Folate and folate-PEG-PAMAM dendrimers: synthesis, characterization, and targeted anticancer drug delivery potential in tumor bearing mice

Ligand-mediated targeting of drugs especially in anticancer drug delivery is an effective approach. Dendrimers, due to unique surface topologies, can be a choice in this context. In the present study, PAMAM (polyamidoamine) dendrimers up to fourth generation were synthesized and characterized through infrared (IR), nuclear magnetic resonance (NMR), electrospray ionization (ESI) mass spectrometric, and transmission electron microscopic (TEM) techniques. Primary amines present on the dendritic surface were conjugated through folic acid and folic acid-PEG (poly(ethylene glycol))-NHS (N-hydroxysuccinimide) conjugates. Tumor in mice was induced through the use of KB cell culture. Prepared dendritic conjugates were evaluated for the anticancer drug delivery potential using 5-FU (5-fluorouracil) in tumor-bearing mice. Approximately 31% of 5-FU was loaded in folate-PEG-dendritic conjugates. Results indicated that folate-PEG-dendrimer conjugate was significantly safe and effective in tumor targeting compared to a non-PEGylated formulation. Tailoring of dendrimers via PEG-folic acid reduced hemolytic toxicity, which led to a sustained drug release pattern as well as highest accumulation in the tumor area.     

Hyperbranched double hydrophilic block copolymer micelles of poly(ethylene oxide) and polyglycerol for pH-responsive drug delivery

We report the synthesis of a well-defined hyperbranched double hydrophilic block copolymer of poly(ethylene oxide)-hyperbranched-polyglycerol (PEO-hb-PG) to develop an efficient drug delivery system. In specific, we demonstrate the hyperbranched PEO-hb-PG can form a self-assembled micellar structure on conjugation with the hydrophobic anticancer agent doxorubicin, which is linked to the polymer by pH-sensitive hydrazone bonds, resulting in a pH-responsive controlled release of doxorubicin. Dynamic light scattering, atomic force microscopy, and transmission electron microscopy demonstrated successful formation of the spherical core-shell type micelles with an average size of about 200 nm. Moreover, the pH-responsive release of doxorubicin and in vitro cytotoxicity studies revealed the controlled stimuli-responsive drug delivery system desirable for enhanced efficiency. Benefiting from many desirable features of hyperbranched double hydrophilic block copolymers such as enhanced biocompatibility, increased water solubility, and drug loading efficiency as well as improved clearance of the polymer after drug release, we believe that double hydrophilic block copolymer will provide a versatile platform to develop excellent drug delivery systems for effective treatment of cancer.     

Photoresponsive poly(S-(o-nitrobenzyl)-L-cysteine)-b-PEO from a L-cysteine N-carboxyanhydride monomer: synthesis, self-assembly, and phototriggered drug release

A photoresponsive S-(o-nitrobenzyl)-l-cysteine N-carboxyanhydride (NBC-NCA) monomer was for the first time designed, and the related poly(S-(o-nitrobenzyl)-l-cysteine)-b-poly(ethylene glycol) (PNBC-b-PEO) block copolymers were synthesized from the ring-opening polymerization (ROP) of NBC-NCA in DMF solution at 25 °C. Their molecular structures, physical properties, photoresponsive self-assembly, and drug release of PNBC-b-PEO were thoroughly investigated. The β-sheet conformational PNBC block within copolymers presented a thermotropic liquid crystal phase behavior, and the crystallinity of PEO block was progressively suppressed over the PNBC composition. The characteristic absorption peaks of these copolymers at about 310 and 350 nm increased over UV irradiation time and then leveled off, indicating that the o-nitrobenzyl groups were gradually photocleaved from copolymers until the completion of photocleavage. The PNBC-b-PEO copolymers self-assembled into spherical nanoparticles in aqueous solution, presenting a photoresponsive self-assembly behavior, together with a size reduction of nanoparticles after irradiation. The anticancer drug doxorubicin can be released in a controlled manner by changing the light irradiation time, which was induced by gradually photocleaving the PNBC core of nanoparticles. This work provides a facile strategy not only for the synthesis of photoresponsive polypeptide-based block copolymers but also for the fabrication of photoresponsive nanomedicine potential for anticancer therapy.     

