Injectable and biodegradable poly(organophosphazene) hydrogel as a delivery system of docetaxel for cancer treatment

Abstract

Although docetaxel (DTX) is an advanced taxoid, further augmentation of its properties is still required, such as improvement in its low aqueous solubility. Herein, we report the development of biodegradable/injectable poly(organophosphazene) (PPZ) hydrogels for the delivery of DTX without the use of organic solvents. An aqueous solution of PPZ containing α-amino-ω-methoxy-poly(ethylene glycol) (AMPEG) 750 instead of AMPEG 550 was prepared, thereby increasing the erosion capacity of the hydrogel by judicious balance of the hydrophobic/hydrophilic moieties. The safety of the hydrogel was demonstrated using a biocompatibility test. The PPZ aqueous solution (8?wt%) containing DTX exhibited a thermosensitive sol–gel–sol transition that was independent of the concentration of DTX (1–3?mg/mL). The in vitro release study indicated that the dominant release mechanism was either erosion or diffusion/erosion-controlled release depending on the DTX content of the hydrogel. The in vivo anticancer effect of the intratumorally injected PPZ system in human gastric cancer cell-xenografted mice was evaluated, which demonstrated a significantly (p?<?0.01) enhanced effect of the DTX-PPZ hydrogel system compared to the control (DTX solution, i.v.). In conclusion, the PPZ hydrogel may be a promising candidate for DTX delivery, affecting a decrease in the size of tumors with little toxicity prior to exeresis.     

A local drug delivery system based on visible light-cured glycol chitosan and doxorubicin⋅hydrochloride for thyroid cancer treatment in vitro and in vivo

Systemic drug delivery systems (SDDSs) for thyroid cancer treatment are associated with serious side effects including nausea, anorexia, and hair loss as a result of damage to normal tissues. In this study, we investigated the feasibility of a local DDS (LDDS) based on visible light-cured glycol chitosan (GC) hydrogel and doxorubicin?hydrochloride (DOX?HCl), called GC10/DOX, on thyroid cancer treatment in vivo. Visible light irradiation increased the storage modulus and swelling ratio of the GC10/DOX hydrogel precursor. The release of DOX?HCl from GC10/DOX exhibited two unique patterns comprising an initial burst within 18?hours, followed by a controlled and sustained release thereafter. In vitro cell viability testing showed that GC10/DOX had a greater antitumor effect than free DOX?HCl and GC10 hydrogel controls. In vivo, local injection of GC10/DOX near tumor tissue led to a superior antitumor effect compared with controls consisting of free DOX?HCl intravenously injected to the tail vein of thyroid cancer-bearing mouse and GC10 hydrogel subcutaneously injected near the tumor. Altogether, our results suggest that GC10/DOX may have clinical potential for thyroid cancer treatment.     

HSA-based multi-target combination therapy: regulating drugs’ release from HSA and overcoming single drug resistance in a breast cancer model

Multi-drug delivery systems, which may be promising solution to overcome obstacles, have limited the clinical success of multi-drug combination therapies to treat cancer. To this end, we used three different anticancer agents, Cu(BpT)Br, NAMI-A, and doxorubicin (DOX), to build human serum albumin (HSA)-based multi-drug delivery systems in a breast cancer model to investigate the therapeutic efficacy of overcoming single drug (DOX) resistance to cancer cells in vivo, and to regulate the drugs’ release from HSA. The HSA complex structure revealed that NAMI-A and Cu(BpT)Br bind to the IB and IIA sub-domain of HSA by N-donor residue replacing a leaving group and coordinating to their metal centers, respectively. The MALDI-TOF mass spectra demonstrated that one DOX molecule is conjugated with lysine of HSA by a pH-sensitive linker. Furthermore, the release behavior of three agents form HSA can be regulated at different pH levels. Importantly, in vivo results revealed that the HSA–NAMI-A–Cu(BpT)Br–DOX complex not only increases the targeting ability compared with a combination of the three agents (the NAMI-A/Cu(BpT)Br/DOX mixture), but it also overcomes DOX resistance to drug-resistant breast cancer cell lines.     

