Mariusz Skwarczynski

Polyacrylate Dendrimer Nanoparticles: A Self‐Adjuvanting Vaccine Delivery System

(Figure Presented) Special delivery: An effective group A streptococci vaccine is formed from a delivery device consisting of well-defined dendritic structures with nanoscale dimensions (see picture). The structures are designed to display multiple copies of the minimal B-cell epitopes, which were in the optimal conformation on the surface of the nanoparticles. The nanoparticles can be administered without the aid of an adjuvant.

Peptide-Based Subunit Nanovaccines

Classical vaccines incorporating live or attenuated microorganisms possess several disadvantages and cannot be applied against cancer and some pathogens. Modern vaccines utilizing immunogenic subunits derived from a particular pathogen are able to overcome these obstacles but need a specific delivery system for their efficacy. Nanotechnology has opened a new window into these delivery methodologies. A nano-sized formulation of subunit vaccines has been proven to be very effective in inducing cellular and humoral immune responses. Here, we review a number of peptide vaccine delivery strategies based on nanoparticles composed of polymers, peptides, lipids, and inorganic materials.

Recent progress in adjuvant discovery for peptide-based subunit vaccines

Peptide-based subunit vaccines are of great interest in modern immunotherapy as they are safe, easy to produce and well defined. However, peptide antigens produce a relatively weak immune response, and thus require the use of immunostimulants (adjuvants) for optimal efficacy. Developing a safe and effective adjuvant remains a challenge for peptide-based vaccine design. Recent advances in immunology have allowed researchers to have a better understanding of the immunological implication of related diseases, which facilitates more rational design of adjuvant systems. Understanding the molecular structure of the adjuvants allows the establishment of their structure-activity relationships which is useful for the development of next-generation adjuvants. This review summarizes the current state of adjuvants development in the field of synthetic peptide-based vaccines. The structural, chemical and biological properties of adjuvants associated with their immunomodulatory effects are discussed.

O-N intramolecular acyl migration reaction in the development of prodrugs and the synthesis of difficult sequence-containing bioactive peptides

NOintramolecular acyl migration in Ser‐ or Thr‐containing peptides is a well‐known side reaction in peptide chemistry. It results in the mutual conversion of ester and amide bonds. Our medicinal chemistry study focused on the fact that the O‐acyl product can be readily converted to the original N‐acyl form under neutral or slightly basic conditions in an aqueous buffer and the liberated ionized amino group enhances the water solubility of O‐acyl products. Because of this, we have developed a novel class of “ON intramolecular acyl migration”‐type water‐soluble prodrugs of HIV‐1 protease inhibitors. These prodrugs released the parent drugs via a simple chemical mechanism with no side reaction. In this study, we applied this strategy to important cancer chemotherapeutic agents, paclitaxel and its derivatives, to develop water‐soluble taxoid prodrugs, and found that these prodrugs, 2′‐O‐isoform of taxoids, showed promising results with higher water solubility and proper kinetics in their parent drug formation by a simple pH‐dependent chemical mechanism with ON intramolecular acyl migration. These results suggest that this strategy would be useful in toxicology and medical economics.

Recent advances in peptide-based subunit nanovaccines

Vaccination is the most efficient way to protect humans against pathogens. Peptide-based vaccines offer several advantages over classical vaccines, which utilized whole organisms or proteins. However, peptides alone are not immunogenic and need a delivery system that can boost their recognition by the immune system. In recent years, nanotechnology-based approaches have become one of the most promising strategies in peptide vaccine delivery. This review summarizes knowledge on peptide vaccines and nanotechnology-based approaches for their delivery. The recently reported nano-sized delivery platforms for peptide antigens are reviewed, including nanoparticles composed of polymers, peptides, lipids, inorganic materials and nanotubes. The future prospects for peptide-based nanovaccines are discussed.