Reduction-Responsive Disassemblable Core-Cross-Linked Micelles Based on Poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide)-Lipoic Acid Conjugates for Triggered Intracellular Anticancer Drug Release

Reduction-sensitive reversibly core-cross-linked micelles were developed based on poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide)-lipoic acid (PEG-b-PHPMA-LA) conjugates and investigated for triggered doxorubicin (DOX) release. Water-soluble PEG-b-PHPMA block copolymers were obtained with M(n,PEG) of 5.0 kg/mol and M(n,HPMA) varying from 1.7 and 4.1 to 7.0 kg/mol by reversible addition-fragmentation chain transfer (RAFT) polymerization. The esterification of the hydroxyl groups in the PEG-b-PHPMA copolymers with lipoic acid (LA) gave amphiphilic PEG-b-PHPMA-LA conjugates with degrees of substitution (DS) of 71-86%, which formed monodispersed micelles with average sizes ranging from 85.3 to 142.5 nm, depending on PHPMA molecular weights, in phosphate buffer (PB, 10 mM, pH 7.4). These micelles were readily cross-linked with a catalytic amount of dithiothreitol (DTT). Notably, PEG-b-PHPMA(7.0k)-LA micelles displayed superior DOX loading content (21.3 wt %) and loading efficiency (90%). The in vitro release studies showed that only about 23.0% of DOX was released in 12 h from cross-linked micelles at 37 °C at a low micelle concentration of 40 μg/mL, whereas about 87.0% of DOX was released in the presence of 10 mM DTT under otherwise the same conditions. MTT assays showed that DOX-loaded core-cross-linked PEG-b-PHPMA-LA micelles exhibited high antitumor activity in HeLa and HepG2 cells with low IC(50) (half inhibitory concentration) of 6.7 and 12.8 μg DOX equiv/mL, respectively, following 48 h incubation, while blank micelles were practically nontoxic up to a tested concentration of 1.0 mg/mL. Confocal laser scanning microscope (CLSM) studies showed that DOX-loaded core-cross-linked micelles released DOX into the cell nuclei of HeLa cells in 12 h. These reduction-sensitive disassemblable core-cross-linked micelles with excellent biocompatibility, superior drug loading, high extracellular stability, and triggered intracellular drug release are promising for tumor-targeted anticancer drug delivery.     

Development of novel water-soluble photocleavable protective group and its application for design of photoresponsive paclitaxel prodrugs

A novel coumarin-based highly water-soluble photocleavable protective group was designed and synthesized, and then this photosensitive protecting group was used to design paclitaxel prodrugs. These novel paclitaxel conjugates demonstrated excellent water solubility, over 100mgmL(-1). Thus, the use of a detergent in the formulation can be omitted completely, even at high doses. Phototaxel 11 released the parent drug, paclitaxel, quickly and efficiently by minimal tissue-damaging 365nm UV light irradiation at low power, while laser activation at 355nm led to extensive decomposition of the prodrug. The carbamate-type prodrug, phototaxel 11, was stable in the dark prior to activation, whereas carbonate-type phototaxel 9 demonstrated poor stability under aqueous conditions. For such prodrugs, tumor-tissue targeting after administration could be achieved by selective light delivery, similar to that used in photodynamic therapy. In addition, newly designed coumarin derivative 8 can be applied in organic chemistry as a photosensitive protective group and for the design of caged compounds.     

