Conjugates For Drug Delivery Research Articles

Self-assembly of protein-polymer conjugates for drug delivery

Protein-polymer conjugates are a class of molecules that combine the stability of polymers with the diversity, specificity, and functionality of biomolecules. These bioconjugates can result in hybrid materials that display properties not found in their individual components and can be particularly relevant for drug delivery applications. Engineering amphiphilicity into these bioconjugate materials can lead to phase separation and the assembly of high-order structures. The assembly, termed self-assembly, of these hierarchical structures entails multiple levels of organization: at each level, new properties emerge, which are, in turn, influenced by lower levels. Here, we provide a critical review of protein-polymer conjugate self-assembly and how these materials can be used for therapeutic applications and drug delivery. In addition, we discuss central bioconjugate design questions and propose future perspectives for the field of protein-polymer conjugate self-assembly.

Peptide-Chitosan Engineered Scaffolds for Biomedical Applications

Peptides are signaling epitopes that control many vital biological events. Increased specificity, synthetic feasibility with concomitant lack of toxicity, and immunogenicity make this emerging class of biomolecules suitable for different applications including therapeutics, diagnostics, and biomedical engineering. Further, chitosan, a naturally occurring linear polymer composed of d-glucosamine and N-acetyl-d-glucosamine units, possesses anti-microbial, muco-adhesive, and hemostatic properties along with excellent biocompatibility. As a result, chitosan finds application in drug/gene delivery, tissue engineering, and bioimaging. Despite these applications, chitosan demonstrates limited cell adhesion and lacks biosignaling. Therefore, peptide-chitosan hybrids have emerged as a new class of biomaterial with improved biosignaling properties and cell adhesion properties. As a result, recent studies encompass increased application of peptide-chitosan hybrids as composites or conjugates in drug delivery, cell therapy, and tissue engineering and as anti-microbial material. This review discusses the recent investigations involving chitosan-peptide materials and uncovers various aspects of these interesting hybrid materials for biomedical applications.

Effects of the Molecular Weight of Hyaluronic Acid in a Carbon Nanotube Drug Delivery Conjugate

Hyaluronic acid (HA) is a ubiquitous biopolymer involved in many pathophysiological roles. One HA receptor, the cluster of differentiation CD44 protein, is often overexpressed in tumor cells. As such, HA has attracted considerable interest in the development of drug delivery formulations, given its intrinsic targetability toward CD44 overexpressing cells. The present study is focused on examining the correlation of HA molecular weight with its targetability properties. A library of conjugates obtained by linking the amino group of the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) to the carboxylic residues of HA of different molecular weight (6.4, 17, 51, 200, and 1,500 kDa) were synthesized and fully characterized. The HA-DMPE conjugates were then used to non-covalently functionalize the highly hydrophobic single-walled carbon nanotubes (CNT), and further encapsulate the anticancer drug doxorubicin (DOX). Our results show that the complexes DOX/CNT/HA-DMPE maintain very good and stable dispersibility. Drug release studies indicated a pH-responsive release of the drug from the nanocarrier. Cell viability tests demonstrated that all HA modified CNTs have good biocompatibility, and specific targeting toward cells overexpressing the CD44 receptor. Among all the molecular weights tested, the 200 kDa HA showed the highest increase in cellular uptake and cytotoxic activity. All these promising attributes make CNT/HA200-DMPE a “smart” platform for tumor-targeted delivery of anticancer agents.

Tracking the Footprints of Paclitaxel Delivery and Mechanistic Action via SERS Trajectory in Glioblastoma Cells.

