Polymer-drug Conjugates Research Articles

Nanoparticles for Drug Delivery and Strategies for Reversing Tumor Drug Resistance

Cancer poses a great threat and challenge to human health. However, the most widely used chemotherapy drugs show resistance due to various reasons, such as cellular efflux, poor targeting, obvious side effects. On the other hand, as a new drug delivery vehicle, nanoparticles have attracted extensive attention due to their good targeting and low toxicity. Various nanoparticles for drug delivery, including liposomes, polymer nanoparticles, micelles, drug-polymer conjugates, dendrimers, nanoshells, magnetic nanoparticles, drug nanocrystals, and extracellular vesicles, are reviewed in this paper.

Evaluation of the Cytotoxicity of Cationic Polymers on Glioblastoma Cancer Stem Cells.

Cationic polymers such as polyethylenimine (PEI) have found a pervasive place in laboratories across the world as gene delivery agents. However, their applications are not limited to this role, having found a place as delivery agents for drugs, in complexes known as polymer-drug conjugates (PDCs). Yet a potentially underexplored domain of research is in their inherent potential as anti-cancer therapeutic agents, which has been indicated by several studies. Even more interesting is the recent observation that certain polycations may present a significantly greater toxicity towards the clinically important cancer stem cell (CSC) niche than towards more differentiated bulk tumour cells. These cells, which possess the stem-like characteristics of self-renewal and differentiation, are highly implicated in cancer drug resistance, tumour recurrence and poor clinical prognosis. The search for compounds which may target and eliminate these cells is thus of great research interest. As such, the observation in our previous study on a PEI-based PDC which showed a considerably higher toxicity of PEI towards glioblastoma CSCs (GSCs) than on more differentiated glioma (U87) cells led us to investigate other cationic polymers for a similar effect. The evaluation of the toxicity of a range of different types of polycations, and an investigation into the potential source of GSC's sensitivity to such compounds is thus described.

Design, fabrication and characterization of silane tailored surface of halloysite based polymer nanocomposites

AbstractIn recent years, polymeric drug conjugates, nanoparticles, nanocapsules, liposomes, micelles, dendrimers, and nanogels have been gained a great attention. Organically modified layered nanoclays have become an attractive hybrid biomaterial due to their wide range of uses, which can be designed with desired properties in a wide variety of applications from industry to medicine. Functional water‐soluble poly(maleic anhydride‐alt‐acrylic acid) [poly(MA‐alt‐AA)], synthesized in our previous study, was chosen for the prepare of halloysite/polymer nanocomposite. Surface modification of halloysite nanotubes (HNTs) with 3‐aminopropyltriethoxysilane (APTS) was performed to obtain organic functionalized halloysite and also for better compatibility of nanotubes (NTs) with monomers. Nanocomposite were obtained by in situ solution complex‐radical copolymerization via charge transfer complex under conditions of copolymerization, using pristine and APTS functionalized HNTs, acrylic acid (AA), and maleic anhydride (MA) monomers. Optimization study using different clay ratios and recipe for organic–inorganic compatibility also were carried out. Characterization studies of halloysite, modified halloysite, copolymers and the formed copolymer‐HNT nanotubes were enlighten by using spectroscopic analyzes such as, Attenuated Total Reflectance‐Fourier Transform Infrared Spectroscopy (ATR‐FTIR), High resolution Raman (HR‐Raman), X‐Ray Diffraction Measurements (XRD) and X‐Ray Photoelectron Spectroscopy (XPS). Thermal analysis and dynamic mechanical properties were performed with Thermogravimetric Analysis (TGA) and Dynamic Mechanical Analysis (DMA), respectively. Surface morphology was also carried out by Transmission Electron Microscopy (TEM). In the light of these detailed analysis results, it can be briefly concluded that surface modification of HNT, synthesis of copolymer/HNT nanocomposites, and structural characterization successfully achieved.

Degradation of Polymer-Drug Conjugate Nanoparticles Based on Lactic and Itaconic Acid.