Ratiometric delivery of two therapeutic candidates with inherently dissimilar physicochemical property through pH-sensitive core–shell nanoparticles targeting the heterogeneous tumor cells of glioma

Currently, combination drug therapy is one of the most effective approaches to glioma treatment. However, due to the inherent dissimilar pharmacokinetics of individual drugs and blood brain barriers, it was difficult for the concomitant drugs to simultaneously be delivered to glioma in an optimal dose ratio manner. Herein, a cationic micellar core (Cur-M) was first prepared from d-α-tocopherol-grafted-ε-polylysine polymer to encapsulate the hydrophobic curcumin, followed by dopamine-modified-poly-γ-glutamic acid polymer further deposited on its surface as a anion shell through pH-sensitive linkage to encapsulate the hydrophilic doxorubicin (DOX) hydrochloride. By controlling the combinational Cur/DOX molar ratio at 3:1, a pH-sensitive core–shell nanoparticle (PDCP-NP) was constructed to simultaneously target the cancer stem cells (CSCs) and the differentiated tumor cells. PDCP-NP exhibited a dynamic diameter of 160.8?nm and a zeta-potential of –30.5?mV, while its core–shell structure was further confirmed by XPS and TEM. The ratiometric delivery capability of PDCP-NP was confirmed by in vitro and in vivo studies, in comparison with the cocktail Cur/DOX solution. Meanwhile, the percentage of CSCs in tumors was significantly decreased from 4.16% to 0.95% after treatment with PDCP-NP. Overall, PDCP-NP may be a promising carrier for the combination therapy with drug candidates having dissimilar physicochemical properties.     

Ultrafine PEG-PLA fibers loaded with both paclitaxel and doxorubicin hydrochloride and their in vitro cytotoxicity

By means of “emulsion-electrospinning”, both hydrophobic and hydrophilic drugs, paclitaxel (PTX) and doxorubicin hydrochloride (DOX), were successfully loaded into PEG-PLA nanofiber mats to realize multi-drug delivery. The release behaviors of both the drugs from the same fiber mats were ascribed to their solubility properties and distribution status in the fibers. Due to its high hydrophilicity, DOX was easy to diffuse out from the fibers, and its release rate was always faster than that of hydrophobic PTX. Moreover, the release rate of PTX was accelerated by DOX’s release from the same drug-loaded fibers. In vitro cytotoxicity against rat Glioma C6 cells indicated that the dual drug combination showed a higher inhibition and apoptosis against C6 cells than a single drug-loaded system, which suggests the promise for multi-drug delivery on combination therapy.     

Prodrug-based nano-drug delivery system for co-encapsulate paclitaxel and carboplatin for lung cancer treatment

Context: Paclitaxel (PTX) and carboplatin (CBP) are widely used for the combined chemotherapy of non-small cell lung cancer (NSCLC). However, the development of multidrug resistance of cancer cells, as well as systemic toxic side effects resulting from nonspecific localization of anticancer drugs to non-tumor areas are major obstacles to the success of chemotherapy in treating cancers.

Objective: This study aimed to engineer a prodrug-based nano-drug delivery system for co-encapsulate hydrophilic (CBP) and hydrophobic anti-tumor drugs (PTX). This system was expected to resolve the multidrug resistance cause by single drug, and the dual-drug-loaded liposome was also planned to specifically target the cancer cells without obvious influence on normal cells and tissues.

Methods: In this paper, PLGA-PEG-CBP was synthesized by the conjugation between the carboxylic group of PLGA-PEG-COOH and the amino group of CBP. Then, self-assembled nanoparticles for combination delivery of PTX and PLGA-PEG-CBP (PTX/CBP NPs) were prepared by solvent displacement technique. The in vitro and in vivo anti-tumor efficacy was assessed in NCL-H460 human non-small cell lung carcinoma cell line.

Results: PTX/CBP NPs achieved the highest cytotoxic effect among all formulations in vitro, as compared with single drug delivery NPs. In vivo investigation on NSCLC animal models showed that co-delivery of PTX and CBP possessed high tumor-targeting capacity and strong anti-tumor activity.

