Pectin Matrix as Oral Drug Delivery Vehicle for Colon Cancer Treatment

Colon cancer is the fourth most common cancer globally with 639,000 deaths reported annually. Typical chemotherapy is provided by injection route to reduce tumor growth and metastasis. Recent research investigates the oral delivery profiles of chemotherapeutic agents. In comparison to injection, oral administration of drugs in the form of a colon-specific delivery system is expected to increase drug bioavailability at target site, reduce drug dose and systemic adverse effects. Pectin is suitable for use as colon-specific drug delivery vehicle as it is selectively digested by colonic microflora to release drug with minimal degradation in upper gastrointestinal tract. The present review examines the physicochemical attributes of formulation needed to retard drug release of pectin matrix prior to its arrival at colon, and evaluate the therapeutic value of pectin matrix in association with colon cancer. The review suggests that multi-particulate calcium pectinate matrix is an ideal carrier to orally deliver drugs for site-specific treatment of colon cancer as (1) crosslinking of pectin by calcium ions in a matrix negates drug release in upper gastrointestinal tract, (2) multi-particulate carrier has a slower transit and a higher contact time for drug action in colon than single-unit dosage form, and (3) both pectin and calcium have an indication to reduce the severity of colon cancer from the implication of diet and molecular biology studies. Pectin matrix demonstrates dual advantages as drug carrier and therapeutic for use in treatment of colon cancer.     

蛋白质和多肽药物长效性研究进展

基于分子生物学和重组技术的发展,蛋白质和多肽已经成为一类重要的药物,但是其稳定性差,生物利用率低,半衰期短等问题也日益受到关注。本文重点介绍了一些新的给药途径和给药系统,例如鼻腔、颊等给药途径以及黏膜给药系统、透皮给药系统、缓控释技术等给药系统的进展。综述了对于蛋白质和多肽药物进行定点突变和化学修饰,以达到增加其长效性的一些新方法。     

Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology. Effective treatment of this disorder has been hampered by the lack of availability of agents that selectively target affected joint tissue. We developed a novel pH-sensitive drug delivery system of dexamethasone (Dex) based on an N-(2-hydroxypropyl)methacrylamide copolymer (P-Dex) and have shown that the delivery system specifically accumulates in inflamed joints in an animal model of arthritis. We hypothesize that the arthrotropism of the delivery system and the local acidosis-mediated drug release provide superior therapeutic efficacy and potentially reduced side effects in RA treatment. The initial in vitro drug-release study confirmed that the Dex release is indeed dependent upon the environmental pH. At pH 5, 37°C, the conjugate shows the highest level of drug release. When administered systemically in an adjuvant-induced arthritis rat model, P-Dex offers superior and longer-lasting anti-inflammatory effects compared with systemically administered free Dex. In addition, greater bone and cartilage preservation was observed with the P-Dex treatment compared with free Dex treatment. Our data indicate that the differential effect of the conjugate is related to its selective accumulation, potential macrophage-mediated retention, and pH-sensitive drug release (extracellular and intracellular) in arthritic joints. This newly developed drug delivery system provides a unique method for selective targeting of glucocorticoids to inflamed joints which may potentially reduce systemic side effects.     

Engineering of TIMP‐3 as a LAP‐fusion protein for targeting to sites of inflammation

Tissue inhibitor of metalloproteinase (TIMP)‐3 is a natural inhibitor of a range of enzymes that degrade connective tissue and are involved in the pathogenesis of conditions such as arthritis and cancer. We describe here the engineering of TIMP‐3 using a novel drug‐delivery system known as the ‘LAP technology’. This involves creating therapeutic proteins in fusion with the latency‐associated peptide (LAP) from the cytokine TGF‐? to generate proteins that are biologically inactive until cleavage of the LAP to release the therapy. LAP‐TIMP‐3 was successfully expressed in mammalian cells and the presence of the LAP resulted in a 14‐fold increase in the quantity of recombinant TIMP‐3 produced. LAP‐TIMP‐3 was latent until release from the LAP by treatment with matrix metalloproteinase when it could inhibit proteases of the adamalysins and adamalysins with thrombospondin motifs families, but not matrix metalloproteinases, indicating that this version of TIMP‐3 is a more specific inhibitor than the native protein. There was sufficient protease activity in synovial fluid from human joints with osteoarthritis to release TIMP‐3 from the LAP fusion. These results demonstrate the potential for development of TIMP‐3 as a novel therapy for conditions where upregulation of catabolic enzymes are part of the pathology.     