The design and development of an efficacious tumor-specific drug-delivery system is a challenging task. In this study, we have synthesized target-specific small peptide substrates on an octaguanidine sorbitol scaffold, named small molecular targeted drug-delivery conjugate (SMTDDC). The SMTDDC fabrication, with dual targeting cRGD and Cathepsin B (Cath B)-specific tripeptide (Glu-Lys-Phe), altered the microtubule network of glioblastoma cells by the orchestrated release of the cytotoxic paclitaxel (PTX). Cath B assisted PTX delivery was monitored by high-performance liquid chromatography and Surface-Enhanced Raman Scattering (SERS) modalities. The time-dependent SERS fingerprinting and imaging revealed a fast and accurate PTX release profile and subsequent in vitro cytotoxicity as well as the apoptotic events and microtubule network alteration in U-87 MG glioblastoma cells. Furthermore, SMTDDC displayed adequate stability under physiological conditions and demonstrated biocompatibility toward red blood cells and lymphocytes. This study indicated a new insight on SERS-guided peptidomimetic sorbitol molecular transporter, enabling a greater promise with high potential for the further development of PTX delivery in glioblastoma treatment.

Microparticles of Lamivudine-Poly-ε-Caprolactone Conjugate for Drug Delivery via Internalization by Macrophages.

The past decade may be considered as revolutionary in the research field focused on the physiological function of macrophages. Unknown subtypes of these cells involved in pathological mechanisms were described recently, and they are considered as potential drug delivery targets. The innate ability to internalize foreign bodies exhibited by macrophages can be employed as a therapeutic strategy. The efficiency of this uptake depends on the size, shape and surface physiochemical properties of the phagocyted objects. Here, we propose a method of preparation and preliminary evaluation of drug-polymer conjugate-based microspheres for macrophage targeted drug delivery. The aim of the study was to identify crucial uptake-enhancing parameters for solid, surface modified particles. A model drug molecule—lamivudine—was conjugated with poly-ε-caprolactone via ring opening polymerization. The conjugate was utilized in a solvent evaporation method technique to form solid particles. Interactions between particles and a model rat alveolar cell line were evaluated by flow cytometry. The polymerization product was characterized by a molecular weight of 3.8 kDa. The surface of the obtained solid drug-loaded cores of a hydrodynamic diameter equal to 2.4 µm was modified with biocompatible polyelectrolytes via a layer-by-layer assembly method. Differences in the internalization efficiency of four particle batches by the model RAW 264.7 cell line suggest that particle diameter and surface hydrophobicity are the most influential parameters in terms of phagocytic uptake.

DNA Oligonucleotide-Functionalized Liposomes: Bioconjugate Chemistry, Biointerfaces, and Applications.

Interfacing DNA with liposomes has produced a diverse range of programmable soft materials, devices, and drug delivery vehicles. By simply controlling liposomal composition, bilayer fluidity, lipid domain formation, and surface charge can be systematically varied. Recent development in DNA research has produced not only sophisticated nanostructures but also new functions including ligand binding and catalysis. For noncationic liposomes, a DNA is typically covalently linked to a hydrophobic or lipid moiety that can be inserted into lipid membranes. In this article, we discuss fundamental biointerfaces formed between DNA and noncationic liposomes. The methods to prepare such conjugates and the interactions at the membrane interfaces are also discussed. The effect of DNA lateral diffusion on fluid bilayer membranes and the effect of membrane on DNA assembly are emphasized. DNA hybridization can be programmed to promote fusion of lipid membranes. Representative applications of this conjugate for drug delivery, biosensor development, and directed assembly of materials are briefly described toward the end. Some future research directions are also proposed to further understand this biointerface.

Site-Specific Conjugation of Polymers to Proteins.

Conjugation of polymer to protein has been widely employed in therapeutics, medicine, biotechnology, and enzymatic catalysis. The synergistic effect benefits both counterparts and potentially overcomes their inherent limitations. This article reviews the strategies for the site-specific synthesis of well-defined protein-polymer conjugates, aiming to provide a toolbox for the community. First, it is essential to set a definite reactive site on the protein because the position of the reaction site can directly influence the reaction activity and the bioactivity of the protein after modification. The origins of the specific functional groups on protein include the utilization of the unique natural amino acid, mutagenesis to introduce a sole reactive amino acid, chemical modification, noncanonical amino acid incorporation, and enzyme-mediated introduction of functional groups. Second, the main conjugation methods, i.e., "grafting to" and "grafting from" methods, are summarized and compared with each other. In the "grafting to" method, a comprehensive investigation on the reactions used to attach an end functional polymer chain to a protein is conducted according to the position of the target site and its nature. In the "grafting from" method, a comparison between the commonly used controlled polymerization, i.e., atom transfer radical polymerization (ATRP) and reversible addition-fragmentation transfer (RAFT), is surveyed. Further, a special case where a noncovalent bond is adopted to link the protein and polymer together is investigated due to its high specificity and reversibility, typically biotin-(strept)avidin-based interactions and metal-mediated conjugation. Finally, applications of protein-polymer conjugates in drug delivery, biomedicine, biosensor, and the disease-related protein self-assembly are illustrated. This precise review on the conjugation of polymer chain to protein to form well-defined protein-polymer conjugates summarizes the representative strategies and may provide useful cues in the areas of biotechnology, therapeutic drugs, and biomedicine.