Phosphonium-containing diblock copolymers for enhanced colloidal stability and efficient nucleic Acid delivery

RAFT polymerization successfully controlled the synthesis of phosphonium-based AB diblock copolymers for nonviral gene delivery. A stabilizing block of either oligo(ethylene glycol(9)) methyl ether methacrylate or 2-(methacryloxy)ethyl phosphorylcholine provided colloidal stability, and the phosphonium-containing cationic block of 4-vinylbenzyltributylphosphonium chloride induced electrostatic nucleic acid complexation. RAFT polymerization generated well-defined stabilizing blocks (M(n) = 25000 g/mol) and subsequent chain extension synthesized diblock copolymers with DPs of 25, 50, and 75 for the phosphonium-containing block. All diblock copolymers bound DNA efficiently at ± ratios of 1.0 in H(2)O, and polyplexes generated at ± ratios of 2.0 displayed hydrodynamic diameters between 100 and 200 nm. The resulting polyplexes exhibited excellent colloidal stability under physiological salt or serum conditions, and they maintained constant hydrodynamic diameters over 24 h. Cellular uptake studies using Cy5-labeled DNA confirmed reduced cellular uptake in COS-7 and HeLa cells and, consequently, resulted in low transfection in these cell lines. Serum transfection in HepaRG cells, which are a predictive cell line for in vivo transfection studies, showed successful transfection using all diblock copolymers with luciferase expression on the same order of magnitude as Jet-PEI. All diblock copolymers exhibited low cytotoxicity (>80% cell viability). Promising in vitro transfection and cytotoxicity results suggest future studies involving the in vivo applicability of these phosphonium-based diblock copolymer delivery vehicles.     

A novel 5-fluorouracil prodrug using hydroxyethyl starch as a macromolecular carrier for sustained release

The objective of this study was to develop a sustained-release drug delivery system for 5-fluorouracil (5-FU) to improve its short half-life. 5-Fluorouracil-1-acetic acid (FUAC) was prepared and then conjugated to hydroxyethyl starch (HES) through ester bonds. The conjugates were relatively stable in acidic buffer solution at pH 5.8 and slowly released FUAC but became more sensitive to hydrolysis with an increase in the pH and temperature. The conjugates were degraded to FUAC both in human and rat plasma with half-time life of 20.4 h and 24.6 h, respectively. Both 5-FU and FUAC were released in a rat liver homogenate following a 12 h incubation of the conjugates. The pharmacokinetic behavior was evaluated in rats after intravenous injection of 5-FU, FUAC and the conjugates. The drug release data in vitro and in vivo indicated that HES is a promising carrier for the sustained-release of antitumor drugs.     

Effect of tyrosine-derived triblock copolymer compositions on nanosphere self-assembly and drug delivery

We have obtained structure-activity relations for nanosphere drug delivery as a function of the chemical properties of a tunable family of self-assembling triblock copolymers. These block copolymers are synthesized with hydrophobic oligomers of a desaminotyrosyl tyrosine ester and diacid and hydrophilic poly(ethylene glycol). We have calculated the thermodynamic interaction parameters for the copolymers with anti-tumor drugs to provide an understanding of the drug binding by the nanospheres. We find that there is an optimum ester chain length, C8, for nanospheres in terms of their drug loading capacities. The nanospheres release the drugs under dialysis conditions, with release rates strongly influenced by solution pH. The nanospheres, which are themselves non-cytotoxic, deliver the hydrophobic drugs very effectively to tumor cells as measured by cell killing activity in vitro and thus offer the potential for effective parentarel in vivo delivery of many hydrophobic therapeutic agents.     

Norbornene derived doxorubicin copolymers as drug carriers with pH responsive hydrazone linker