Computer simulation of the delivery of etanidazole to brain tumor from PLGA wafers: comparison between linear and double burst release systems

This paper presents the computer simulation results on the delivery of Etanidazole (radiosensitizer) to the brain tumor and examines several factors affecting the delivery. The simulation consists of a 3D model of tumor with poly(lactide-co-glycolide) (PLGA) wafers with 1% Etanidazole loading implanted in the resected cavity. A zero-order release device will produce a concentration profile in the tumor which increases with time until the drug in the carrier is depleted. This causes toxicity complications during the later stages of drug treatment. However, for wafers of similar loading, such release results in a higher drug penetration depth and therapeutic index as compared to the double drug burst profile. The numerical accuracy of the model was verified by the similar results obtained in the two-dimensional and three-dimensional models.     

Peptide hydrogels for affinity-controlled release of therapeutic cargo: Current and potential strategies

The development of devices for the precise and controlled delivery of therapeutics has grown rapidly over the last few decades. Drug delivery materials must provide a depot with delivery profiles that satisfy pharmacodynamic and pharmacokinetic requirements resulting in clinical benefit. Therapeutic efficacy can be limited due to short half-life and poor stability. Thus, to compensate for this, frequent administration and high doses are often required to achieve therapeutic effect, which in turn increases potential side effects and systemic toxicity. This can potentially be mitigated by using materials that can deliver drugs at controlled rates, and material design principles that allow this are continuously evolving. Affinity-based release strategies incorporate a myriad of reversible interactions into a gel network, which have affinities for the therapeutic of interest. Reversible binding to the gel network impacts the release profile of the drug. Such affinity-based interactions can be modulated to control the release profile to meet pharmacokinetic benchmarks. Much work has been done developing affinity-based control in the context of polymer-based materials. However, this strategy has not been widely implemented in peptide-based hydrogels. Herein, we present recent advances in the use of affinity-controlled peptide gel release systems and their associated mechanisms for applications in drug delivery.     

A novel vascular-targeting peptide for gastric cancer delivers low-dose TNFα to normalize the blood vessels and improve the anti-cancer efficiency of 5-fluorouracil

Various vascular-targeted agents fused with tumor necrosis factor α (TNFα) have been shown to improve drug absorption into tumor tissues and enhance tumor vascular function. TCP-1 is a peptide selected through in vivo phage library biopanning against a mouse orthotopic colorectal cancer model and is a promising agent for drug delivery. This study further investigated the targeting ability of TCP-1 phage and peptide to blood vessels in an orthotopic gastric cancer model in mice and assessed the synergistic anti-cancer effect of 5-fluorouracil (5-FU) with subnanogram TNFα targeted delivered by TCP-1 peptide. In vivo phage targeting assay and in vivo colocalization analysis were carried out to test the targeting ability of TCP-1 phage/peptide. A targeted therapy for improvement of the therapeutic efficacy of 5-FU and vascular function was performed through administration of TCP-1/TNFα fusion protein in this model. TCP-1 phage exhibited strong homing ability to the orthotopic gastric cancer after phage injection. Immunohistochemical staining suggested that and TCP-1 phage/TCP-1 peptide could colocalize with tumor vascular endothelial cells. TCP-1/TNFα combined with 5-FU was found to synergistically inhibit tumor growth, induce apoptosis and reduce cell proliferation without evident toxicity. Simultaneously, subnanogram TCP-1/TNFα treatment normalized tumor blood vessels. Targeted delivery of low-dose TNFα by TCP-1 peptide can potentially modulate the vascular function of gastric cancer and increase the drug delivery of chemotherapeutic drugs.     

S-protected thiolated chitosan: Synthesis and in vitro characterization

Purpose of the present study was the generation and evaluation of novel thiolated chitosans, so-named S-protected thiolated chitosans as mucosal drug delivery systems. Stability of all conjugates concerning swelling and disintegration behavior as well as drug release was examined. Mucoadhesive properties were evaluated in vitro on intestinal mucosa. Different thiolated chitosans were generated displaying increasing amounts of attached free thiol groups on the polymer, whereby more than 50% of these thiol groups were linked with 6-mercaptonicotinamide. Based on the implementation of this hydrophobic residue, the swelling behavior was 2-fold decreased, whereas stability was essentially improved. Their mucoadhesive properties were 2- and 14-fold increased compared to corresponding thiolated and unmodified chitosans, respectively. Release studies out of matrix tablets comprising the novel conjugates revealed a controlled release of a model peptide. Accordingly, S-protected thiomers represent a promising type of mucoadhesive polymers for the development of various mucosal drug delivery systems.     