Conclusions: The PTX/CBP NPs constructed in this research offers an effective strategy for targeted combinational lung cancer therapy.     

The effective combination therapy against human osteosarcoma: doxorubicin plus curcumin co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system

Objective: To overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) in osteosarcoma (OS), biodegradable lipid-coated polymeric nanoparticles (LPNs) were explored for the loading of doxorubicin (DOX) and curcumin (CUR).

Methods: DOX plus CUR co-encapsulated LPNs (DOX?+?CUR LPNs) of mixed lipid monolayer shell and biodegradable polymer core were prepared. The cytotoxicity effect of DOX?+?CUR LPNs, single drug loaded LPNs, and free drug solutions were evaluated on human OS cell line KHOS cells and mice KHOS cells xenograft in vivo.

Results: DOX?+?CUR LPNs displayed a curative effect on OS cell lines than the free drug counterparts. Also, best anti-OS effects were observed on the animal model compared with other groups tested.

Conclusion: This promising dual drugs co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system enhanced the cell delivery and activity of drugs against human OS cancer cell lines and in cancer bearing mice. This research may offer new options for the treatment of OS.     

pH triggered injectable amphiphilic hydrogel containing doxorubicin and paclitaxel

Injectable hydrogel with hydrophobic microdomains for incorporating both hydrophilic and hydrophobic drugs, herein doxorubicin hydrochloride (DOX) and paclitaxel (PTX), was synthesized through dynamic bonding of glycol chitosan and benzaldehyde capped poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) via Schiff's reaction triggered by environmental pH. Rheology tests show that the inclusion of hydrophilic drug decreases the gelation time and gains more robust gel, while the addition of hydrophobic drug has opposite influences. Dual-drug release from the DOX+PTX loaded gels was observed and the release rate can be accelerated by decreasing the environmental pH from physiological (7.4) to weak acidic pH (6.8). In vivo investigation proved that the gels were able to diminish the amount of DOX in blood circulation and limit the DOX-induced cardiotoxicity. By intratumoral administration, the hydrogel-drug formulations resulted in efficient growth inhibition of subcutaneous tumor (B16F10) on C57LB/6 mouse model. The advantage of the current system for DOX+PTX combination therapy was demonstrated by a prolongation of survival time in comparison with the single drug therapy.     

Co-delivery of doxorubicin and siRNA for glioma therapy by a brain targeting system: angiopep-2-modified poly(lactic-co-glycolic acid) nanoparticles

It is very challenging to treat brain cancer because of the blood–brain barrier (BBB) restricting therapeutic drug or gene to access the brain. In this research project, angiopep-2 (ANG) was used as a brain-targeted peptide for preparing multifunctional ANG-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), which encapsulated both doxorubicin (DOX) and epidermal growth factor receptor (EGFR) siRNA, designated as ANG/PLGA/DOX/siRNA. This system could efficiently deliver DOX and siRNA into U87MG cells leading to significant cell inhibition, apoptosis and EGFR silencing in vitro. It demonstrated that this drug system was capable of penetrating the BBB in vivo, resulting in more drugs accumulation in the brain. The animal study using the brain orthotopic U87MG glioma xenograft model indicated that the ANG-targeted co-delivery of DOX and EGFR siRNA resulted in not only the prolongation of the life span of the glioma-bearing mice but also an obvious cell apoptosis in glioma tissue.     

Transdermal administration of melatonin coupled to cryopass laser treatment as noninvasive therapy for prostate cancer

