrophobic drug loading capacity (up to 25 wt % docetaxel) and tunable properties. The polymers are synthesized through one-step rapid polycondensation of two nontoxic building blocks: L-cystine ester and versatile fatty diacids, which make the polymer redox responsive and give it a tunable polymer structure, respectively. Alterations to the diacid structure could rationally tune the physicochemical properties of the polymers and the corresponding NPs, leading to the control of NP size, hydr...

Methods in Molecular Biology, 2009

pH-sensitive liposomes have been designed to deliver active compounds specifically to acidic intr... more pH-sensitive liposomes have been designed to deliver active compounds specifically to acidic intracellular organelles and to augment their cytoplasmic concentrations. These systems combine the protective effects of other liposomal formulations with specific environment-controlled drug release. They are stable at physiological pH, but abruptly discharge their contents when endocytosed into acidic compartments, allowing the drug to be released before it is exposed to the harsh environment of lysosomes.

ACS Symposium Series, 2006

In the last decades, the rapid advances in the understanding of the role of proteins and peptides... more In the last decades, the rapid advances in the understanding of the role of proteins and peptides in several diseases have propelled them as therapeutic entities. Protein delivery is a challenge and one of the new approaches to their administration is to implant cells producing the ...

Monographs in Supramolecular Chemistry, 2013

Trends in Molecular Medicine, 2015

The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of various ... more The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of various diseases, including cancer. The unique properties of nanoparticles (NPs), such as large surface-to-volume ratio, small size, the ability to encapsulate various drugs, and tunable surface chemistry, give them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make NPs a mode of treatment potentially superior to conventional cancer therapies. This review highlights the most recent developments in cancer treatment using NPs as drug delivery vehicles, including promising opportunities in targeted and combination therapy.

Mathematical modeling of drug release from biodegradable microspheres is designed to improve unde... more Mathematical modeling of drug release from biodegradable microspheres is designed to improve understanding of phenomena involved in this complex process. In spite of the considerable information obtained from conventional models, their use of equation curve fitting often limits the possibility to generalize their results. The objective of the presented study is to develop a model involving a three-dimensional cellular automaton to simulate both polymer erosion and drug diffusion independently. The model involves millions of independent cells in different states representing the components present in microspheres. The different states allow representation of polymer, drug, pores and solvent. For erosion, each cell is defined with a life expectancy and its chance of being eroded evolves according to the number of direct neighbours containing solvent. For diffusion, drug-containing cells are allowed to randomly diffuse their content in their neighbouring solvent-containing cells. Good correlations are obtained between simulations and two sets of experimental data obtained from release study at different pH. The model offers some insights about important drug release phases, like burst and subsequent release. Graphical representations obtained from the cellular automaton are also compared to SEM images. Cellular automaton proves to be an interesting tool for drug release modeling offering insights on the phenomena involved.

Journal of Controlled Release, 2011

Macromolecular binders consist of polymers, dendrimers, and oligomers with binding properties for... more Macromolecular binders consist of polymers, dendrimers, and oligomers with binding properties for endogenous or exogenous substrates. This field, at the frontier of host/guest chemistry and pharmacology, has met a renewed interest in the past decade due to the clinical success of several sequestrants, like sevelamer hydrochloride (Renagel®) or sugammadex (Bridion®). In many instances, multivalent binding by the macromolecular drugs can modify the properties of the substrate, and may prevent it from reaching its site of action and/or trigger a biological response. From small (e.g., ions) to larger substrates (e.g., bacteria and cells), this review presents the state-of-the-art of macromolecular binders and provides detailed illustrative examples of recent developments bearing much promise for future pharmaceutical applications.