Accurate assay of enantiopurity of 1-hydroxy- and 2-hydroxyalkylphosphonate esters

Enantiomerically pure (Rp)-tert-butylphenylphosphinothioic acid and quinine were successfully used for the direct determination of the enantiomeric purity of diethyl 1-hydroxyalkylphosphonates. Only quinine was effective as a chiral solvating agent for the determination of the enantiomeric excess of diethyl 2-hydroxyalkylphosphonates. Copyright (C) 1996 Elsevier Science Ltd

Self-adjuvanting polyacrylic nanoparticulate delivery system for group A streptococcus (GAS) vaccine

UNLABELLED Infection with Streptococcus pyogenes, commonly known as group A Streptococcus (GAS), is responsible for acute and postinfectious complications, including rheumatic fever and rheumatic heart disease (RHD). RHD is a global health burden, and Australias indigenous population has one of the highest incidences of RHD worldwide. A potential peptide (J14) vaccine candidate has been previously identified from the C-terminal region of the M protein. However, such peptide-based vaccine development is hampered by a lack of carriers and adjuvants suitable for humans use. We have developed a fully synthetic peptide subunit vaccine candidate based on polyacrylate dendritic polymer. Intranasal administration of this nanoparticulate construct without additional adjuvant induced J14-specific IgG, which was also capable of in vitro opsonization of GAS, highlighting the potential of self-adjuvanting polyacrylate nanoparticle-based construct as a peptide vaccine delivery platform that may afford promising opportunities for treating systemic GAS infection. FROM THE CLINICAL EDITOR Polyacrylate dendrimers offer a unique approach to a nasally administered vaccine for addressing rheumatic heart disease. This paper describes the delivery of the J14 peptide, a C-terminal derivative of M-protein in group A Streptococcus.

Development of novel water-soluble photocleavable protective group and its application for design of photoresponsive paclitaxel prodrugs

A novel coumarin-based highly water-soluble photocleavable protective group was designed and synthesized, and then this photosensitive protecting group was used to design paclitaxel prodrugs. These novel paclitaxel conjugates demonstrated excellent water solubility, over 100mgmL(-1). Thus, the use of a detergent in the formulation can be omitted completely, even at high doses. Phototaxel 11 released the parent drug, paclitaxel, quickly and efficiently by minimal tissue-damaging 365nm UV light irradiation at low power, while laser activation at 355nm led to extensive decomposition of the prodrug. The carbamate-type prodrug, phototaxel 11, was stable in the dark prior to activation, whereas carbonate-type phototaxel 9 demonstrated poor stability under aqueous conditions. For such prodrugs, tumor-tissue targeting after administration could be achieved by selective light delivery, similar to that used in photodynamic therapy. In addition, newly designed coumarin derivative 8 can be applied in organic chemistry as a photosensitive protective group and for the design of caged compounds.

Peptide Conjugation via CuAAC ‘Click’ Chemistry

The copper (I)-catalyzed alkyne azide 1,3-dipolar cycloaddition (CuAAC) or ‘click’ reaction, is a highly versatile reaction that can be performed under a variety of reaction conditions including various solvents, a wide pH and temperature range, and using different copper sources, with or without additional ligands or reducing agents. This reaction is highly selective and can be performed in the presence of other functional moieties. The flexibility and selectivity has resulted in growing interest in the application of CuAAC in various fields. In this review, we briefly describe the importance of the structural folding of peptides and proteins and how the 1,4-disubstituted triazole product of the CuAAC reaction is a suitable isoster for an amide bond. However the major focus of the review is the application of this reaction to produce peptide conjugates for tagging and targeting purpose, linkers for multifunctional biomacromolecules, and reporter ions for peptide and protein analysis.

Liposome-based delivery system for vaccine candidates: constructing an effective formulation

The discovery of liposomes in 1965 by Bangham and coworkers changed the prospects of drug delivery systems. Since then, the application of liposomes as vaccine delivery systems has been studied extensively. Liposomal vaccine delivery systems are made up of nano- or micro-sized vesicles consisting of phospholipid bilayers, in which the bioactive molecule is encapsulated/entrapped, adsorbed or surface coupled. In general, liposomes are not immunogenic on their own; thus, liposomes combined with immunostimulating ligands (adjuvants) or various other formulations have been used as vaccine delivery systems. A thorough understanding of formulation parameters allows the design of effective liposomal vaccine delivery systems. This article provides an overview of various factors that influence liposomal immunogenicity. In particular, the effects of vesicle size, surface charge, bilayer composition, lamellarity, pegylation and targeting of liposomes are described.