Recombinant protein-based polymers for advanced drug delivery

Advances in recombinant techniques have led to the development of genetically engineered polymers with exquisite control over monomer sequence and polymer length. The ability to study how precise structures correlate with function has provided opportunities for the utility of these polymers in drug delivery. Chemically derived and developed methods of synthesis have yielded many useful polymers for drug delivery to-date, including those currently used in patients. However they have drawbacks, including limitations involved in statistical characterization of conventional polymer synthetic techniques. Encoding at the genetic level and production of such recombinant polymers in organisms allow for precise order and accuracy of amino acid residues and production of monodisperse polymers with specific function and physicochemical properties. Research into elastin-like, silk-like, and silk-elastinlike protein polymers for example has led to the development of delivery systems based on natural motifs of structural proteins to take advantage of their physicochemical properties. Additionally, protein based polymers on other natural motifs and de novo designs are starting to produce promising constructs for drug and gene delivery applications where precise control over structure promises correlation with function and guides the development of new and improved constructs. Clinical applications based on recombinant polymers for delivery of bioactive agents have not been realized at this point. However lessons learned from fundamental research with these polymers can be used to guide design of safe and effective systems for use in the clinic. This tutorial review summarizes progress made in the design and utility of recombinant polymers in drug and gene delivery and discusses challenges and future directions of such polymers for this purpose.     

Nanoscale coordination polymers for platinum-based anticancer drug delivery

Pt-containing nanoscale coordination polymer (NCP) particles with the formula of Tb2(DSCP)3(H2O)12 (where DSCP represents disuccinatocisplatin), NCP-1, were precipitated from an aqueous solution of Tb3+ ions and DSCP bridging ligands via the addition of a poor solvent. SEM and TEM images showed that as-synthesized NCP-1 exhibited a spherical morphology with a DLS diameter of 58.3 +/- 11.3 nm. NCP-1 particles were stabilized against rapid dissolution in water by encapsulation in shells of amorphous silica. The resulting silica-coated particles NCP-1' exhibited significantly longer half-lives for DSCP release from the particles (a t1/2 of 9 h for NCP-1' with 7 nm silica coating vs t1/2 of 1 h for as-synthesized NCP-1). In vitro cancer cell cytotoxicity assays with the human colon carcinoma cell line (HT-29) showed that internalized NCP-1' particles readily released the DSCP moieties which were presumably reduced to cytotoxic Pt(II) species to give the Pt-containing NCPs anticancer efficacy superior to the cisplatin standard. The generality of this degradable nanoparticle formulation should allow for the design of NCPs as effective delivery vehicles for a variety of biologically and medically important cargoes such as therapeutic and imaging agents.     

Zwitterionic polymers: Addressing the barriers for drug delivery

Nanocarriers play an important role in drug delivery for disease treatment. However, nanocarriers face a series of physiological barriers after administration such as blood clearance, nonspecific tissue/cell localization, poor cellular uptake, and endosome trapping. These physiological barriers seriously reduce the accumulation of drugs in target action site, which results in poor therapeutic efficiency. Although polyethylene glycol (PEG) can increase the blood circulation time of nanocarriers, its application is limited due to the “PEG dilemma”. Zwitterionic polymers have been emerging as an appealing alternative to PEG owing to their excellent performance in resisting nonspecific protein adsorption. Importantly, the diverse structures bring functional versatility to zwitterionic polymers beyond nonfouling. This review focuses on the structures and characters of zwitterionic polymers, and will discuss and summarize the application of zwitterionic polymers for drug delivery. We will highlight the strategies of zwitterionic polymers to address the physiological barriers during drug delivery. Finally, we will give some suggestions that can be utilized for the development of zwitterionic polymers for drug delivery. This review will also provide an outlook for this field. Our aim is to provide a comprehensive and systemic review on the application of zwitterionic polymers for drug delivery and promote the development of zwitterionic polymers.     

Stimuli responsive polymers for biomedical applications

Polymers that can respond to external stimuli are of great interest in medicine, especially as controlled drug release vehicles. In this critical review, we consider the types of stimulus response used in therapeutic applications and the main classes of responsive materials developed to date. Particular emphasis is placed on the wide-ranging possibilities for the biomedical use of these polymers, ranging from drug delivery systems and cell adhesion mediators to controllers of enzyme function and gene expression (134 references).     