Journal of Controlled Release, 2012

Recent advances in chemistry and material sciences have witnessed the emergence of an increasing ... more Recent advances in chemistry and material sciences have witnessed the emergence of an increasing number of novel and complex nanosized carriers for the delivery of drugs and imaging agents. Nevertheless, this raise in complexity does not necessarily offer more efficient systems. The lack of performance experienced by several colloidal drug carriers during the preclinical and clinical development processes can be explained by inadequate pharmacokinetic/biodistribution profiles and/or unacceptable toxicities. A comprehensive understanding of the body characteristics is necessary to predict and prevent these problems from the early stages of nanomaterial conception. In this manuscript, we review and discuss the anatomical and physiological elements which must be taken into account when designing new carriers for delivery or imaging purposes. This article gives a general overview of the main organs involved in the elimination of nanosized materials and briefly summarizes the knowledge acquired over more than 30 years of research and development in the field of drug targeting.

Biomaterials, 2009

The purpose of this work was to characterize the pharmacokinetics (PK) and biodistribution of pHr... more The purpose of this work was to characterize the pharmacokinetics (PK) and biodistribution of pHresponsive N-isopropylacrylamide (NIPAAm) copolymers, and to determine the impact of some physicochemical parameters on their biological profiles. Radiolabeled copolymers of NIPAAm and methacrylic acid (MAA) of different molecular weight, amphiphilicity and lower critical solution temperature (LCST) were synthesized and injected intravenously to rats. The PK and excretion profiles were monitored over 48 h. It was found that elimination occurred mainly through urinary excretion, which was principally governed by molecular weight. Above a threshold of 32,000, the polymer chains avoided glomerular filtration and presented prolonged circulation times. Moreover, the presence of alkyl moieties at the chain extremity influenced circulation time and tissue distribution of polymer chains, hypothetically through formation of micellar structures. The polymers with an LCST situated below the physiological temperature did not circulate for prolonged periods in the bloodstream and were highly captured by the organs of the mononuclear phagocyte system. Finally, the complexation of an alkylated pH-sensitive polymer with a molecular weight of 10,000 to the bilayer of PEGylated liposomes produced a drastic change in the PK parameters, indicating that the polymer remained anchored in the phospholipid bilayer in the bloodstream. These data indicate that stable pH-sensitive liposomes can be produced using excretable NIPAAm copolymers.

Biomacromolecules, 2007

Poly(ethylene oxide)-block-poly(styrene oxide) (PEO-b-PSO) and PEO-b-poly(butylene oxide) (PEO-b-... more Poly(ethylene oxide)-block-poly(styrene oxide) (PEO-b-PSO) and PEO-b-poly(butylene oxide) (PEO-b-PBO) of different chain lengths were synthesized and characterized for their self-assembling properties in water by dynamic/static light scattering, spectrofluorimetry, and transmission electron microscopy. The resulting polymeric micelles were evaluated for their ability to solubilize and protect the anticancer drug docetaxel (DCTX) from degradation. The drug release kinetics as well as the cytotoxicity of the loaded micelles were assessed in vitro. All polymers formed micelles with a highly viscous core at low critical association concentrations (<10 mg/L). Micelle morphology depended on the nature of the hydrophobic block, with PBO- and PSO-based micelles yielding monodisperse spherical and cylindrical nanosized aggregates, respectively. The maximum solubilization capacity for DCTX ranged from 0.7 to 4.2% and was the highest for PSO micelles exhibiting the longest hydrophobic segment. Despite their high affinity for DCTX, PEO-b-PSO micelles were not able to efficiently protect DCTX against hydrolysis under accelerated stability testing conditions. Only PEO-b-PBO bearing 24 BO units afforded significant protection against degradation. In vitro, DCTX was released slower from the latter micelles, but all formulations possessed a similar cytotoxic effect against PC-3 prostate cancer cells. These data suggest that PEO-b-P(SO/BO) micelles could be used as alternatives to conventional surfactants for the solubilization of taxanes.

American Journal of Health-System Pharmacy, 2012

Physical compatibility of calcium gluconate and magnesium sulfate injections and magnesium (Ca/Mg... more Physical compatibility of calcium gluconate and magnesium sulfate injections and magnesium (Ca/Mg) versus placebo on response to FOLFOX + bevacizumab (BEV) in the CONcePT trial. J Clin Oncol. 2008; 26(suppl):abstract 4010. 5. Particulate matter in injections (general information chapter 788). In: The United States pharmacopeia, 33rd rev., and The national formulary, 28th ed. Rockville, MD: United States Pharmacopeial Convention; 2010. 6. Chan P, Bishop A, Kupiec TC et al. Compatibility of ceftobiprole medocaril with selected drugs during simulated Y-site administration. Am J Health-Syst Pharm. 2008; 65:1545-51.