Slow release and delivery of antisense oligonucleotide drug by self-assembled peptide amphiphile nanofibers

Antisense oligonucleotides provide a promising therapeutic approach for several disorders including cancer. Chemical stability, controlled release, and intracellular delivery are crucial factors determining their efficacy. Gels composed of nanofibrous peptide network have been previously suggested as carriers for controlled delivery of drugs to improve stability and to provide controlled release, but have not been used for oligonucleotide delivery. In this work, a self-assembled peptide nanofibrous system is formed by mixing a cationic peptide amphiphile (PA) with Bcl-2 antisense oligodeoxynucleotide (ODN), G3139, through electrostatic interactions. The self-assembly of PA-ODN gel was characterized by circular dichroism, rheology, atomic force microscopy (AFM) and scanning electron microscopy (SEM). AFM and SEM images revealed establishment of the nanofibrous PA-ODN network. Due to the electrostatic interactions between PA and ODN, ODN release can be controlled by changing PA and ODN concentrations in the PA-ODN gel. Cellular delivery of the ODN by PA-ODN nanofiber complex was observed by using fluorescently labeled ODN molecule. Cells incubated with PA-ODN complex had enhanced cellular uptake compared to cells incubated with naked ODN. Furthermore, Bcl-2 mRNA amounts were lower in MCF-7 human breast cancer cells in the presence of PA-ODN complex compared to naked ODN and mismatch ODN evidenced by quantitative RT-PCR studies. These results suggest that PA molecules can control ODN release, enhance cellular uptake and present a novel efficient approach for gene therapy studies and oligonucleotide based drug delivery.     

Chitosan matrix with three dimensionally ordered macroporous structure for nimodipine release

Three dimensionally ordered macroporous (3DOM) chitosan (3D-CS) matrix with interconnected pores in the nanometer range was developed as a drug carrier for the first time. 3D-CS was prepared using a template-assisted assembly and characterized by SEM, TGA, N(2) adsorption and FT-IR. As a model drug, nimodipine (NMDP) was incorporated into the pores of 3D-CS matrix. The solid state properties of NMDP-loaded samples were characterized by SEM, XRD, DSC and FT-IR. Dissolution studies showed that release behavior of the drug was markedly affected by the particle size of the matrix. With a relatively small matrix particle size, formulations of NMDP-3D-CS-0.5 and NMDP-3D-CS-1 exhibited rapid release patterns. However, on increasing the amount of carrier, release rate of the drug decreased. The pH-dependent slow-release characteristic of 3D-CS matrix delivery system was demonstrated by investigating the release behavior of NMDP at different pH values.     

Physical blends of starch graft copolymers as matrices for colon targeting drug delivery systems

Colon targeting drug delivery systems have attracted many researchers due to the distinct advantages they present such as near neutral pH, longer transit time and reduced enzymatic activity. Moreover, in recent studies, colon specific drug delivery systems are gaining importance for use in the treatment of local pathologies of the colon and also for the systemic delivery of protein and peptide drugs.In previous works, our group has developed different types of hydrophilic matrices with grafted copolymers of starch and acrylic monomers with a wide range of physicochemical properties which have demonstrated their ability in controlled drug release. Since the cost of synthesizing a new polymeric substance and testing for its safety is enormous, polymer physical blends are frequently used as excipients in controlled drug delivery systems due to their versatility. So, the aim of this work is to combine two polymers which offer different properties such as permeability for water and drugs, pH sensitivity and biodegradability in order to further enhance the release performance of various drugs. It was observed that these physical blend matrices offer good controlled release of drugs, as well as of proteins and present suitable properties for use as hydrophilic matrices for colon-specific drug delivery.     

In Vitro and In Vivo Evaluation of a Hydrogel Reservoir as a Continuous Drug Delivery System for Inner Ear Treatment

Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear.     