Current advances in molecularly imprinted polymers and their release mechanisms in drug delivery systems

Molecularly imprinted polymer (MIP) has gained wide interest among researchers due to its unique molecular recognition of the template that is suitable as a drug carrier. Therefore, the preparation and formulation of the MIP are significant to suit the needs of the intended use. Due to its significance in drug delivery, this review aims to highlight various methods in the preparation of MIP, the composition for both controlled and stimuli-responsive drug delivery systems, and the release mechanism of the drugs. In drug delivery systems, MIP should have a sustained release performance as well as flexibility in surface modification for targeted delivery via a range of stimuli-responses, including  external stimuli (magnetic, light) and internal stimuli (pH, temperature, redox, biological). The properties of sustained release and targeted delivery of the MIP can improve the drug's therapeutic efficacy as well as the breakthrough for the tumor targeting application.     

A new approach towards acid sensitive copolymer micelles for drug delivery

A new micellar system capable of selective release of its contents under mildly acidic conditions is described.     

Catechol polymers for pH-responsive, targeted drug delivery to cancer cells

A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug-polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug-polymer conjugates. The pH-sensitive catechol-boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases.     

Therapeutic systems and controlled drug delivery

Therapeutic systems can provide pre-programmed, unattended delivery of a drug at a rate, and for a time period, established to meet a specific therapeutic need. The system can be designed to minimize the patient's intervention and to optimize compliance with the prescribed regimen. The ocular therapeutic system described here for the control of intraocular pressure in glaucoma delivers pilocarpine at 20 or 40 μg/h for one week, and fits comfortably into the cul-de-sac of the eye. The intrauterine progesterone contraceptive system described here represents a new approach to steroidal contraception that localizes the effect of the hormone progesterone to the uterus, delivering the hormone at a rate of 65 μg/day for one year. Both of these systems are designed to deliver drug into their immediate locale, and are thus topical dosage forms. The transdermal therapeutic system described here has been designed to deliver scopolamine across intact skin and into systemic blood to achieve an antinausea effect. The pharmacokinetics of scopolamine are such that, to minimize the time required for the onset of drug action, drug should be presented at an initially high rate, i.e. as a priming dose, to attain the therapeutically effective drug level, and then at a constant rate, so as to maintain the therapeutically effective level. This system functions according to the priming dose/maintenance rate design requirement.     

Cyclodextrin based novel drug delivery systems

The versatile pharmaceutical material cyclodextrin’s (CDs) are classified into hydrophilic, hydrophobic, and ionic derivatives. By the early 1950s the basic physicochemical characteristics of cyclodextrins had been discovered, since than their use is a practical and economical way to improve the physicochemical and pharmaceutical properties such as solubility, stability, and bioavailability of administered drug molecules. These CDs can serve as multi-functional drug carriers, through the formation of inclusion complex or the form of CD/drug conjugate and, thereby potentially serving as novel drug carriers. This contribution outlines applications and comparative benefits of use of cyclodextrins (CDs) and their derivatives in the design of novel delivery systems like liposomes, microspheres, microcapsules, nanoparticles, cyclodextrin grafted cellulosic fabric, hydrogels, nanosponges, beads, nanogels/nanoassemblies and cyclodextrin-containing polymers. The article also focuses on the ability of CDs to enhance the drug absorption across biological barriers, the ability to control the rate and time profiles of drug release, drug safety, drug stability, and the ability to deliver a drug to targeted site. The article highlight’s on needs, limitations and advantages of CD based delivery systems. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes.     

Overview on natural hydrophilic polysaccharide polymers in drug delivery

Nanotechnology is poised to make potentially revolutionary innovations in areas of biomedical science, such as gene therapy and drug therapy. A recently developed nanodelivery strategy involves the use of hydrophilic polymers as carriers of proteins and siRNA. By controlling the reaction conditions during polymer production, various degrees of anionic charge, cationic charge, and cross‐linking can be added, thereby changing their capabilities as protein and nucleic acid carriers and promoting effective cell membrane permeation. The efficiency of a specific controlled‐release polymeric system is determined in part by its unique physical and chemical properties and biodegradation rate. In this review, we will summarize recent progress in the ability to modify drug release of hydrophilic polymers nanoparticles.     

Lipid carrier systems for targeted drug and gene delivery

For effective chemotherapy, it is necessary to deliver therapeutic agents selectively to their target sites, since most drugs are associated with both beneficial effects and side effects. The use of lipid dispersion carrier systems, such as lipid emulsions and liposomes, as carriers of lipophilic drugs has attracted particular interest. A drug delivery system can be defined as a methodology for manipulating drug distribution in the body. Since drug distribution depends on the carrier, administration route, particle size of the carrier, lipid composition of the carrier, electric charge of the carrier and ligand density of the targeting carrier, these factors must be optimized. Recently, the lipid carrier system has also been applied to gene delivery systems for gene therapy. However, in both drug and gene medicine cases, a lack of cell-selectivity limits the wide application of this kind of drug and/or gene therapy. Therefore, lipid carrier systems for targeted drug and gene delivery must be developed for the rational therapy. In this review, we shall focus on the progress of research into lipid carrier systems for drug and gene delivery following systemic or local injection.     

