Search

Global cancer prevalence has continuously increased in the last decades despite substantial progress achieved for patient care. Cancer is no longer recognized as a singular disease but as a plurality of different ones, leading to the important choice of the drug administration route and promoting the development of novel drug-delivery systems (DDS). Due to their structural diversity, therapeutic cancer drugs present specific challenges in physicochemical properties that can adversely affect their efficacy and toxicity profile. These challenges are addressed by innovative DDS to improve bioavailability, pharmacokinetics and biodistribution profiles. Here, we define the drug delivery challenges related to oral, intravenous, subcutaneous or alternative routes of administration, and review innovative DDS, marketed or in development, that answer those challenges.

Significance Functionalization of proteins and biopolymers with chemical modifications can be utilized to alter their chemical and biophysical properties. In contrast to traditional chemical functionalization strategies, the use of nonstandard amino acids enables precise positioning of functional groups. Here, we report that multisite conjugation of fatty acids, at precise sites harboring genetically encoded nonstandard amino acids with bioorthogonal chemical handles, can be employed to tune the half-life of proteins in a mouse model. This programmable approach could offer a technical foundation for the modification of protein and peptide therapeutics to improve their efficacy or pharmacokinetic profile (e.g., to prevent rapid clearance and reduce frequency of administration)., The use of biologics in the treatment of numerous diseases has increased steadily over the past decade due to their high specificities, low toxicity, and limited side effects. Despite this success, peptide- and protein-based drugs are limited by short half-lives and immunogenicity. To address these challenges, we use a genomically recoded organism to produce genetically encoded elastin-like polypeptide–protein fusions containing multiple instances of para-azidophenylalanine (pAzF). Precise lipidation of these pAzF residues generated a set of sequence-defined synthetic biopolymers with programmable binding affinity to albumin without ablating the activity of model fusion proteins, and with tunable blood serum half-lives spanning 5 to 94% of albumin’s half-life in a mouse model. Our findings present a proof of concept for the use of genetically encoded bioorthogonal conjugation sites for multisite lipidation to tune protein stability in mouse serum. This work establishes a programmable approach to extend and tune the half-life of protein or peptide therapeutics and a technical foundation to produce functionalized biopolymers endowed with programmable chemical and biophysical properties with broad applications in medicine, materials science, and biotechnology.

Nanoparticles are of long-standing interest for the treatment of neurological diseases such as glioblastoma. Most past work focused on methods to introduce nanoparticles into the brain, suggesting that reaching the brain interstitium will be sufficient to ensure therapeutic efficacy. However, optimized nanoparticle design for drug delivery to the central nervous system is limited by our understanding of their cellular deposition in the brain. Here, we investigated the cellular fate of poly(lactic acid) nanoparticles presenting different surface chemistries, after administration by convection-enhanced delivery. We demonstrate that nanoparticles with ‘stealth' properties mostly avoid internalization by all cell types, but internalization can be enhanced by functionalization with bio-adhesive end-groups. We also show that association rates measured in cultured cells predict the extent of internalization of nanoparticles in cell populations. Finally, evaluating therapeutic efficacy in an orthotopic model of glioblastoma highlights the need to balance significant uptake without inducing adverse toxicity., There have been numerous attempts to develop nanomaterials to reach cells of the central nervous system for drug delivery. Here, the authors investigate the cellular fate of polymer-based nanoparticles with varying surface chemistries after administration directly into the brain.

Glioblastoma multiforme (GBM) is a fatal brain tumor characterized by infiltration beyond the margins of the main tumor mass and local recurrence after surgery. The blood-brain barrier (BBB) poses the most significant hurdle to brain tumor treatment. Convection-enhanced delivery (CED) allows for local administration of agents, overcoming the restrictions of the BBB. Recently, polymer nanoparticles have been demonstrated to penetrate readily through the healthy brain when delivered by CED, and size has been shown to be a critical factor for nanoparticle penetration. Because these brain-penetrating nanoparticles (BPNPs) have high potential for treatment of intracranial tumors since they offer the potential for cell targeting and controlled drug release after administration, here we investigated the intratumoral CED infusions of PLGA BPNPs in animals bearing either U87 or RG2 intracranial tumors. We demonstrate that the overall volume of distribution of these BPNPs was similar to that observed in healthy brains; however, the presence of tumors resulted in asymmetric and heterogeneous distribution patterns, with substantial leakage into the peritumoral tissue. Together, our results suggest that CED of BPNPs should be optimized by accounting for tumor geometry, in terms of location, size and presence of necrotic regions, to determine the ideal infusion site and parameters for individual tumors.