Tuberculosis (TB) is still a significant threat to human health. A promising solution is engineering nanoparticulate drug carriers to deliver anti-TB molecules. Itaconic acid (ITA) potentially has anti-TB activity; however, its incorporation in nanoparticles (NP) is challenging. Here we show an approach for preparing polymer-ITA conjugate NPs and a methodology for investigating the NP degradation and ITA release mechanism. The conjugate was synthesized by the two-directional growing of polylactic acid (PLA) chains, followed by capping their extremities with ITA. The poly(lactate)-itaconate PLA-ITA was then used to formulate NPs. The degradation and drug release processes of the polymer conjugate NPs were studied qualitatively and quantitatively. The molecular structures of released species were characterized by using liquid NMR spectroscopy and mass spectrometry. We discovered a complex NP hydrolysis process forming diverse oligomers, as well as monomeric lactic acid (LA) and drug ITA. The slow degradation process led to a low release of free drugs, although raising the pH from 5.3 to 7.4 induced a slight increase in the amounts of released products. TEM images showed that bulk erosion is likely to play the primary role in the degradation of PLA-ITA NPs. The overall results and methodology can be of interest for understanding the mechanisms of NP degradation and drug release of this new polymer-drug conjugate system.

Ultrasound-mediated delivery of flexibility-tunable polymer drug conjugates for treating glioblastoma.

Effective chemotherapy delivery for glioblastoma multiforme (GBM) is limited by drug transport across the blood-brain barrier and poor efficacy of single agents. Polymer-drug conjugates can be used to deliver drug combinations with a ratiometric dosing. However, the behaviors and effectiveness of this system have never been well investigated in GBM models. Here, we report flexible conjugates of hyaluronic acid (HA) with camptothecin (CPT) and doxorubicin (DOX) delivered into the brain using focused ultrasound (FUS). In vitro toxicity assays reveal that DOX-CPT exhibited synergistic action against GBM in a ratio-dependent manner when delivered as HA conjugates. FUS is employed to improve penetration of DOX-HA-CPT conjugates into the brain in vivo in a murine GBM model. Small-angle x-ray scattering characterizations of the conjugates show that the DOX:CPT ratio affects the polymer chain flexibility. Conjugates with the highest flexibility yield the highest efficacy in treating mouse GBM in vivo. Our results demonstrate the association of FUS-enhanced delivery of combination chemotherapy and the drug-ratio-dependent flexibility of the HA conjugates. Drug ratio in the polymer nanocomplex may thus be employed as a key factor to modulate FUS drug delivery efficiency via controlling the polymer flexibility. Our characterizations also highlight the significance of understanding the flexibility of drug carriers in ultrasound-mediated drug delivery systems.

Combination of polythyleneimine regulating autophagy prodrug and Mdr1 siRNA for tumor multidrug resistance

Multidrug resistance (MDR) has been restricting the efficacy of chemotherapy, which mainly include pump resistance and non-pump resistance. In order to fight overall MDR, a novel targeted gene/drug co-deliver nano system is developed, which can suppress the drug efflux pumps and modulate autophagy to overcoming both pump and non-pump resistance. Here, small interfere RNA (siRNA) is incorporated into polymer-drug conjugates (PEI-PTX, PP) which are composed of polyethyleneimine (PEI) and paclitaxel (PTX) via covalent bonds, and hyaluronic acid (HA) is coated on the surface of PP/siRNA to achieve long blood cycle and CD44-targeted delivery. The RNA interference to mdr1 gene is combined with autophagy inhibition by PP, which efficiently facilitate apoptosis of Taxol-resistant lung cancer cells (A549/T). Further study indicates that PEI in PP may play a significant role to block the autophagosome–lysosome fusion process by means of alkalizing lysosomes. Both in vitro and in vivo studies confirm that the nanoassemblies can successfully deliver PTX and siRNA into tumor cells and significantly inhibited A549/T tumor growth. In summary, the polymeric nanoassemblies provide a potential strategy for combating both pump and non-pump resistance via the synergism of RNAi and autophagy modulation.

Hydrophobicity Effects of γ-Glutamyl Transpeptidase-Responsive Polymers on the Catalytic Activity and Transcytosis Efficacy.

