Preface

Downloaded by 80.82.77.83 on January 19, 2018 | http://pubs.acs.org Publication Date (Web): November 15, 2017 | doi: 10.1021/bk-2017-1271.pr001

Preface This book has its sources in the symposium with the same title, held at the 252nd ACS National Meeting in Philadelphia, PA on August 21–25, 2016. The symposium was sponsored by the ACS Division of Colloid and Surface Chemistry, as part of its continuing symposia on amphiphiles and their self-assemblies. I am indebted to Dr. Ramanathan Nagarajan (Natick Soldier Research, Development & Engineering Center, Natick, MA), Program Chair for ACS Division of Colloid and Surface Chemistry, for his efforts to accommodate this symposium, for his scientific contributions to the symposium and to this book, and for his constant support. The main focus of the book is the design, synthesis and characterization of amphiphile self-assemblies and the dynamic assessment of these assemblies as delivery systems for drugs and nucleic acids. As delivery systems, these supra-molecular assemblies have the ability to change the pharmacokinetics and volume of distribution of their cargo, to protect it from premature decomposition or inactivation, and to control the spatial-temporal location and duration of the therapeutic effect associated with cargo delivery. Many biocompatible/biodegradable delivery systems present in the market today or in advanced clinical trials are made of self-assembled amphiphilic molecules of different types and molecular weights. Their physicochemical and delivery abilities are determined by physicochemical parameters of individual amphiphiles and of the loaded cargo. Therefore, substantial efforts were made towards the design of novel amphiphiles with encapsulation and delivery properties tailored for different cargos and for different biological applications. Different chapters of the book present delivery systems made out of large variety of amphiphiles, including simple surfactants, gemini surfactants, pseudo-gemini surfactants, lipids, lipophilic polycations, dendrimers, natural and synthetic polymers and their conjugates. The cargo encapsulated by these amphiphiles is quite diverse too: chemotherapeutic cytotoxic drugs, peptide, proteins, nucleic acids (pDNA, siRNA, mRNA). The book also presents the formulation protocols and parameters used in the component or cargo loading process, with theoretical support and rationale. It reveals how formulation technology can affect the drug loading ability, physicochemical properties, dynamic stability and unloading properties of the delivery system, across different classes of amphiphiles and cargos. Two main different strategies are currently used in the design of amphiphilebased delivery systems for drugs and nucleic acids. In formulation-based strategies, amphiphiles of different packing parameters and physicochemical properties are blended together, simultaneously or sequentially with the cargo, ix Ilies; Control of Amphiphile Self-Assembling at the Molecular Level: Supra-Molecular Assemblies with Tuned ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


each individual amphiphile being added to overcome a specific delivery barrier. The formulation parameters depend on the individual properties of the individual amphiphiles, cargo, and on the assembly that is desired to be obtained. An alternative approach involves the design of multi-purpose amphiphiles that can overcome several barriers and play multiple roles in the delivery system. The later strategy relies on in-depth understanding of the delivery barriers and on the antagonistic processes of loading/release in the context of these particular barriers. Acquired knowledge is used to encode different structural elements in the molecular structure of self-assembling amphiphiles, aiming towards the simplification the formulations and a better, more reproducible control of the cargo handling. The book brings together contributions from researchers relying on both strategies, aimed to foster a more cohesive understanding on how structure, packing parameter, physicochemical and interfacial properties of individual amphiphiles affect their self-assembling, loading, dynamic stability and release properties, in vitro and in vivo. The book starts with a chapter (Chapter 1) from our group dedicated to nucleic acid (pDNA, siRNA, mRNA) delivery via pyridinium amphiphiles, presenting the unique properties of these amphiphiles that recommend them for this delivery purpose. Recent progresses made in the design of pyridinium amphiphiles at all levels (polar head, linker, hydrophobic anchor, counterion(s)) were reviewed, covering lipids, gemini surfactants, pseudo-gemini surfactants, and lipophilic polycations. Structure-activity and structure-property relationships were made across these classes of amphiphiles, benchmarking their efficiency against established formulations used in human clinical trials, in vitro and in vivo. In the next chapter (Chapter 2), Nagarajan et al. present in depth the challenges for effectively deliver siRNA in terms of carrier vehicles and reveal solutions based on the use of polymer micelles based on block polyelectrolytes, in conjunction with peptides, nanoparticles, dendrimers, and lipids, in a comprehensive review of current state-of-the art. The chapter discusses in detail the main factors affecting polyelectrolyte complexation with siRNA and shows how the size and composition of the micelles can be controlled by the molecular properties of siRNA and the block copolymer. Nucleic acid delivery is also the subject of Chapter 3, contributed by Anchordoquy’s group, which provides a detailed and up-to-date perspective related to utilization of cholesterol in formulations for nucleic acid delivery. The authors reveal the use of cholesterol as an alternative to “stealth” technology based on PEGylation and presents the advantages of the nanodomains formed by high amounts of cholesterol within lipid nanoparticles. Among them, one may cite the reduction of adsorption of proteins upon intravenous injection (with detrimental effects on targeting of nanoparticles) and the significant reduction of toxicity of the delivery vehicle. The chapter covers all aspects of nucleic acid delivery systems with small amphiphiles (cationic lipids), including structure, serum stability, protein absorption and inactivation, uptake, cytotoxicity, immunogenicity and targeting issues, in vitro and in vivo. Selwa and Iorga present in Chapter 4 an interesting parallel between the use of nanoparticles for drug delivery applications and the computational methods useful for modeling the self-assembly process. The chapter highlights the different parameters critical for the success of computer simulations, including granularity x Ilies; Control of Amphiphile Self-Assembling at the Molecular Level: Supra-Molecular Assemblies with Tuned ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