Synthesis, characterization, and in-vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E

Vitamin E refers to a group of saturated tocopherol (T) isomers and the biologically more active unsaturated tocotrienol (T3) isomers. PEGylated α-tocopherol, commercially known as Vitamin E TPGS, has been used as an emulsifier and therapeutic agent for children with vitamin E deficiency. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. The current work was therefore undertaken to synthesize and characterize the water soluble polyethylene glycol (PEG 350 and 1000) derivatives of T and T3. Yield and the identity of the synthesized products were confirmed by 1H NMR, mass spectroscopy, HPLC, and thermal analysis. The self-assembly of the PEGylated vitamin E isomers in water at critical micelle concentrations (CMC) was further confirmed by size, zeta, and Cryo-TEM image analysis. While stable at pH 7.4, PEG conjugates were found to rapidly hydrolyze at pH 1.2. Our data showed that PEGylated T3 isomers were significantly more active as inhibitors for P-glycoprotein than PEGylated T. The in vitro cytotoxicity of the conjugates was also tested against a large panel of normal and tumorigenic cells. Of the conjugates, γ-T3PGS 1000 and δ-T3PGS 1000 were found to have the least toxicity against non-tumorigenic breast and pancreatic cell lines, which may be advantageous for its use as functional excipients in drug delivery. The results from the current work have demonstrated the feasibility of synthesizing PEGylated conjugates of vitamin E isomers and highlighted the potential use of these conjugates in drug delivery as functional and safer excipients especially for γ-T3PGS 1000 and δ-T3PGS 1000 conjugate.

Dendrimer-drug Conjugates in Drug Delivery and Targeting

Background: Conjugation of several bio-actives to macromolecular nanocarriers is a promising approach to improve the efficiency and reduce side effects. Dendrimer represents a novel class of synthetic nanocarriers, comprised of different branched materials with tailor-made functionalities to conjugate wide varieties of bioactive molecules, therapeutic agents and different pharmacological substances including antibodies, ligands etc. Such opportunistic properties has been equally explored for the purpose of diagnostic applications as well. Methods: We have accomplished thorough bibliographic search and compilation of referred/indexed peer-reviewed literature to concisely review the above mentioned concept. The organized study was carried out concerned for dendrimer-drug conjugates employed in drug delivery and targeting to specific sites for their biological and clinical evaluation. Results: One hundred forty one papers were referred in this review after throughout literature survey. The conjugation is favorable and is easy to perform with the carriers like dendrimers due to its unique properties and multiple functional groups at the surface. The present review highlights the general properties class and applications of dendrimers in drug delivery. The focus is particularly on the dendrimer drug conjugates which are comparatively less explored area than the non-covalent dendrimer drug interactions. Conclusion: Conjugation of drugs to the dendrimers has particularly resulted into the increased drug payload and improved drug activity as evidenced by the reports discussed here in this article. Therefore in future it would be more advantageous to explore the dendrimer drug conjugation approaches for delivering drugs through dendrimers. Keywords: Conjugation, dendrimer, drug delivery, nanocarrier, targeting.

Disulfide-based multifunctional conjugates for targeted theranostic drug delivery.