Advanced Drug Delivery Reviews, 2012

The application of nanotechnology to personalized medicine provides an unprecedented opportunity ... more The application of nanotechnology to personalized medicine provides an unprecedented opportunity to improve the treatment of many diseases. Nanomaterials offer several advantages as therapeutic and diagnostic tools due to design flexibility, small sizes, large surface-to-volume ratio, and ease of surface modification with multivalent ligands to increase avidity for target molecules. Nanomaterials can be engineered to interact with specific biological components, allowing them to benefit from the insights provided by personalized medicine techniques. To tailor these interactions, a comprehensive knowledge of how nanomaterials interact with biological systems is critical. Herein, we discuss how the interactions of nanomaterials with biological systems can guide their design for diagnostic, imaging and drug delivery purposes. A general overview of nanomaterials under investigation is provided with an emphasis on systems that have reached clinical trials. Finally, considerations for the development of personalized nanomedicines are summarized such as the potential toxicity, scientific and technical challenges in fabricating them, and regulatory and ethical issues raised by the utilization of nanomaterials.

ACS Nano, 2010

Injectable scavenging nanocarriers have been proposed as detoxifying agents when there are no spe... more Injectable scavenging nanocarriers have been proposed as detoxifying agents when there are no specific antidotes to treat pharmacological overdoses. They act by capturing the drug in situ, thereby restricting distribution in tissues. In the clinic, the only systems used for that purpose are parenteral lipid emulsions, which are relatively inefficient in terms of uptake capacity. In this study, we investigated long-circulating liposomes with a transmembrane pH gradient as treatment for diltiazem intoxication. The unique ion-trapping properties of the vesicles toward ionizable compounds were exploited to sequester the drug in the bloodstream and limit its pharmacological effect. After in vitro optimization of the formulation, the in vivo scavenging properties of the liposomes were demonstrated by examining the drug's pharmacokinetics. The reduced volume of distribution and increased area under the plasma concentration versus time curve in animals treated with liposomes indicated limited tissue distribution. The vesicles exerted a similar but more pronounced effect on deacetyl-diltiazem, the principal active metabolite of the drug. This in vivo uptake of both drug and metabolite altered the overall pharmacological outcome. In rats receiving an intravenous bolus of diltiazem, the liposomes tempered the hypotensive decline and maintained higher average blood pressure for 1 h. The detoxifying action of liposomes was even stronger when the rats received higher doses of the drug via perfusion. In conclusion, the present work provided clear evidence that liposomes with a transmembrane pH gradient are able to change the pharmacokinetics and pharmacodynamics of diltiazem and its metabolite and confirmed their potential as efficient detoxifying nanocarriers.

Nanomedicine: Nanotechnology, Biology and Medicine, 2014

Microfluidic synthesis of nanoparticles (NPs) can enhance the controllability and reproducibility... more Microfluidic synthesis of nanoparticles (NPs) can enhance the controllability and reproducibility in physicochemical properties of NPs compared to bulk synthesis methods. However, applications of microfluidic synthesis are typically limited to in vitro studies due to low production rates. Herein, we report the parallelization of NP synthesis by 3D hydrodynamic flow focusing (HFF) using a multilayer microfluidic system to enhance the production rate without losing the advantages of reproducibility, controllability, and robustness. Using parallel 3D HFF, polymeric poly(lactide-co-glycolide)-b-polyethyleneglycol (PLGA-PEG) NPs with sizes tunable in the range of 13-150 nm could be synthesized reproducibly with high production rate. As a proof of concept, we used this system to perform in vivo pharmacokinetic and biodistribution study of small (20 nm diameter) PLGA-PEG NPs that are otherwise difficult to synthesize. Microfluidic parallelization thus enables synthesis of NPs with tunable properties with production rates suitable for both in vitro and in vivo studies.