Dendritic polymers: from efficient catalysis to drug delivery

Dendritic polymers constitute an intriguing class of macromolecules that offer tremendous potential in designing new materaisl for applications in areas such as catalysis and small molecule loading and delivery. Synthesis of a variety of dendritic polymers using a simple and highly versatile synthetic methodology has enabled us to carry out a detailed investigation of dendritic effects in transition metal catalyzed organic transformations. Small dye molecules such as p-nitroaninline and DR1 could be loaded into the intrinsic cavities of the backbone of 3,5-dihydroxybenzyl alcohol based dendrimers, leading to a change in physical properties of both the dye and the dendrimer. We are also exploring the use of dendrimers as templates to prepare network carriers containing cavities of predetermined size and disposition.     

Controlled drug delivery systems based on calixarenes

Recent advances on calixarene-based drug delivery systems in the form of inclusion complexes, amphiphilic self-assembly nanocarriers including micelles, hydrogels, vesicles and liposomes, and supramolecular nanovalves on mesoporous silicas, were reviewed and discussed.     

Temperature and pH dual‐sensitive polyaspartamide derivatives for antitumor drug delivery

The pH‐sensitive tertiary amino groups were introduced to synthesize temperature and pH dual‐sensitive degradable polyaspartamide derivatives (phe/DEAE‐g‐PHPA) containing pendant aromatic structures and ionizable tertiary amino groups. The thermo/pH‐responsive behavior of phe/DEAE‐g‐PHPA polymer can be tuned by adjusting the graft copolymer composition. Due to the pH sensitivity of the phe/DEAE‐g‐PHPA‐g‐mPEG polymer with hydrophilic long PEG chain, the micelles and the anticancer drug‐loaded micelles were prepared by a quick pH‐changing method without using toxic organic solvent. The obtained polymeric micelles, paclitaxel‐loaded micelles and doxorubicin‐loaded micelles were stable under physiological conditions. Both the drug‐loaded micelles showed much faster release at pH 5 than at pH 7.4. The doxorubicin‐loaded micelles showed obvious and better anticancer activity against both HepG2 and HeLa cells than free doxorubicin. Thus these nontoxic, dual thermo‐ and pH‐sensitive phe/DEAE‐g‐PHPA‐g‐mPEG micelles may be a promising anticancer drug delivery system. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 879–888     

Two sides to supramolecular drug delivery systems

Although still in its infancy, there is a rapidly increasing interest in the development of supramolecular drug delivery systems (SDDSs). As chemists, the most challenging task ahead of us is to narrow the gap between SDDSs development in the lab, and clinical drug carriers. Only then will we achieve our ultimate goal of the successful translation of SDDSs to life saving medicines.     

Exosome-based drug delivery systems in cancer therapy

Exosome, which is a kind of extracellular vesicles with size around 40-160 nm, plays an important role in cell-to-cell communication in multiple diseases. Especially in tumor microenvironment, exosomes are the important pathway to transit proteins, nucleic acids and small molecules between different kinds of cells. Based on these characteristics, exosomes are served as both therapeutic agents and drug delivery systems in cancer therapy. In this review, the applications of exosomes as drug delive...     

Molecular-scale drug delivery systems loaded with oxaliplatin for supramolecular chemotherapy

Smart strategies that can decrease the side effect and enhance the therapeutic efficacy of chemotherapy are in urgent need to meet the special demands of cance r therapy.Herein,two wate r-soluble macrocyclic hosts,i.e.,a carboxylated leaning tower[6]arene(CLT6) and a carboxylated [2]biphenyl-extended pillar[6]arene(CBpP6),are used to load chemotherapy drug oxaliplatin(OxPt) by forming inclusion complexes(OxPt■CLT6 and OxPt■CBpP6) through host-guest interactions.Interestingly,OxPt can be released from the macrocyclic cavities of these drug delivery systems(DDSs) via the competitive binding effect of spermine(SPM) because of the stronger binding abilities of CLT6/CBpP6 toward SPM as compared with OxPt,leading to enhanced cytotoxicity on SPM-overexpressed cancer cells,such as breast cancer MCF-7 cells.Moreover,compared to free OxPt,due to the low concentration of SPM in normal cells,OxPt■CGT6 and OxPt■CBpP6 demonstrated a decreased cytotoxicity on liver L02 cells,which is beneficial fo r reducing the side effect of anticancer drug during chemotherapy.Such a strategy might be extended to other antitumor drugs and water-soluble macrocycles with suitable cavity sizes to achieve controllable drug delivery and enhanced anticancer ability in supramolecular chemotherapy