Melatonin, a pineal gland hormone, exerts oncostatic activity in several types of human cancer, including prostate, the most common neoplasia and the third most frequent cause of male cancer death in the developed world. The growth of androgen-sensitive LNCaP prostate cancer cells in mice is inhibited by 3?mg/kg/week melatonin (0.09?mg/mouse/week) delivered by i.p. injections, which is equivalent to a dose of 210?mg/week in humans. The aim of this study is to test an alternative noninvasive delivery route based on transdermal administration of melatonin onto the tumor area followed by cryopass-laser treatment. Two groups of immunodepressed mice were studied, one (n?=?10) subjected to 18 cryopass-laser therapy sessions and one (n?=?10) subjected to the same treatment without melatonin. These groups were compared with mice treated with i.p.-administered melatonin or vehicle with the same time schedule. We found that cryopass-laser treatment is as efficient as i.p. injections in reducing the growth of LNCaP tumor cells, affecting plasma melatonin and redox balance. Furthermore, both delivery routes share the same effects on the involved biochemical pathway driven by hypoxia-inducible factor 1α. However, cryopass-laser, as used in the present experimental setup, is less efficient than i.p delivery route in increasing the melatonin content and Nrf2 expression in the tumor mass. We conclude that cryopass-laser treatment may have impact for melatonin-based therapy of prostate cancer, by delivering drugs transdermally without causing pain and targeting directly on the site of interest, thereby potentially making long-term treatments more sustainable.     

Cytotoxic enhancement of hexapeptide-conjugated micelles in EGFR high-expressed cancer cells

Objectives: The aim of this study was to develop the hexapeptide-conjugated active targeting micelles for delivery of doxorubicin (DOX) and paclitaxel (PTX) to EGFR high-expressed cancer cells.

Methods: A hexapeptide, which mimicked the EGFR, was applied as a targeting ligand. The active targeting micelles were prepared using the synthesized poly(D,L-lactide-co-glycolide)–PEG copolymer conjugated with the hexapeptide. The micelles were used for encapsulating DOX and/or PTX, and the cellular uptake, in vitro drug release and cellular viability of drug-loaded peptide-conjugated and peptide-free micelles were investigated.

Results: The particle size of drug-loaded peptide-conjugated and peptide-free micelles was < 150 nm with narrow size distribution. The uptake of peptide-conjugated micelles was more efficient in EGFR high-expressed MDA-MB-468 and SKOV3 cells than in EGFR low-expressed HepG2 cells. The in vitro release of DOX and PTX was faster in pH 4.0 (500 U lipase) than in pH 7.4 release medium. The cytotoxicity in terms of IC₅₀ of DOX/PTX-loaded peptide-conjugated micelles was 4.8-folds lower than that of peptide-free micelles and 18.2-folds lower than DOX/PTX drug solution in SOKV3 cells.

Conclusion: The peptide-conjugated micelles acted as a nanocarrier to increase intracellular accumulation of anticancer drugs in EGFR high-expressed SKOV3 cancer cells to enhance cell cytotoxicity.     

Folate-modified doxorubicin-loaded nanoparticles for tumor-targeted therapy

Context: Polymeric nanoparticles (NPs) have been used frequently as drug delivery vehicles. Surface modification of polymeric NPs with specific ligands defines a new biological identity, which assists in targeting of the nanocarriers to specific cancers cells.

Objective: The aim of this study is to develop a kind of modified vector which could target the cancer cells through receptor-mediated pathways to increase the uptake of doxorubicin (DOX).

Methods: Folate (FA)-conjugated PEG–PE (FA–PEG–PE) ligands were used to modify the polymeric NPs. The modification rate was optimized and the physical–chemical characteristics, in vitro release, and cytotoxicity of the vehicle were evaluated. The in vivo therapeutic effect of the vectors was evaluated in human nasopharyngeal carcinoma KB cells baring mice by giving each mouse 100?µl of 10?mg/kg different solutions.

Results: FA–PEG–PE-modified NPs/DOX (FA-NPs/DOX) have a particle size of 229?nm, and 86% of drug loading quantity. FA-NPs/DOX displayed remarkably higher cytotoxicity (812?mm³ tumor volume after 13?d of injection) than non-modified NPs/DOX (1290?mm³) and free DOX solution (1832?mm³) in vivo.

Conclusion: The results demonstrate that the modified drug delivery system (DDS) could function comprehensively to improve the efficacy of cancer therapy. Consequently, the system was shown to be a promising carrier for delivery of DOX, leading to the efficiency of antitumor therapy.     