Active transcytosis has recently sparked great interest in drug delivery as a novel route for tumor extravasation and infiltration. However, the rational design of transcytosis-inducing nanomedicines remains challenging. We recently demonstrated that the γ-glutamyl transpeptidase (GGT)-responsive polymer cationization induced efficient adsorption-mediated transcytosis (AMT). However, it remains unclear how the nanomedicines' physicochemical properties influence the GGT-responsive cationization and induced transcytosis behaviors. Herein, through a combination of experimental techniques and molecular dynamics (MD) simulations, we find that the random copolymers with high hydrophobic monomers tend to form compact structures accessible to the catalytic site of GGT, leading to a fast cationization and thus high transcytosis efficiency, while the homopolymers of the hydrophilic GGT-sensitive monomers have elongated structures unable to enter the active site and thus exhibit poor GGT sensitivity. As a result, the more hydrophobic polymer-drug conjugates with high camptothecin contents exhibit higher GGT-responsive activity, which in turn leads to faster cationization and cellular internalization, enhanced tumor infiltration, and more potent antitumor activity. These findings indicate the hydrophobicity is a main parameter determining the GGT catalytic activity and transcytosis efficiency of the GGT-activatable co(homo)polymers, providing guidelines for the rational design of GGT-induced charge reversal carriers for transcytotic nanomedicines.

Tumor-Targeting Polymer–Drug Conjugate for Liver Cancer Treatment In Vitro

Bufalin (buf) has poor solubility in aqueous solution, poor tumor targeting, and many non-specific toxic and side effects. The advantages of high-molecular-weight polymer conjugates are that they can improve the water solubility of buf, prolong plasma half-life, and reduce non-specific toxicity. A novel water-soluble polymer-drug conjugate with buf and fluorescein pendants was prepared by the combination of reversible addition-fragmentation transfer (RAFT) polymerization and click chemistry. Its anticancer performance and cellular uptake behavior against liver cancer were investigated in vitro. The polymer-buf conjugates exhibit controlled release and tumor-targeting capabilities, showing promise for clinical applications.

Comparative study of dual delivery of gemcitabine and curcumin using CD44 targeting hyaluronic acid nanoparticles for cancer therapy

Dual-delivery nanoparticles of gemcitabine (GEM) and curcumin (CUR) conjugated on hyaluronic acid (HA) were successfully developed for targeting to cancer cells. The polymer-drug conjugates (PDCs) were synthesized by grafting GEM onto CUR (hydrazone)-HA (ChH) conjugates using ester (non-pH-sensitive) and hydrazone (pH-sensitive) bonds to form two different chemical structures; random graft: GeChH and block graft: (GhC)hH, respectively. The GeChH and (GhC)hH nanoparticles were prepared by solvent diffusion evaporation. The (GhC)hH nanoparticles showed superior characteristics with smaller particle size (221 nm), narrower size distribution (PDI 0.01) and lower critical aggregation concentration (CAC 0.28 mg/mL), as compared to the GeChH nanoparticles. The release profile of GEM and CUR from both nanoparticles was specific and fast in the acidic microenvironment (pH 5.0–6.5) while retarded at physiological pH (pH 7.4), indicating pH-dependence. In particular, the GEM released from (GhC)hH nanoparticles at pH 7.4 was less than that from the GeChH nanoparticles, suggesting the suitability for anticancer drug delivery. In vitro cytotoxicity study revealed that the (GhC)hH nanoparticles had higher toxicity and synergistic effect in all cell lines (PANC-1, A549, HCT116 and Caco-2 cells) when compared to the GeChH nanoparticles and the GEM/CUR solution. The in vitro cellular uptake study supported that both nanoparticles could be internalized into the cells and deposited around the nuclei. Moreover, the %uptake of the (GhC)hHFITC nanoparticles was higher than that of the GeChHFITC nanoparticles in both A549 and HCT116 cells. After HA blockade treatment, the %uptake of the nanoparticles significantly decreased, indicating that HA targeting to CD44 receptors played an important role to enhance specificity to the cancer cells. In summary, the developed (GhC)hH nanoparticles could provide dual delivery of GEM and CUR which would be beneficial for cancer therapy.

Core-Coordinated Elliptic Polymer Nanoparticles Loading Copper(II) and Chlorambucil for Cooperative Chemodynamic/Chemotherapy.