Theranostics, chemical entities designed to combine therapeutic effects and imaging capability within one molecular system, have received considerable attention in recent years. Much of this interest reflects the promise inherent in personalized medicine, including disease-targeted treatments for cancer patients. One important approach to realizing this latter promise involves the development of so-called theranostic conjugates, multicomponent constructs that selectively target cancer cells and deliver cytotoxic agents while producing a readily detectable signal that can be monitored both in vitro and in vivo. This requires the synthesis of relatively complex systems comprising imaging reporters, masked chemotherapeutic drugs, cleavable linkers, and cancer targeting ligands. Ideally, the cleavage process should take place within or near cancer cells and be activated by cellular components that are associated with cancer states or specifically expressed at a higher level in cancer cells. Among the cleavable linkers currently being explored for the construction of such localizing conjugates, disulfide bonds are particularly attractive. This is because disulfide bonds are stable in most blood pools but are efficiently cleaved by cellular thiols, including glutathione (GSH) and thioredoxin (Trx), which are generally found at elevated levels in tumors. When disulfide bonds are linked to fluorophores, changes in emission intensity or shifts in the emission maxima are typically seen upon cleavage as the result of perturbations to internal charge transfer (ICT) processes. In well-designed systems, this allows for facile imaging. In this Account, we summarize our recent studies involving disulfide-based fluorescent drug delivery conjugates, including preliminary tests of their biological utility in vitro and in vivo. To date, a variety of chemotherapeutic agents, such as doxorubicin, gemcitabine, and camptothecin, have been used to create disulfide-based conjugates, as have a number of fluorophores, including naphthalimide, coumarin, BODIPY, rhodol, and Cy7. The resulting theranostic core (drug-disulfide-fluorophore) can be further linked to any of several site-localizing entities, including galactose, folate, biotin, and the RGD (Arg-Gly-Asp) peptide sequence, to create systems with an intrinsic selectivity for cancer cells over normal cells. Site-specific cleavage by endogenous thiols serves to release the cytotoxic drug and produce an easy-to-monitor change in the fluorescence signature of the cell. On the basis of the results summarized in this Account, we propose that disulfide-based cancer-targeting theranostics may have a role to play in advancing drug discovery efforts, as well as improving our understanding of cellular uptake and drug release mechanisms.

Liposomal conjugates for drug delivery to the central nervous system.

Treatments of central nervous system (CNS) diseases often fail due to the blood–brain barrier. Circumvention of this obstacle is crucial for any systemic treatment of such diseases to be effective. One approach to transfer drugs into the brain is the use of colloidal carrier systems—amongst others, liposomes. A prerequisite for successful drug delivery by colloidal carriers to the brain is the modification of their surface, making them invisible to the reticuloendothelial system (RES) and to target them to specific surface epitopes at the blood–brain barrier. This study characterizes liposomes conjugated with cationized bovine serum albumin (cBSA) as transport vectors in vitro in porcine brain capillary endothelial cells (PBCEC) and in vivo in rats using fluorescently labelled liposomes. Experiments with PBCEC showed that sterically stabilized (PEGylated) liposomes without protein as well as liposomes conjugated to native bovine serum albumin (BSA) were not taken up. In contrast, cBSA-liposomes were taken up and appeared to be concentrated in intracellular vesicles. Uptake occurred in a concentration and time dependent manner. Free BSA and free cBSA inhibited uptake. After intravenous application of cBSA-liposomes, confocal fluorescence microscopy of brain cryosections from male Wistar rats showed fluorescence associated with liposomes in brain capillary surrounding tissue after 3, 6 and 24 h, for liposomes with a diameter between 120 and 150 nm, suggesting successful brain delivery of cationized-albumin coupled liposomes.