Thermosensitive hydrogels for drug delivery

Introduction: Controlled drug delivery has been widely applied in areas such as cancer therapy and tissue regeneration. Thermosensitive hydrogel-based drug delivery systems have increasingly attracted the attention of the drug delivery community, as the drugs can be readily encapsulated and released by the hydrogels.

Areas covered: Thermosensitive hydrogels that can serve as drug carriers are discussed in this paper. Strategies used to control hydrogel properties, in order to tailor drug release kinetics, are also reviewed. This paper also introduces applications of the thermosensitive hydrogel-based drug delivery systems in cancer therapy and tissue regeneration.

Expert opinion: When designing a drug delivery system using thermosensitive hydrogels, one needs to consider what type of thermosensitive hydrogel needs to be used, and how to manipulate its properties to meet the desired drug release kinetics. For material selection, both naturally derived and synthetic thermosensitive polymers can be used. Various methods can be used to tailor thermosensitive hydrogel properties in order to achieve the desired drug release profile.     

Tumor-preferential sustained drug release enhances antitumor activity of block copolymer micelles

Abstract

Nanoparticles are widely used as drug carriers for controlled, tumor-targeted delivery of various anticancer agents that have biopharmaceutical limitations such as water solubility and tissue permeability. Growing evidence suggests that nanoparticles not only reduce toxic side effects of anticancer drugs but also improve the therapeutic efficacy as a function of their drug-release profile. The purpose of this study is to confirm such hypothetical effects of tunable drug release on improving antitumor activity of nanoparticles in vitro and in vivo, using block copolymer micelles as drug carriers. Micelles were prepared from poly(ethylene glycol)-poly(aspartate) block copolymers modified with hydrazide (HYD), aminobenzoate hydrazide (ABZ) and glycine hydrazide (GLY) linkers to achieve a pH-dependent, tunable release of doxorubicin (DOX), a model anticancer drug. Regardless of the drug-release profile, all three micelles showed similar properties in vitro, such as pH-dependent drug release, intracellular drug delivery and cancer cell growth inhibition. However, micelles releasing DOX slowly in vitro showed that the most effective antitumor activity in vivo, compared to the micelles releasing drugs faster. These results demonstrate that tumor-preferential sustained drug release can enhance the antitumor activity of the micelles.     

Bioresponsive functional nanogels as an emerging platform for cancer therapy

Introduction: Bioresponsive nanogels with a crosslinked three-dimensional structure and an aqueous environment that undergo physical or chemical changes including swelling and dissociation in response to biological signals such as mild acidity, hyperthermia, enzymes, reducing agents, reactive oxygen species (ROS), and adenosine-5?-triphosphate (ATP) present in tumor microenvironments or inside cancer cells have emerged as an appealing platform for targeted drug delivery and cancer therapy.

Areas covered: This review highlights recent designs and development of bioresponsive nanogels for facile loading and triggered release of chemotherapeutics and biotherapeutics. The in vitro and in vivo antitumor performances of drug-loaded nanogels are discussed.

Expert opinion: Bioresponsive nanogels with an excellent stability and safety profile as well as fast response to biological signals are unique systems that mediate efficient and site-specific delivery of anticancer drugs, in particular macromolecular drugs like proteins, siRNA and DNA, leading to significantly enhanced tumor therapy compared with the non-responsive counterparts. Future research has to be directed to the development of simple, tumor-targeted and bioresponsive multifunctional nanogels, which can be either constructed from natural polymers with intrinsic targeting ability or functionalized with targeting ligands. We anticipate that rationally designed nanotherapeutics based on bioresponsive nanogels will become available for future clinical cancer treatment.