Chemodynamic therapy (CDT) reflects an innovative cancer treatment modality; however, to enhance its relatively low therapeutic efficiency, rational combination with extra therapeutic modes is highly appreciated. Here, core-coordinated amphiphilic, elliptic polymer nanoparticles (Cu/CBL-POEGEA NPs) are constructed via the self-assembly of a glutathione (GSH)-responsive polymer-drug conjugate, bearing side-chain acylthiourea (ATU) motifs which behave as ligands capable of coordinating Cu(II), such a design is featured by combined chemo (CT)/CDT with dual GSH depletion collectively triggered by the Cu(II) reduction reaction and disulfide bond breakage. To do so, an amphiphilic random copolymer poly[oligo(ethylene glycol)ethyl acrylate-co-thiourea] [P(OEGEA-co-ATU)] is synthesized, followed by conjugation of chlorambucil (CBL) to ATU motifs linked via a disulfide bond, thus yielding the targeted P[OEGEA-co-(ATU-g-CBL)]. In such a system, hydrophilic POEGEA serves as the biocompatible section and ATU motifs coordinate Cu(II), resulting in core-coordinated elliptic Cu/CBL-POEGEA NPs. Benefitting from the GSH-induced reduction reaction, Cu(II) is converted into Cu(I) and subsequently react with endogenous H2O2 to create •OH, realizing GSH-depletion-promoted CDT. Additionally, the disulfide bond endows GSH-responsive CBL release and provokes further GSH decline, finally realizing combined CDT/CT toward enhancing antitumor outcomes, and in vitro as well as in vivo studies indeed reveal remarkable efficacy. Such a system can provide valuable advantages to create novel nanomedicines toward cascade antitumor therapy.

Polyethylenimine, an Autophagy-Inducing Platinum-Carbene-Based Drug Carrier with Potent Toxicity towards Glioblastoma Cancer Stem Cells.

Simple SummaryThe resistance of tumours to treatment and their tendency to reoccur following successful treatment are major problems for long-term cancer patient survival. Research has identified a special subset of cells in tumours with stem-cell-like properties to be at the heart of this problem. Thus, the development of new chemotherapeutic compounds with unique characteristics that may target this subset of cancer cells is of great interest in the pursuit of more effective cancer treatments. This work describes one such compound, being a new platinum-based compound attached to a long polymer molecule in order to enhance its anti-cancer properties. Importantly, the stem-cell-like subset of cells seems to be considerably more sensitive to the toxicity of the polymer itself than the bulk of tumour cells, with an interesting mode of cell death which has characteristics different to that of more “classical” anti-cancer therapeutics.The difficulty involved in the treatment of many tumours due to their recurrence and resistance to chemotherapy is tightly linked to the presence of cancer stem cells (CSCs). This CSC sub-population is distinct from the majority of cancer cells of the tumour bulk. Indeed, CSCs have increased mitochondrial mass that has been linked to increased sensitivity to mitochondrial targeting compounds. Thus, a platinum-based polyethylenimine (PEI) polymer–drug conjugate (PDC) was assessed as a potential anti-CSC therapeutic since it has previously displayed mitochondrial accumulation. Our results show that CSCs have increased specific sensitivity to the PEI carrier and to the PDC. The mechanism of cell death seems to be necrotic in nature, with an absence of apoptotic markers. Cell death is accompanied by the induction of a protective autophagy. The interference in the balance of this pathway, which is highly important for CSCs, may be responsible for a partial reversion of the stem-like phenotype observed with prolonged PEI and PDC treatment. Several markers also indicate the cell death mode to be capable of inducing an anti-cancer immune response. This study thus indicates the potential therapeutic perspectives of polycations against CSCs.

Poly(2-oxazoline) - Ferrostatin-1 drug conjugates inhibit ferroptotic cell death.

Ferroptosis is a form of non-apoptotic iron induced cell death mechanism implicated in neurodegeneration, yet can be ameliorated with potent radical scavengers such as ferrostatin-1 (Fer-1). Currently, Fer-1 suffers from low water solubility, poor biodistribution profile and is unsuitable for clinical application. Fer-1 polymer-drug conjugates (PDCs) for testing as an anti-ferroptosis therapeutic candidate have yet to be described. Here, we report the synthesis and characterization of a library of water-soluble Fer-1 based poly(2-oxazoline)-drug conjugates. The cationic ring opening polymerization (CROP) of water-soluble 2-oxazoline monomers, and a novel protected aromatic aldehyde 2-oxazoline (DPhOx), produced defined copolymers, which after deprotection were available for modification with Fer-1 via reductive amination and Schiff base chemistry. The conjugates were tested for their activity against RSL3-induced ferroptosis in vitro, and first structure-activity relationships were established. Irreversibly conjugated Fer-1 PDCs possessing an arylamine structural motif showed a greatly increased anti-ferroptosis activity compared to reversibly (Schiff base) linked Fer-1. Overall, this work introduces the first active ferrostatin-PDCs and a new highly tuneable poly(2-oxazoline)-based PDC platform, which provides access to next generation polymeric nanomaterials for anti-ferroptosis applications.