Translating Nanotechnology from Bench to Pharmaceutical Market: Barriers, Success, and Promises

Nanotechnology is a buzzword of this millennium and it has transformed the face of research in science and technology. The advent of nanotechnology has also influenced the biomedical and pharmaceutical research since last decade. Various nano-architectures have been designed for improving the therapeutic performance of drugs, proteins, peptides, and genes and to achieve their targeting at the site of action. Although nanotechnology has demonstrated dramatic potential in drug delivery research, like any technology, its real success depends on the ability of drug delivery scientists to translate and scale innovations to the commercial pharmaceutical products. It is indeed a very challenging task to successfully overcome manufacturing, clinical, and regulatory hurdles associated with a nanotech product. Nevertheless, the pharmaceutical industry has witnessed commercialization of the nanotechnology-based products for various applications. In the present special issue, we have tried to consolidate various aspects of existing and upcoming nanotechnologies for drug delivery. Contribution by V. Morigi et al. takes an overview of business potential and market trend of pharmaceutical nanotechnology. The authors have also discussed financial aspects of nanotechnology by citing noteworthy examples of few nanotech products that have already been commercialized. This contribution could be useful to scientists aiming to start up nanotechnological business ventures. Contribution by N. Anton et al. demonstrates how nanotechnology can change the face of conventional drug delivery systems. In this interesting investigation, the authors demonstrate that coating of conventional tablets with lipid nanoemulsion can be used to modulate the release of the drug from tablet matrix. The paper by P. Severino et al. gives an account of potential of solid lipid nanocarriers for the oral delivery of drugs and peptides. The authors have provided information about the lipids that can be used for oral delivery, role of lipids in the oral delivery, toxicological aspects of lipid nanocarriers, and products under clinical development. S. Banerjee et al. have given a complete overview of polyethylene-glycol- (PEG-) based conjugates for drug delivery. The contribution fosters understanding design aspects of and chemistry behind PEG-based nano-architectures for drug delivery. Furthermore, the paper has a detailed discussion on the various PEG-conjugates available in the pharmaceutical market. Contribution by A. Garcia et al. highlights the potential of particle replication in nonwetting templates (PRINT), a platform technology based on lithographic techniques for drug delivery applications. The contribution clearly demonstrates potential of PRINT technology to generate particles of various, but precise, morphology for a variety of drugs and biotechnology-based therapeutics (proteins and siRNA). The application of PRINT technology for generating aerosols for pulmonary applications has also been described. This contribution is an example of the attributes required from a nanofabrication technique to circumvent manufacturing-related issues in pharmaceutical nanotechnology. The paper by F. Lallemand et al. delineates various aspects of and challenges in ocular drug delivery and systematically describes development of Novasorb, a cationic nanoemulsion-based platform ocular delivery system. The authors have furnished a detailed description of the formulation development aspects and ocular safety of excipients which is followed by in vivo proof-of-concept and clinical development. This paper gives clear insight into various challenges faced for developing nanomedicine for ocular delivery. The paper by J. D. Heidel and T. Schleup throws light on the various applications of self-assembled nanocarriers consisting of cyclodextrin based polymers. The authors describe various developmental aspects of two platforms based on cyclodextrin-based polymers (Cyclosert and RONDEL) which can enable efficient delivery of drugs or nucleic-acid-based therapeutics. The translational aspects of both the nanocarriers and in vivo proof-of-concept have also been furnished in this paper. The research paper by J. Rios-Doria et al. gives insight into developmental aspects of a pH sensitive cross-linked polymeric micelle technology (IVECT). The authors describe synthesis of the polymeric micelles, their ability to encapsulate various drugs, and in vivo proof-of-concept for anticancer drugs like daunorubicin and BB4007431. In a nutshell, we believe that this special issue would give readers insight into various aspects involved in translating nanotechnology from bench to pharmaceutical market. Moreover, the special issue also includes some contributions about nanotechnologies that are currently under clinical development. Abhijit A. Date Rajesh R. Patil Riccardo Panicucci Eliana B. Souto Robert W. Lee

Effect of Gold Nanoparticle Conjugation on Peptide Dynamics and Structure

Molecular dynamics simulations were used to characterize the structure and dynamics for several peptides and the effect of conjugating them to a gold nanoparticle. Peptide structure and dynamics were compared for two cases: unbound peptides in water, and peptides bound to the gold nanoparticle surface in water. The results show that conjugating the peptides to the gold nanoparticle usually decreases conformational entropy, but sometimes increases entropy. Conjugating the peptides can also result in more extended structures or more compact structures depending on the amino acid sequence of the peptide. The results also suggest that if one wishes to use peptide-nanoparticle conjugates for drug delivery it is important that the peptides contain secondary structure in solution because in our simulations the peptides with little to no secondary structure adsorbed to the nanoparticle surface.