Abbreviations: AIE, aggregation-induced emission; ATP, adenosine-5?-triphosphate; ATRP, atom transfer radical polymerization; BSA, bovine serum albumin; CBA, cystamine bisacrylamide; CC, Cytochrome C; CDDP, cisplatin; CT, computed tomography; DC, dendritic cell; DiI, 1,1?-dioctadecyl-3,3,3?,3?-tetramethylindocarbocyanine perchlorate; DOX, doxorubicin; dPG, dendritic polyglycerol; DTT, dithiothreitol; EAMA, 2-(N,N-diethylamino)ethyl methacrylate; EPR, enhanced permeability and retention; GrB, granzyme B; GSH, glutathione tripeptide; HA, hyaluronic acid; HAase, hyaluronidases; HCPT, 10-Hydroxycamptothecin; HEP, heparin; HPMC, hydroxypropylmethylcellulose; LBL, layer-by-layer; MTX, methotrexate; NCA, N-carboxyanhydride; OVA, ovalbumin; PAH, poly(allyl amine hydrochloride); PBA, phenylboronic acid; PCL, polycaprolactone; PDEAEMA, poly(2-diethylaminoethyl methacrylate); PDGF, platelet derived growth factor; PDPA, poly(2-(diisopropylamino)ethyl methacrylate); PDS, pyridyldisulfide; PEG, poly(ethylene glycol); PEGMA, polyethyleneglycol methacrylate; PEI, polyethyleneimine; PHEA, poly(hydroxyethyl acrylate); PHEMA, poly(2-(hydroxyethyl) methacrylate; PNIPAM, poly(N-isopropylacrylamide); PMAA, poly(methacrylic acid); PPDSMA, poly(2-(pyridyldisulfide)ethyl methacrylate); PTX, paclitaxel; PVA, poly(vinyl alcohol); QD, quantum dot; RAFT, reversible addition-fragmentation chain transfer; RGD, Arg-Gly-Asp peptide; ROP, ring-opening polymerization; ROS, reactive oxygen species; TMZ, temozolomide; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; VEGF, vascular endothelial growth factor.     

Glucosamine-anchored doxorubicin-loaded targeted nano-niosomes: pharmacokinetic,toxicity and pharmacodynamic evaluation

Background: Efficacy of anticancer drug is limited due to non-selectivity and toxicities allied with the drug; therefore the heart of the present work is to formulate drug delivery systems targeted selectively towards cancer cells with minimal toxicity to normal cells.

Purpose: Targeted drug delivery system of doxorubicin (DOX)-loaded niosomes using synthesized N-lauryl glucosamine (NLG) as a targeting ligand.

Methods: NLG-anchored DOX niosomes were developed using ethanol injection method.

Results: Developed niosomes had particle size <150?nm and high entrapment efficiency ～90%. In vivo pharmacokinetics exhibited long circulating nature of targeted niosomes with improved bioavailability, which significantly reduced CL and Vd than DOX solution and non-targeted niosomes (35 fold and 2.5 fold, respectively). Tissue-distribution study and enzymatic assays revealed higher concentration of DOX solution in heart while no toxicity to major organs with developed targeted niosomes was observed. Solid skin melanoma tumor model in mice manifested the commendable targeting potential of targeted niosomes with significant reduction in tumor volume and high % survival rate without drop in body weight in comparison with DOX solution and non-targeted niosomes of DOX.

Conclusion: The glucosamine-anchored DOX-loaded targeted niosomes showed its potential in cancer targeted drug therapy with reduced toxicity. Abbreviations ALT alanine transaminase

CL clearance

CPK creatinine phosphokinase

DOX doxorubicin

EDC.HCL ethyl carbidimide hydrochloride

GLUT glucose transporter

GSH glutathione S-transferase

LDH lactate dehydrogenase

LHRH luteinizing hormone-releasing hormone

MDA malonaldehyde

NHS N-hydroxy succinimide

NLG N-lauryl glucosamine

NTAR DoxNio non-targeted doxorubicin niosomes

PBS phosphate buffer saline

RGD argynyl glycyl aspartic acid

SGOT serum glutamate oxaloacetate transaminase

SGPT serum glutamate pyruvate transaminase

SOD superoxide dismutase

TAR DoxNio targeted doxorubicin niosomes

Vd volume of distribution

     

Intratracheal <Emphasis Type="BoldItalic">Versus</Emphasis> Intravenous Liposomal Delivery of siRNA,Antisense Oligonucleotides and Anticancer Drug