at which particles are represented, force field parameters, initial setup and system composition. It also presents relevant applications of in silico approaches in drug delivery using peptides, copolymers, lipids, and/or mixtures of them as self-assembling amphiphiles. In Chapter 5, Sakurai and collaborators are also combining theory and experiments to show the impact of PEGylation density on structure, stability and drug delivery properties of micelle and liposome delivery systems. The authors present solutions for quantitative characterization of PEG chains tethered onto the nanoparticle surface via light scattering and small-angle X-ray scattering, relating the density of PEG chains to protein absorption in the corona and circulation time in vivo, biocompatibility and targeting ability. In Chapter 6, Fischer and collaborators provide a detailed overview of self-assembled lipoprotein-based nanoparticles and discuss key characteristics that recommend them as efficient drug and nucleic acid delivery systems. Authors are revealing how a wide range of starting components can be accommodated due to the versatility of the self-assembling process of lipoproteins to provide tunable control of size, stability, and functionality. Valuable insights related to orthogonal strategies for incorporation of bioactive cargo molecules (drugs, nucleic acids, proteins) are presented, for applications ranging from multifunctional vaccine formulations to targeted drug delivery. In Chapter 7, Chu and Liu present a similar comprehensive overview for self-assembled systems made out of inorganic-organic hybrid amphiphiles, which consist of hydrophilic inorganic heads and hydrophobic organic tails. Different systems are reviewed, emphasizing synthetic details, key properties and structure-property relationships, together with the main techniques used to characterize them. Extremely interesting is the hierarchical organization of some of the supra-molecular structures presented, supported by TEM, X-ray diffraction, electronic spectra and molecular modeling techniques. Also interesting examples are provided towards controlled self-assembly/disassembly process, triggered by stimuli such as light, heat, magnetic field and solvent polarity, and towards tenability of size/morphology of some assemblies via modulation of electrostatic interaction, hydrophobic interaction, hydrogen bonding, or π-π stacking. Lanza and collaborators are presenting in Chapter 8 recent progresses achieved by combining contact-facilitated drug delivery with sn2 phospholipid prodrugs, for both imaging and treatment. The technology is exemplified in great detail for vascular constrained lipid-encapsulated particles delivering anti-angiogenic therapies, such as fumagillin or docetaxel, and for micelles penetrating through inflamed endothelium into disseminated cancers, such as in multiple myeloma with anti-cMyc payloads. Details are provided towards the assembly and labelling of each delivery system, their structure and physicochemical properties, in vivo dynamic, as well as towards the controlled disassembly via specific (local) enzymatic action. A large collection of in vivo data acquired in different animal models, presented in great detail, proved the minimization of premature drug diffusional loss during circulation and the increase target cell bioavailability. The impact of enzymatic degradation on the selective blood/target stability of drug delivery systems based on self-assembled amphiphilic block copolymers is presented in the Chapter 9, authored by our group. Using a dynamic light xi Ilies; Control of Amphiphile Self-Assembling at the Molecular Level: Supra-Molecular Assemblies with Tuned ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