Polymeric Conjugates for Drug Delivery

The field of polymer therapeutics has evolved over the past decade and has resulted in the development of polymer-drug conjugates with a wide variety of architectures and chemical properties. Whereas traditional non-degradable polymeric carriers such as poly(ethylene glycol) (PEG) and N-(2-hydroxypropyl methacrylamide) (HPMA) copolymers have been translated to use in the clinic, functionalized polymer-drug conjugates are increasingly being utilized to obtain biodegradable, stimuli-sensitive, and targeted systems in an attempt to further enhance localized drug delivery and ease of elimination. In addition, the study of conjugates bearing both therapeutic and diagnostic agents has resulted in multifunctional carriers with the potential to both "see and treat" patients. In this paper, the rational design of polymer-drug conjugates will be discussed followed by a review of different classes of conjugates currently under investigation. The design and chemistry used for the synthesis of various conjugates will be presented with additional comments on their potential applications and current developmental status.

Microfluidic approach for highly efficient synthesis of heparin-based bioconjugates for drug delivery

This paper demonstrates the highly efficient synthesis of amphiphilic heparin-folic acid-retinoic acid (HFR) bioconjugates with a high drug coupling ratio by a microfluidic approach. The microfluidic synthesis enabled the conjugation of 17 molecules of retinoic acid to each heparin chain with 21 possible groups for attachment after reacting for several minutes. In contrast, about 11 molecules of the drug were covalently conjugated to one heparin chain after 4 days in the bulk reaction. The microfluidic based-HFR bioconjugates readily self-assembled in aqueous media to form uniform nanoparticles, while the product from the bulk reaction formed non-uniform nanoparticles with broad size distribution. The HFR nanoparticles with high drug content effectively delivered the drug to folate receptor-positive cancer cells with superior cellular uptake and selective cytotoxicity in vitro compared to HFR nanoparticles synthesized in bulk reaction. With the ability to achieve high drug content in heparin carrier within a short reaction time, the microfluidic technique offers new alternatives for the efficient synthesis of polymer-based conjugates for drug delivery.

Vitamin B12 in drug delivery: breaking through the barriers to a B12 bioconjugate pharmaceutical

Importance of the field: Vitamin B12 (B12) is a rare and vital micronutrient for which mammals have developed a complex and highly efficient dietary uptake system. This uptake pathway consists of a series of proteins and receptors, and has been utilized to deliver several bioactive and/or imaging molecules from 99mTc to insulin.Areas covered in this review: The current field of B12-based drug delivery is reviewed, including recent highlights surrounding the very pathway itself.What the reader will gain: Despite over 30 years of work, no B12-based drug delivery conjugate has reached the market-place, hampered by issues such as limited uptake capacity, gastrointestinal degradation of the conjugate or high background uptake by healthy tissues. Variability in dose response among individuals, especially across ageing populations and slow oral uptake (several hours), has also slowed development and interest.Take home message: This review is intended to stress again the great potential, as yet not fully realized, for B12-based therapeutics, tumor imaging and oral drug delivery. This review discusses recent reports that demonstrate that the issues noted above can be overcome and need not be seen as negating the great potential of B12 in the drug delivery field.

Poly(amidoamine) dendrimer-erythromycin conjugates for drug delivery to macrophages involved in periprosthetic inflammation

Erythromycin (EM), an antibiotic that has been used for infectious diseases, is now gaining attention because of its novel anti-inflammatory effects. We explore a dendrimer-EM nanodevice for sustained treatment of orthopedic inflammation. To sustain pharmacological activity, EM was conjugated to poly(amidoamine) dendrimer (PAMAM) through an ester bond. A bifunctional PAMAM dendrimer was prepared having neutral hydroxy and reactive amine groups on the surface and was reacted with EM prodrug (EM-2′-glutarate). The cytotoxicity, efficacy and antibacterial properties were evaluated on macrophages (RAW 264.7 cells) associated with periprosthetic inflammation. The conjugate is noncytotoxic and showed significant reduction of nitrite level (by 42% as compared with untreated cells and free EM). The zone of inhibition of the conjugate on bacterial growth at different concentrations showed similar activity compared to free EM. The anti-inflammatory properties of EM combined with the targeting potential of the dendrimer can lead to sustained and targeted intracellular delivery. From the Clinical Editor In this study, a specific dendrimer-erythromycin conjugate nanodevice is investigated for the treatment of periprosthetic inflammation. The anti-inflammatory properties of erythromycin combined with the targeting potential of the dendrimer can lead to sustained and targeted intracellular delivery.