Well-Defined pH-Responsive Self-Assembled Block Copolymers for the Effective Codelivery of Doxorubicin and Antisense Oligonucleotide to Breast Cancer Cells.

The worldwide steady increase in the number of cancer patients motivates the development of innovative drug delivery systems for combination therapy as an effective clinical modality for cancer treatment. Here, we explored a design concept based on poly(ethylene glycol)-b-poly(2-(dimethylamino)ethyl methacrylate)-b-poly(2-hydroxyethyl methacrylate-formylbenzoic acid) [PEG-b-PDMAEMA-b-P(HEMA-FBA)] for the dual delivery of doxorubicin (DOX) and GTI2040 (an antisense oligonucleotide for ribonucleotide reductase inhibition) to MCF-7 breast cancer cells. PEG-b-PDMAEMA-b-PHEMA, the precursor copolymer, was prepared through chain extensions from a PEG-based macroinitiator via two consecutive atom transfer radical polymerization (ATRP) steps. Then, it was modified at the PHEMA block with 4-formylbenzoic acid (FBA) to install reactive aldehyde moieties. A pH-responsive polymer-drug conjugate (PDC) was obtained by conjugating DOX to the polymer structure via acid-labile imine linkages, and subsequently self-assembled in an aqueous solution to form DOX-loaded self-assembled nanoparticles (DOX-SAN) with a positively charged shell. DOX-SAN condensed readily with negatively charged GTI2040 to form GTI2040/DOX-SAN nanocomplexes. Gel-retardation assay confirmed the affinity between GTI2040 and DOX-SAN. The GTI2040/DOX-SAN nanocomplex at N/P ratio of 30 exhibited a volume-average hydrodynamic size of 136.4 nm and a zeta potential of 21.0 mV. The pH-sensitivity of DOX-SAN was confirmed by the DOX release study based on the significant cumulative DOX release at pH 5.5 relative to pH 7.4. Cellular uptake study demonstrated favorable accumulation of GTI2040/DOX-SAN inside MCF-7 cells compared with free GTI2040/DOX. In vitro cytotoxicity study indicated higher therapeutic efficacy of GTI2040/DOX-SAN relative to DOX-SAN alone because of the downregulation of the R2 protein of ribonucleotide reductase. These outcomes suggest that the self-assembled pH-responsive triblock copolymer is a promising platform for combination therapy, which may be more effective in combating cancer than individual therapies.

Biopolymeric Prodrug Systems as Potential Antineoplastic Therapy.

Nowadays, cancer represents a major public health issue, a substantial economic issue, and a burden for society. Limited by numerous disadvantages, conventional chemotherapy is being replaced by new strategies targeting tumor cells. In this context, therapies based on biopolymer prodrug systems represent a promising alternative for improving the pharmacokinetic and pharmacologic properties of drugs and reducing their toxicity. The polymer-directed enzyme prodrug therapy is based on tumor cell targeting and release of the drug using polymer–drug and polymer–enzyme conjugates. In addition, current trends are oriented towards natural sources. They are biocompatible, biodegradable, and represent a valuable and renewable source. Therefore, numerous antitumor molecules have been conjugated with natural polymers. The present manuscript highlights the latest research focused on polymer–drug conjugates containing natural polymers such as chitosan, hyaluronic acid, dextran, pullulan, silk fibroin, heparin, and polysaccharides from Auricularia auricula.