Since their introduction in the late 60′, nanotechnologies applied to medicine, called nanomedicines, are believed to have the potential to be the mankind's first “giant step” toward treatment of severe diseases. Among others, they could provide an original solution for the treatment of brain impairments, such as stroke, allowing developing and commercializing more efficient therapeutic solutions. However, despite clear improvement in pharmacokinetic properties and reductions of adverse side effects when using nanomedicines, only modest therapeutic benefits were achieved in humans. This may be due to specific issues in the nanoformulation development process and evaluation, which hampered their translation from the bench to the bedside. In this review, we aim to tackle some of the key challenges that have to be taken into account when developing and evaluating a new nanomedicines, with a special emphasis on the development of nanomedicines for the treatment of stroke.

Gene delivery is known to be a complicated multi-step biological process . It has been observed that subtle differences in the structure and properties of polymeric materials used for gene delivery can lead to dramatic differences in transfection efficiency. Therefore, screening of properties is pivotal to optimizing the polymer. So far, most polymeric materials are built in a “bottom-up” manner, i.e. synthesized from monomers that allow modification of polymer composition or structural factors. With this method, we previously synthesized and screened a library of biodegradable poly(amine- co -ester) (PACE) terpolymers for optimized DNA delivery. However, it can be tedious and time consuming to synthesize a polymer library for screening, particularly when small changes of a factor need to be tested, when multiple factors are involved, and when the effects of different factors are synergistic. In the present work, we evaluate the potential of PACE to deliver mRNA. After observing that mRNA transfection efficiency was highly dependent on both end group composition and molecular weight (MW) of PACE in a synergistic manner, we developed a “top-down” process we called actuation , to simultaneously vary these two factors. Some of the actuated PACE (aPACE) materials presented superior mRNA delivery properties compared to regular PACE, with up to a 10 6-fold-increase in mRNA transfection efficiency in vitro . Moreover, when aPACE was used to deliver mRNA coding for erythropoietin (EPO) in vivo , it produced high levels of EPO in the blood for up to 48 h without inducing systemic toxicity . This polymer constitutes a new delivery vehicle for mRNA-based treatments that provides safe yet potent protein production.

Alzheimer's disease (AD) is a neurodegenerative disorder related, in part, to the accumulation of amyloid-β peptide (Aβ) and especially the Aβ peptide 1-42 (Aβ1-42). The aim of this study was to design nanocarriers able to: (i) interact with the Aβ1-42 in the blood and promote its elimination through the “sink effect” and (ii) correct the memory defect observed in AD-like transgenic mice. To do so, biodegradable, PEGylated nanoparticles were surface-functionalized with an antibody directed against Aβ1-42. Treatment of AD-like transgenic mice with anti-Aβ1-42-functionalized nanoparticles led to: (i) complete correction of the memory defect; (ii) significant reduction of the Aβ soluble peptide and its oligomer level in the brain and (iii) significant increase of the Aβ levels in plasma. This study represents the first example of Aβ1-42 monoclonal antibody-decorated nanoparticle-based therapy against AD leading to complete correction of the memory defect in an experimental model of AD.

Nanomaterials have emerged as important and versatile platforms for the delivery of therapeutics to the brain. This article describes the complex anatomy and physiology of the brain, which create challenges in treating diseases of the central nervous system, and current strategies using nanomedicines to address these challenges. We discuss various approaches to overcome the blood-brain barrier, examples of successful incorporation of therapeutics with nanomaterials, and strategies to achieve efficient delivery of nanomedicines into specific cells.

There is an urgent need to develop new therapeutic approaches for the treatment of severe neurological trauma, such as stroke and spinal cord injuries. However, many drugs with potential neuropharmacological activity, such as adenosine, are inefficient upon systemic administration because of their fast metabolization and rapid clearance from the bloodstream. Here, we show that conjugation of adenosine to the lipid squalene and the subsequent formation of nanoassemblies allows prolonged circulation of this nucleoside, providing neuroprotection in mouse stroke and rat spinal cord injury models. The animals receiving systemic administration of squalenoyl adenosine nanoassemblies showed a significant improvement of their neurologic deficit score in the case of cerebral ischaemia, and an early motor recovery of the hindlimbs in the case of spinal cord injury. Moreover, in vitro and in vivo studies demonstrated that the nanoassemblies were able to extend adenosine circulation and its interaction with the neurovascular unit. This Article shows, for the first time, that a hydrophilic and rapidly metabolized molecule such as adenosine may become pharmacologically efficient owing to a single conjugation with the lipid squalene.