Injectable biodegradable hydrogels composed of hyaluronic acid–tyramine conjugates for drug delivery and tissue engineering

The sequential injection of hyaluronic acid-tyramine conjugates and enzymes forms biodegradable hydrogels in vivo by enzyme-induced oxidative coupling, offering high potential as a promising biomaterial for drug delivery and tissue engineering.

Ternary Conjugates as a Result of Exchange Reactions Between Polyelectrolyte Complexes and Surfactants: Formation and Stability

AbstractSummary: The exchange of sodium polymethacrylate (Na‐PMA) for anionic surfactant sodium dodecylsulfate (SDS) in a polyelectrolyte complex of Na‐PMA and poly(L‐lysine) (PLL) was studied by light scattering techniques. The exchange reaction proceeds inside the complex particles without any aggregation. It causes swelling of the particles and the formation of thick polymer shell around them. In order to prove the formation of the shell, the colloidal stability of the particles in salt solutions was studied. The addition of SDS to a complex solution dramatically increases colloid stability. The stability was found to be independent of the mixing ratio of the initial complex, depending only on the molecular weight of Na‐PMA and slowly decreasing with time. The mechanism of the exchange reaction was proposed. The addition of SDS causes fast substitution of charged units of Na‐PMA for surfactant molecules in the complex and formation of the PLL/SDS complex stabilized by hydrophobic interactions between aliphatic chains of SDS. The Na‐PMA chains cannot be released sufficiently fast from the particles due to entanglements of the chains inside the particles. They build a thick stabilizing shell around the particles and lead to their swelling. This shell protects the particles against coagulation at relatively high salt concentrations. However, such state of the particles does not correspond to thermodynamic equilibrium. Na‐PMA is very slowly released from the particles, decreasing the density of stabilizing shell and stability of the particles in salt solutions. The possible application of ternary conjugates in drug delivery is discussed.Schematic representation of changes in structure and stability of Na‐PMA/PLL complex particles upon the exchange of polyanion Na‐PMA for negatively charged surfactant SDS.magnified imageSchematic representation of changes in structure and stability of Na‐PMA/PLL complex particles upon the exchange of polyanion Na‐PMA for negatively charged surfactant SDS.

Extending nature's leads: the anticancer agent ellipticine.

The natural plant product ellipticine was isolated in 1959 from the Australian evergreen tree of the Apocynaceae family. This compound was found to be an extremely promising anticancer drug. The planar polycyclic structure was found to interact with DNA through intercalation, exhibiting a high DNA binding affinity (10(6) M(-1)). The presence of protonatable ring nitrogens distinguished ellipticine from other simple intercalators. Both monocationic and uncharged species were found to be present under physiological conditions. The positive charge stabilized the binding of ellipticine to nucleic acids, while the more lipophilic uncharged compound was shown to readily penetrate membrane barriers. The structural nature of these compounds offers a plausible basis for the implication of multiple modes of action, including DNA binding, interactions with membrane barriers, oxidative bioactivation and modification of enzyme function; most notably that of topoisomerase II and telomerase. Pharmacologically, a number of toxic side effects have been shown to be problematic, but the amenability of ellipticine towards systematic structural modification has permitted the extensive application of rational drug design. A number of successful ellipticine analogs have been designed and synthesized with improved toxicities and anticancer activities. More recently the synthetic focus has broadened to include the design of hybrid compounds, as well as drug delivery conjugates. Considerable research efforts have been directed towards gaining a greater understanding of the mechanism of action of these drugs that will aid further in the optimization of drug design.