Chemically engineering the drug release rate of a PEG-paclitaxel conjugate using click and steric hindrance chemistries for optimal efficacy

A small molecule drug with poor aqueous solubility can be conjugated to a hydrophilic polymer like poly(ethylene glycol) (PEG) to form an amphiphilic polymer-drug conjugate that self-assembles to form nanoparticles (NPs) with improved solubility and enhanced efficacy. This strategy has been extensively applied to improve the delivery of several small molecule drugs. However, very few reports have succeeded to tune the rate of drug release from these NPs. To the best of our knowledge, there have been no reports of utilizing click and steric hindrance chemistry to modulate the drug release of self-assembling polymer-drug conjugates. In this study, we utilized click chemistry to conjugate methoxy-PEG (mPEG) to an anti-tumor drug, paclitaxel (PTX). A focused library of PTX-Rx-mPEG (x = 0, 1, 2) conjugates were synthesized with different chemical modalities next to the cleavable ester bond to study the effect of increasing steric hindrance on the self-assembly process and the physicochemical properties of the resulting PTX-NPs. PTX-R0-mPEG had no added steric hindrance (x = 0; minimal), PTX-R1-mPEG consisted of two methyl groups (x = 1: moderate), and PTX-R2-mPEG consisted of a phenyl group (x = 2: significant). Drug release studies showed that PTX-NPs released PTX at a decreased rate with increasing steric hindrance. Pharmacokinetic studies showed that the AUC of released PTX from the moderate-release PTX-R1-NP was approximately 20-, 6-, and 3-fold higher than that from free PTX, PTX-R0-NP and PTX-R2-NP, respectively. As a result, among these different PTX formulations, PTX-R1-NP showed superior efficacy in inducing tumor regression and prolonging the animal survival. The tumors treated with PTX-R1-NP displayed the lowest tumor progression markers (Ki68 and CD31) and the highest apoptotic marker (TUNEL) compared to the others. This work emphasizes the importance of taking a systematic approach in designing self-assembling polymer drug conjugates and highlights the potential of utilizing steric hindrance as a tool to tune the drug release rate from such systems.

Sequential acid/reduction response of triblock copolymeric nanomicelles to release camptothecin and toll-like receptor 7/8 agonist for orchestrated chemoimmunotherapy

BackgroundImmunosuppressive tumor immune microenvironment (TIME) lowers immunotherapy effectiveness. Additionally, low penetration efficiency and unpredictable drug release in tumor areas restrict tumor therapy.MethodsA triblock copolymeric micelle (NanoPCPT+PIMDQ) was developed to carry the chemotherapeutic drug camptothecin (CPT) and the TLR7/8 agonist 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c] quinoline-4-amine (IMDQ) to achieve deep tumor penetration and on-demand drug release by responding to acid and reduction stimuli sequentially. The synergistic antitumour efficacy of NanoPCPT+PIMDQ was assessed both in vitro and in vivo.ResultsNanoPCPT+PIMDQ is composed of a hydrophilic PEG(polyethylene glycol) outer layer, an acid-sensitive EPEMA middle layer, and a drug inner core. Upon intratumoral injection, (i) NanoPCPT+PIMDQ first responds to the acidic tumor microenvironment and disintegrates to PIMDQ and PCPT, penetrating deep regions of the tumor; (ii) tumor cells are killed by the released CPT; (iii) DCs are activated by PIMDQ to increase the infiltration of cytotoxic T lymphocyte (CTL); and (iv) both downregulated Foxp3+ Tregs by CPT and repolarized M2 macrophages by PIMDQ can relieve the TIME.ConclusionThis pH/GSH-responsive triblock polymer-drug conjugate reduces immunosuppression and enhances the infiltration of CTLs by codelivering CPT and IMDQ in a controllable manner, providing a promising platform for synergistic tumor chemoimmunotherapy.

Molecular docking for rationalizing the use of linkers in polymer drug conjugates design for pegylated anti-inflammatory drug delivery

A smart linker is a crucial element throughout the creation of polymer-drug conjugates. It binds different portions or subunits altogether and may be freed by a suitable trigger, resulting in localized drug distribution and enhanced bioavailability. PEG (Polyethylene Glycol) linkers can be synthesized chemically by specifically adding functionalized groups with chemical reactivity at certain structural ends of PEG. Because they may integrate a diverse range of groups, PEG linkers are frequently utilized in molecular biology experiments due to increased water solubility, excellent biocompatibility, and non-immunogenicity. In present work, we have included various linkers which are incorporated in design of PDC’s (polymer drug conjugates) of pegylated NSAIDs (nonsteroidal anti-inflammatory drugs) through PEGylation. The main focus was to investigate the pharmacodynamic changes brought about by these linker’s conjugated to model drug Ibuprofen (IB1-IB7). The tools used for the analysis are Argus Lab 4.0 for molecular docking and pkCMS as ADMET prediction tool. The outcome of this work was, establishment of a method for choosing suitable linker for designing PDC’s for various NSAIDs and other bioactive agents.