Colon Specific Delivery of Indomethacin: Effect of Incorporating pH Sensitive Polymers in Xanthan Gum Matrix Bases

In the present study, an attempt has been made to design controlled release colon-specific formulations of indomethacin by employing pH responsive polymers Eudragit (L100 or S100) in matrix bases comprised of xanthan gum. The prepared tablets were found to be of acceptable quality with low-weight variation and uniform drug content. In vitro release studies indicated rapid swelling and release of significant percentage of drug in the initial period from matrix tablets composed of xanthan gum alone. Addition of pH responsive polymers Eudragit (L100 or S100) to xanthan gum matrix resulted in negligible to very low drug release in the initial period in acidic to weakly acidic medium. Furthermore, with increase in pH of the dissolution medium due to dissolution of Eudragit L100/Eudragit S100 that resulted in the formation of a porous matrix, faster but controlled drug release pattern was observed. Thus, a sigmoidal release pattern was observed from the designed formulations suitable for colonic delivery. Drug release mechanism in all cases was found to be of super case II type, indicating erosion to be the primary cause of drug release. Since the drug release from almost all the matrix bases in the initial phase was negligibly low and followed with controlled release for about 14–16 h, it was concluded that a matrix design of this composition could have potential applications as a colon-specific drug delivery device with additional advantage of easy scale-up and avoidance of all-or-none phenomenon associated with coated colon-specific systems.     

A Review About the Drug Delivery from Microsponges

Microparticulate drug delivery systems have shown a great interest in the pharmaceutical area. They allow the increase of drug therapeutic efficacy and the reduction of side effects. In this context, microsponges represent a new model of porous polymer microspheres, which allow the entrapment of a wide range of active agents. During the development, it is necessary the characterization of the system and among of the most important tests are the release and permeation profile analysis. They can demonstrate the behavior of drug in a specific site with a particular application condition and are related to therapeutic efficacy. Therefore, this review provides an overview of drug delivery profile from microsponges. Methods for determination of in vitro release and ex vivo permeation studies are detailed. Examples of drug delivery from microsponges administered in different sites are also discussed with aim to provide an understanding of the use of this strategy to modify the drug delivery.     

Rheological Characterization and Drug Release Studies of Gum Exudates of Terminalia catappa Linn

The present study was undertaken to evaluate the gum exudates of Terminalia catappa Linn. (TC gum) as a release retarding excipient in oral controlled drug delivery system. The rheological properties of TC gum were studied and different formulation techniques were used to evaluate the comparative drug release characteristics. The viscosity was found to be dependent on concentration and pH. Temperature up to 60°C did not show significant effect on viscosity. The rheological kinetics evaluated by power law, revealed the shear thinning behavior of the TC gum dispersion in water. Matrix tablets of TC gum were prepared with the model drug dextromethorphan hydrobromide (DH) by direct compression, wet granulation and solid dispersion techniques. The dissolution profiles of the matrix tablets were compared with the pure drug containing capsules using the USP Basket apparatus with 500 ml phosphate buffer of pH 6.8 as a dissolution medium. The drug release from the compressed tablets containing TC gum was comparatively sustained than pure drug containing capsules. Even though all the formulation techniques showed reduction of dissolution rate, aqueous wet granulation showed the maximum sustained release of more than 8 h. The release kinetics estimated by the power law revealed that the drug release mechanism involved in the dextromethorphan matrix is anomalous transport as indicated by the release exponent n values. Thus the study confirmed that the TC gum might be used in the controlled drug delivery system as a release-retarding polymer.     

Paclitaxel delivery to brain tumors from hydrogels: a computational study

Malignant gliomas are aggressive forms of primary brain tumors characterized by a poor prognosis. The most successful treatment so far is the local implantation of polymer carriers (Gliadel® wafers) for the sustained release of carmustine. To improve the effectiveness of local drug treatment, new polymer carriers and pharmacological agents are currently being investigated. Of particular interest is a set of novel thermo‐gelling polymers for the controlled release of hydrophobic drugs such as paclitaxel (e.g., OncoGel?). Herein, we use computational mass transport simulations to investigate the effectiveness of paclitaxel delivery from hydrogel‐forming polymer carriers. We found similar (within 1–2 mm) therapeutic penetration distances of paclitaxel when released from these hydrogels as compared with carmustine released from Gliadel® wafers. Effective therapeutic concentrations were maintained for >30 days for paclitaxel when released from the hydrogel as compared with 4 days for carmustine released from Gliadel® wafers. Convection in brain tissue prevented the formation of a uniform drug concentration gradient around the implant. In addition, the surface area to volume ratio of the gel is an important factor that should be considered to maintain a controlled release of paclitaxel within the degradation lifetime of the polymer matrix. © 2011 American Institute of Chemical Engineers Biotechnol. Prog., 2011     