Nanotechnology, in conjunction with convection-enhanced delivery (CED), has gained traction as a promising method to treat many debilitating neurological diseases, including gliomas. One of the key parameters to evaluate the effectiveness of delivery is the volume of distribution (V d ) of nanoparticles within the brain parenchyma. Measurements of V d are commonly made using fluorescent reporter systems. However, reported analyses lack accurate and robust methods for determining V d . Current methods face the problems of varying background intensities between images, high intensity aggregates that can shift intensity distributions, and faint residual backgrounds that can occur as artifacts of fluorescent imaging. These problems can cause inaccurate results to be reported when a percentage of the maximum intensity is set as the threshold value. Here we show an implementation of Otsu’s method more reliably selects accurate threshold values than the fixed-threshold method. We also introduce a goodness of fit value η that quantifies the appropriateness of using Otsu’s method to calculate V d . Adoption of Otsu’s method and reporting of η may help standardize fluorescent image analysis of nanoparticles administered by convection-enhanced delivery.

New treatments for glioblastoma multiforme (GBM) are desperately needed, as GBM prognosis remains poor, mainly due to treatment resistance, poor distribution of therapeutics in the tumor tissue, and fast metabolism of chemotherapeutic drugs in the brain extracellular space. Convection-enhanced delivery (CED) of nanoparticles (NPs) has been shown to improve the delivery of chemotherapeutic drugs to the tumor bed, providing sustained release, and enhancing survival of animals with intracranial tumors. Here we administered gemcitabine, a nucleoside analog used as a first line treatment for a wide variety of extracranial solid tumors, within squalene-based NPs using CED, to overcome the above-mentioned challenges of GBM treatment. Small percentages of poly(ethylene) glycol (PEG) dramatically enhanced the distribution of squalene-gemcitabine nanoparticles (SQ-Gem NPs) in healthy animals and tumor-bearing animals after administration by CED. When tested in an orthotopic model of GBM, SQ-Gem-PEG NPs demonstrated significantly improved therapeutic efficacy compared to free gemcitabine, both as a chemotherapeutic drug and as a radiosensitizer. Furthermore, MR contrast agents were incorporated into the SQ-Gem-PEG NP formulation, providing a way to non-invasively track the NPs during infusion.

Drug delivery to the brain is a challenge because of the many mechanisms that protect the brain from the entry of foreign substances. Numerous molecules which could be active against brain disorders are not clinically useful due to the presence of the blood-brain barrier. Nanoparticles can be used to deliver these drugs to the brain. Encapsulation within colloidal systems can allow the passage of nontransportable drugs across this barrier by masking their physicochemical properties. It should be noted that the status of the blood-brain barrier is different depending on the brain disease. In fact, in some pathological situations such as tumors or inflammatory disorders, its permeability is increased allowing very easy translocation of carriers. This chapter gathers the promising results obtained by using nanoparticles as drug delivery systems with the aim to improve the therapy of some CNS diseases such as brain tumor, Alzheimer's disease, and stroke. The data show that several approaches can be investigated: (1) carrying drug through a permeabilized barrier, (2) crossing the barrier thanks to receptor-mediated transcytosis pathway in order to deliver drug into the brain parenchyma, and also (3) targeting and treating the endothelial cells themselves to preserve locally the brain tissue. The examples given in this chapter contribute to demonstrate that delivering drugs into the brain is one of the most promising applications of nanotechnology in clinical neuroscience.

Drug delivery to the brain is one of the major challenges in the treatment of cerebral diseases and implies extensive understanding of nanomedicine transcytosis pathways across the blood–brain barr...

Given its deadly prognosis, new treatments for glioblastoma multiforme (GBM) are desperately needed. Despite major progress in the development of new chemotherapeutic drugs and improved surgical technique, GBM prognosis remains grim, with a median survival of 15 months, mainly due to the almost invariable tumor recurrence. Convection-enhanced delivery (CED) of nanoparticles (NPs) has been proposed as an efficient way to deliver chemotherapeutic drugs locally into the tumor bed and to enhance treatment of intracranial tumors. Gemcitabine is an antimetabolite, and an effective inhibitor of DNA synthesis, that is used as a first line treatment for a wide variety of solid tumors. Gemcitabine has demonstrated efficacy against human glioma cell lines in vitro, but its clinical effectiveness is limited by its inability to cross the blood-brain barrier (BBB) after systemic delivery, its rapid deamination in the brain interstitial space to its inactive difluorodeoxyuridine metabolite, and its limited uptake by brain tumor cells. Here we propose to use CED to circumvent the BBB, and to administer the chemotherapeutic drug gemcitabine in a squalene-based nanoparticulate form, which is designed to protect the drug from metabolism, to provide a sustained release of the drug, and to enhance its cellular internalization. SQGem NPs were prepared by the nanoprecipitation technique, and presented a diameter of around 120 nm when measured by DLS, with a negative surface charge of around -20 mV. Modification of the surface of SQGem NPs using different amounts of polyethylene glycol (PEG) was performed by incorporating squalenoyl-PEG (SQPEG) to the formulation, providing SQGem/SQPEG NPs. The PEGylated NPs retained the physico-chemical properties of SQGem NPs, and the addition of PEG prevented the aggregation of the particles in aCSF. The stabilized formulations presented significantly larger volumes of distribution (Vd) in the healthy brain and the tumor-bearing brain after administration by CED. We further demonstrated that the combination of a non-distributing formulation and a distributing formulation offered the possibility of tuning the volume distribution of the nanoparticles in the brain tissue, and thus controlling the local drug concentration. To evaluate the effect of PEGylation on therapeutic efficacy, Fischer 344 rats were implanted with RG2 cells, and treated by CED using different SQGem/SQPEG formulations. Given the dual action of gemcitabine as chemotherapeutic and radiosensitizer, we also evaluated the addition of radiation to the treatment schedule. Overall, all formulations increased survival compared to free drug. Finally, as a first step toward clinical translation, we incorporated ultra-small iron particles oxide (USPIO) to the SQGem/SQPEG NPs formulation, to add the possibility of tracking the particles during CED using MRI. These NPs retained suitable characteristics to be administered by CED and were able to distribute in the brain tissue. This study demonstrates for the first time the safe administration of SQGem NPs by CED, providing significant survival improvement compared to the free drug. It also demonstrates a new method to optimize drug distribution by modulating surface properties of the nanoparticles. The administration by CED of optimized SQGem NPs formulations is expected to increase survival and could, in the future, change the way that GBM patients are treated in the US and around the world. Citation Format: Alice Gaudin, Eric Song, King Amanda, Didier Desmaele, Patrick Couvreur, Mark Saltzman. PEGylated squalenoyl-gemcitabine nanoparticles for the treatment of glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B33.