Hyaluronic acid-entecavir conjugates-core/lipid-shell nanohybrids for efficient macrophage uptake and hepatotropic prospects

Drug covalently bound to polymers had formed, lately, platforms with great promise in drug delivery. These drug polymer conjugates (DPC) boosted drug loading and controlled medicine release with targeting ability. Herein, the ability of entecavir (E) conjugated to hyaluronic acid (HA) forming the core of vitamin E coated lipid nanohybrids (EE-HA LPH), to target Kupffer cells and hepatocyte had been proved. The drug was associated to HA with efficiency of 93.48 ± 3.14 % and nanohybrids loading of 22.02 ± 2.3 %. DiI labelled lipidic nanohybrids improved the macrophage uptake in J774 cells with a 21 day hepatocytes retention post intramuscular injection. Finally, in vivo biocompatibility and safety with respect to body weight, organs indices and histopathological alterations were demonstrated. Coating with vitamin E and conjugation of E to HA (a CD44 ligand), could give grounds for prospective application for vectored nano-platform in hepatitis B.

Self-assembled coumarin- and 5-fluorouracil-PEG micelles as multifunctional drug delivery systems

The copper(I)-catalyzed azide/alkyne cycloaddition is recognized as one of the most successful click reactions to access self-assembling amphiphilic polymer-drug conjugates (PDCs). In this way, poor water-soluble drugs can be linked covalently to hydrophilic poly(ethylene glycol) (PEG) to obtain PEGylated drug micelles that can be used as versatile carriers for the delivery of diverse therapeutic agents. In this work, two novel amphiphilic PDCs that combine PEG with privileged scaffolds well-known for their anticancer properties, such as coumarin and 5-fluorouracil, have been synthesized and characterized. These conjugates were able to self-assemble into micelles at relatively high critical micellar concentration, probably due to the large portion of hydrophilic PEG. The micelles allowed to load other anticancer drugs (paclitaxel, curcumin, and gemcitabine), providing a unique opportunity to develop promising co-delivery carriers for synergistic cancer therapy. The Korsmeyer-Peppas mathematical model was used for describing the in vitro kinetics of drug release from the micelles. Similar sustained and controlled drug release profiles were obtained for paclitaxel and curcumin in both conjugates, which was attributed to the excellent stability driven by the strong interaction between polymeric conjugates and drugs in the micelle core. In contrast, the high instability observed for the gemcitabine-loaded micelles provided an initial uncontrolled burst release of drug. A preliminary in vitro cytotoxicity study of the micelles against human pancreatic cancer cells PANC-1 and BxPC-3 was also carried out, demonstrating that both coumarin and 5-fluorouracil retain their anticancer properties after conjugation with PEG.

A biphasic mathematical model for the release of polymer-drug conjugates from poly(vinyl alcohol) hydrogels

BackgroundHydrogels are a popular vehicle for controlled drug release. In comparison with small-soluble drugs of simple diffusion, the release of large polymer-drug conjugates is more complex and could not be predicted by a simple diffusion model. This study was aimed at mathematical modeling of the release of polymer-drug conjugates to design controlled drug-release hydrogel systems. MethodsFluorescein was used as a small model drug, whereas fluorescein isothiocyanate-dextran acted as a polymer-drug conjugates. The molecules were encapsulated in poly(vinyl alcohol)-based hydrogels with different concentrations and degrees of crosslinking. The release data were fitted using a one-diffusion coefficient (1DC) model and a two-diffusion coefficient (2DC) model, performed by Matlab. Significant findingsThe simple 1DC model fitted the release data of small molecules (< 10 kDa) very well, while the more complex 2DC model was needed to predict the release of macromolecules (10–250 kDa) for a better fit. The 2DC model proposed that a hydrogel is a heterogeneous structure with dense and loose areas, and macromolecules diffuse through the two areas with different diffusivity. We further demonstrated that the biphasic model could be applied to design hydrogel systems for precision drug release profiles.