生物相容透皮给药微针治疗浅表肿瘤

复杂的肿瘤微环境导致抗肿瘤药物在肿瘤组织内递送效率低下，严重阻碍了药物对浅表肿瘤的治疗效果。生物相容透皮给药微针凭借较高的机械强度，刺穿皮肤角质层，将微针内的药物递送至浅表肿瘤组织内，提高生物利用度，改善静脉注射、口服给药的肝肾毒性等问题。本文介绍了生物相容透皮给药微针的设计及其在癌症化疗、光动力治疗、光热治疗、免疫治疗、基因治疗等领域的研究进展，对浅表肿瘤的微创、局部递药和精准、高效治疗具有重要指导意义。     

A comprehensive overview of exosomes as drug delivery vehicles — Endogenous nanocarriers for targeted cancer therapy

Exosomes denote a class of secreted nanoparticles defined by size, surface protein and lipid composition, and the ability to carry RNA and proteins. They are important mediators of intercellular communication and regulators of the cellular niche, and their altered characteristics in many diseases, such as cancer, suggest them to be important both for diagnostic and therapeutic purposes, prompting the idea of using exosomes as drug delivery vehicles, especially for gene therapy. This review covers the current status of evidence presented in the field of exosome-based drug delivery systems. Components for successful exosome-based drug delivery, such as choice of donor cell, therapeutic cargo, use of targeting peptide, loading method and administration route are highlighted and discussed with a general focus pertaining to the results obtained in models of different cancer types. In addition, completed and on-going clinical trials are described, evaluating exosome-based therapies for the treatment of different cancer types. Due to their endogenous origin, exosome-based drug delivery systems may have advantages in the treatment of cancer, but their design needs further refinement to justify their usage on the clinical scale.     

Bioresponsive matrices in drug delivery

For years, the field of drug delivery has focused on (1) controlling the release of a therapeutic and (2) targeting the therapeutic to a specific cell type. These research endeavors have concentrated mainly on the development of new degradable polymers and molecule-labeled drug delivery vehicles. Recent interest in biomaterials that respond to their environment have opened new methods to trigger the release of drugs and localize the therapeutic within a particular site. These novel biomaterials, usually termed "smart" or "intelligent", are able to deliver a therapeutic agent based on either environmental cues or a remote stimulus. Stimuli-responsive materials could potentially elicit a therapeutically effective dose without adverse side effects. Polymers responding to different stimuli, such as pH, light, temperature, ultrasound, magnetism, or biomolecules have been investigated as potential drug delivery vehicles. This review describes the most recent advances in "smart" drug delivery systems that respond to one or multiple stimuli.     

Sugar End-Capped Poly-d,l-lactides as Excipients in Oral Sustained Release Tablets

Sugar end-capped poly-d,l-lactide (SPDLA) polymers were investigated as a potential release controlling excipient in oral sustained release matrix tablets. The SPDLA polymers were obtained by a catalytic ring-opening polymerization technique using methyl α-d-gluco-pyranoside as a multifunctional initiator in the polymerization. Polymers of different molecular weights were synthesized by varying molar ratios of monomer/catalyst. The matrix tablets were prepared by direct compression technique from the binary mixtures of SPDLA and microcrystalline cellulose, and theophylline was used as a model drug. The tablet matrices showed in vitro reproducible drug release profiles with a zero-order or diffusion-based kinetic depending on the SPDLA polymer grade used. Further release from the tablet matrices was dependent on the molecular weight of the SPDLA polymer applied. The drug release was the fastest with the lowest molecular weight SPDLA grade, and the drug release followed zero-order rate. With the higher molecular weight SPDLAs, more prolonged dissolution profiles for the matrix tablets (up to 8–10 h) were obtained. Furthermore, the prolonged drug release was independent of the pH of the dissolution media. In conclusion, SPDLAs are a novel type of drug carrier polymers applicable in oral controlled drug delivery systems.