Purpose  To compare systemic intravenous and local intratracheal delivery of doxorubicin (DOX), antisense oligonucleotides (ASO) and small interfering RNA (siRNA). Methods  “Neutral” and cationic liposomes were used to deliver DOX, ASO, and siRNA. Liposomes were characterized by dynamic light scattering, zeta-potential, and atomic force microscopy. Cellular internalization of DOX, ASO and siRNA was studied by confocal microscopy on human lung carcinoma cells. In vivo experiments were carried out on nude mice with an orthotopic model of human lung cancer. Results  Liposomes provided for an efficient intracellular delivery of DOX, ASO, and siRNA in vitro. Intratracheal delivery of both types of liposomes in vivo led to higher peak concentrations and much longer retention of liposomes, DOX, ASO and siRNA in the lungs when compared with systemic administration. It was found that local intratracheal treatment of lung cancer with liposomal DOX was more efficient when compared with free and liposomal DOX delivered intravenously. Conclusions  The present study outlined the clear advantages of local intratracheal delivery of liposomal drugs for the treatment of lung cancer when compared with systemic administration of the same drug.     

Clinical translation of folate receptor-targeted therapeutics

Introduction: Folate receptor?α (FR?α) has been established as a membrane marker for ovarian cancer. In addition, it is frequently overexpressed in other major types of epithelial tumors. FR?α-based tumor-targeted therapy and drug carriers have been an active area of laboratory research for more than 20 years. Recently, there has been a great increase in the effort to finally translate this promising technology into the clinic and bring FR-targeted therapeutics into the market.

Areas covered: Two FR-targeted therapeutic agents have moved into Phase III clinical trials, the monoclonal antibody farletuzumab and the low molecular weight vintafolide, combined with etarfolatide as a companion imaging agent, representing two alternative strategies for targeting the FR.

Expert opinion: Each of the two strategies has advantages and disadvantages. Identification of the best target patient population is likely critical to the ultimate success of FR-targeted agents in the clinic. A successful clinical strategy may require the integration between FR expression analysis and an optimal combination of FR-targeted therapy and standard chemotherapy. Advancement into Phase III trials and the ongoing clinical development of several additional folate conjugates are likely to usher in a new era of clinical translation and validation of FR-targeted imaging and therapeutic agents.     

Assessment of the drug loading,in vitro and in vivo release behavior of novel pH-sensitive hydrogel

Context: As a glucocorticoid drug, dexamethasone has good therapeutic effects for ulcerative colitis. pH-sensitive hydrogels could make conventional changes of volume in response with different pH values. Meanwhile, they could load drugs depending on its internal three-dimensional network structure.

Objective: Appropriate methods were used to improve the drug-loading capacity of hydrogel and exploring the colon-targeting character of dexamethasone hydrogel.

Materials and methods: Different solvents (ethanol and 1,2-propanediol) were employed to dissolve dexamethasone as well as hydrogel monomer materials (poly(ethylene glycol) methyl ether (MPEG)–poly(lactide acid)–acryloyl chloride macromonomer, itaconic acid (IA) and MPEG–methacrylate), then mixing them together to prepare hydrogel through the heat-initiated free radical polymerization method. Differential scanning calorimetry and X-ray diffraction methods were used to verify whether dexamethasone was loaded into hydrogels. In vitro drug release behavior and in vivo pharmacokinetic study were also investigated in detail.

Results: Dexamethasone was successfully loaded into hydrogel, and its loading capacity was improved (5?mg/g). Both the in vitro release study and the in vivo pharmacokinetic study showed the good colon-targeting character of the pH-sensitive P(LE–IA–MEG) hydrogel (T_max?=?1.0?h, C_max?=?2.16?µg/ml of dexamethasone; T_max?=?3.9?h, C_max?=?0.43?µg/ml of dexamethasone hydrogel).

Discussion: Dexamethasone could be targeted to the colon site by P(LE–IA–MEG) hydrogel, thereby improving its therapeutic effect and reduce its side effects.

Conclusion: P(LE–IA–MEG) hydrogel might have great potential application in colon-targeted drug delivery systems.