Purpose: Nanoparticles (NPs) carry important promises for the treatment of neurological diseases, such as glioblastoma multiform (GBM) and Parkinson's disease. Several methods have been developed to achieve higher NP concentrations in the brain, including local infusions using convection enhanced delivery (CED), focused ultrasound, and the use of surface targeting moieties specifically designed to increase the passage across the blood brain barrier (BBB). However, even when sufficient NP amounts are delivered to the targeted region, a better understanding of the interactions between the particles and the brain parenchyma will be necessary to reach clinical efficacy. This is particularly true for polymeric NPs, which behavior can be dramatically influenced by multiple factors such as their size and their surface properties. Here, we investigated the cellular fate of PLA-based nanoparticles of similar size, but bearing different surface modifications, following CED in the healthy brain and the tumor bearing brain. Methods: Four PLA-based NP formulations with different surface modifications (PLA, PLA-PEG, PLA-HPG and PLA-HPG-CHO) and similar size were obtained by emulsion or nanoprecipitation. CED of each formulation was performed in healthy or tumor bearing brain, and comparable volumes of distribution were obtained. 4 h and 24 h after infusion, brains were harvested and processed for flow cytometry analysis and immunohistochemical staining, to quantify particle internalization by neurons, astrocytes, microglia and tumor cells, when applicable. In vitro uptake studies were performed using relevant cell lines for neurons (N27 cells), astrocytes (TNC1), microglia (BV2) and tumors (RG2). Rate of association kinetics of different particles with these cells were derived from an uptake study and then correlated with in vivo internalization results. Finally, to evaluate how different NPs surface modifications and their different internalization patterns can influence survival benefits, the different particles were loaded with epothilone B (EB) and infused into rats bearing RG2 tumors via CED. Results: We observed that in the healthy brain, stealth NPs distributed evenly between neurons, astrocytes and microglia, while exhibiting the highest specificity towards tumor cells in the tumor bearing brain. Overall, the functionalization of PLA NPs with aldehyde groups allowed for an increased uptake by all cell types, in both healthy and tumor bearing brain. These NPs also presented an increased relative uptake by microglia cells in both environments, compared to stealth particles, suggesting the induction of an immune response. Rates of association of NPs in vitro varied significantly between particle types. We were then able to correlate the in vivo uptake of each particle and cell type with in vitro particle association rates with neurons, astrocytes and microglia in culture, demonstrating the possibility of predicting in vivo uptake using in vitro association rates. Finally, comparison of particles in a survival efficacy showed significant differences, highlighting the importance of uptake of NPs. Conclusions: This study demonstrates for the first time that NP surface modifications significantly influence the cellular tropism of NPs in the brain in vivo, and that in vitro association rates can be used to anticipate the different internalization patterns. These differences open the possibility of tuning surface properties to optimize cellular delivery and therapeutic outcome. Acknowledgements: This work is supported by a NIH/NCI R01 grant (#5R01CA149128-04). Citation Format: Eric Song, Alice Gaudin, Amanda R. King, Youngeun Seo, Paul Won, Heewon Suh, Yang Deng, Jiajia Cui, Gregory Tietjen, W Mark Saltzman. Surface chemistry governs cellular tropism of nanoparticles in the brain. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B46.