scattering technique we are revealing how interface-engineered PEG-PBO-PCL triblock copolymers can resist esterases present in blood (endothelial lipase, butyryl cholinesterase, carbonic anhydrase, albumin) better than micelles made out of standard PEG-PCL congeners, but can be degraded faster than these ones by specific esterases such as the PLA2 over-expressed in tumors. These interfacially-engineered micelles thus show selective stability blood/tumor that recommends them as promising delivery systems for chemotherapeutic drugs. Klapper and collaborators are revealing in Chapter 10 a similar drug delivery concept, based on novel A-B-A type triblock copolymers designed to be selectively degraded by enzymes (over)expressed in tumor cells such as MMP-2. The authors are presenting in detail the central peptide block design (recognized and cleaved by MMP-2) and the stepwise development of PLA-based triblock nanocarriers using non-aqueous emulsions as synthetic tool. Thus, block copolymerization of L-lactide using a model bifunctional peptide initiator yielded triblock copolymer nanoparticles. The particles were loaded with dye to allow the investigation of the cargo release and cell internalization properties via Coherent Anti-Stokes Raman Scattering (CARS) microscopy and Two-Photon Fluorescence Microscopy (TPEF) techniques, which confirmed the enzymatically-triggered cargo unloading in vitro. Key to this technology are the biocompatible emulsifiers for the nonaqueous emulsions used to produce the nanoparticles, which are also described in the chapter. Interestingly, these amphiphiles are able to change their polarity from hydrophobic to hydrophilic by irradiation and, therefore facilitate the transfer of the particles from non-aqueous to aqueous media by light-induced processes. In Chapter 11 and Chapter 12, Prud’homme’s group is presenting several applications of inverse flash nanoprecipitation iFNP. This recently developed scalable, controllable, and reproducible process is able to generate nanoparticles highly loaded (typically > 50 wt%) with water soluble molecules, such as proteins and therapeutic peptides. Poly(n-butyl acrylate)-b-poly(acrylic acid) (PBA-b-PAA) and poly(acrylic acid)-b-poly(styrene) (PAA-b-PS) have been used as the stabilizing polymers of these “inverted” nanoparticles, and authors demonstrate an excellent control of nanoparticle size in between 40 and 300 nm. Results of iFNP of biologics with different charges and molecular weights are presented, together with the formulation parameters used in each case. Since the nanoparticles produced by iFNP have a hydrophilic core and hydrophobic corona and are dispersed in organic solvents, further stabilization processing is typically required before they can be further processed for applications in aqueous environments. Stabilization is achieved by ionically gelling the poly(acrylic acid) core with metal cations such as Ca2+, Zn2+, and Fe3+. A 1H-NMR method was developed to evaluate the crosslinking efficiency, which allowed the analysis of efficiency of different metal ions at crosslinking the particle core. The effect of solvent and salt on crosslinking was also investigated and is presented in the first chapter authored by the team. The second chapter from the same group deals with the process of assembling the inverse nanoparticles into microparticles and presents an extraction-based protocol used to rapidly evaluate the impact of iFNP formulation parameters on process losses without the added complexity of producing microparticles. The authors determined that major parameters xii Ilies; Control of Amphiphile Self-Assembling at the Molecular Level: Supra-Molecular Assemblies with Tuned ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


impacting the extraction process are the external osmotic pressure and, for larger biologics, the crosslinking density. Using optimized formulation conditions the team managed to generate microparticles with a target loading of 25% of a model biologic at greater than 90% encapsulation efficiency. The last chapter (Chapter 13), from Ma and Suh, presents an overview of cell penetrating peptides (CPPs) as natural amphiphiles able to readily translocate across the cell membranes. Authors are reviewing all classes of CPPs and their cell-entry mechanisms, and also the published pre-clinical and clinical trials using these natural amphiphiles. Structure-activity relationships are also presented, revealing a strong dependence of properties and uptake mechanism on the amino acid sequence, which dictates the CPP secondary structure and overall interactions with the phospholipid bilayer. The book includes contributing authors from U.S., Europe and Asia, which I believe are at the forefront of their fields of study, providing the reader an upto-date, broad perspective on the latest concepts and technologies related with design, synthesis and characterization of amphiphile self-assemblies and their use as delivery systems for drugs and nucleic acids. The editor is thankful to all scientists who performed the peer-review of the chapters of this book and thus contributed significantly to the improvement of their quality. The professional support from ACS Books - Elizabeth Hernandez, Bob Hauserman, Tracey Glazener, Arlene Furman, Sara Tenney – is gratefully acknowledged. The editor acknowledges Temple University School of Pharmacy - Dr. Peter H. Doukas, Dean - for supporting the ACS Symposium and the development of this book.

Marc A. Ilies Temple University School of Pharmacy Department of Pharmaceutical Sciences Philadelphia, Pennsylvania, United States

xiii Ilies; Control of Amphiphile Self-Assembling at the Molecular Level: Supra-Molecular Assemblies with Tuned ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

Preface

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