The synthesis and complete characterization of both norbornene-derived doxorubicin (mono 1) and polyethylene glycol (mono 2) monomers are clearly described, and their copolymerization by ring-opening metathesis polymerization (ROMP) to get the block copolymer (COPY-DOX) is vividly elaborated. The careful design of these conjugates exhibits properties like well-shielded drug moieties and well-defined nanostructures; additionally, they show solubility in both water and biological medium and also have the important tendency of rendering acid-triggered drug release. The drug release profile suggests the importance of having the hydrazone linker that helps to release the drug exactly at the mild acidic conditions resembling the pH of the cancerous cells. It is also observed that the drug release from micelles of COPY-DOX is significantly accelerated at a mildly acidic pH of 5.5-6, compared to the physiological pH of 7.4, suggesting the pH-responsive feature of the drug delivery system with hydrazone linkages. Confocal laser scanning microscopy (CLSM) measurements indicate that these COPY-DOX micelles are easily internalized by living cells. MTT assays against HeLa and 4T cancer cells showing COPY-DOX micelles have a high anticancer efficacy. All of these results demonstrate that these polymeric micelles that self-assembled from COPY-DOX block copolymers have great scope in the world of medicine, and they also symbolize promising carriers for the pH-triggered intracellular delivery of hydrophobic anticancer drugs.     

5-Fluorouracil Nanoparticles Inhibit Hepatocellular Carcinoma via Activation of the p53 Pathway in the Orthotopic Transplant Mouse Model

Biodegradable polymer nanoparticle drug delivery systems provide targeted drug delivery, improved pharmacokinetic and biodistribution, enhanced drug stability and fewer side effects. These drug delivery systems are widely used for delivering cytotoxic agents. In the present study, we synthesized GC/5-FU nanoparticles by combining galactosylated chitosan (GC) material with 5-FU, and tested its effect on liver cancer in vitro and in vivo. The in vitro anti-cancer effects of this sustained release system were both dose- and time-dependent, and demonstrated higher cytotoxicity against hepatic cancer cells than against other cell types. The distribution of GC/5-FU in vivo revealed the greatest accumulation in hepatic cancer tissues. GC/5-FU significantly inhibited tumor growth in an orthotropic liver cancer mouse model, resulting in a significant reduction in tumor weight and increased survival time in comparison to 5-FU alone. Flow cytometry and TUNEL assays in hepatic cancer cells showed that GC/5-FU was associated with higher rates of G0–G1 arrest and apoptosis than 5-FU. Analysis of apoptosis pathways indicated that GC/5-FU upregulates p53 expression at both protein and mRNA levels. This in turn lowers Bcl-2/Bax expression resulting in mitochondrial release of cytochrome C into the cytosol with subsequent caspase-3 activation. Upregulation of caspase-3 expression decreased poly ADP-ribose polymerase 1 (PARP-1) at mRNA and protein levels, further promoting apoptosis. These findings indicate that sustained release of GC/5-FU nanoparticles are more effective at targeting hepatic cancer cells than 5-FU monotherapy in the mouse orthotropic liver cancer mouse model.     

Self-assembled micelles of biodegradable triblock copolymers based on poly(ethyl ethylene phosphate) and poly(-caprolactone) as drug carriers

A series of novel amphiphilic triblock copolymers of poly(ethyl ethylene phosphate) and poly(-caprolactone) (PEEP-PCL-PEEP) with various PEEP and PCL block lengths were synthesized and characterized. These triblock copolymers formed micelles composed of a hydrophobic core of poly(-caprolactone) (PCL) and a hydrophilic shell of poly(ethyl ethylene phosphate) (PEEP) in aqueous solution. The micelle morphology was spherical, determined by transmission electron microscopy. It was found that the size and critical micelle concentration values of the micelles depended on both hydrophobic PCL block length and PEEP hydrophilic block length. The in vitro degradation characteristics of the triblock copolymers were investigated in micellar form, showing that these copolymers were completely biodegradable under enzymatic catalysis of Pseudomonas lipase and phosphodiesterase I. These triblock copolymers were used for paclitaxel (PTX) encapsulation to demonstrate the potential in drug delivery. PTX was successfully loaded into the micelles, and the in vitro release profile was found to be correlative to the polymer composition. These biodegradable triblock copolymer micelles are potential as novel carriers for hydrophobic drug delivery.     

PAMAM dendrimer-based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality

Poly(amidoamine) (PAMAM) dendrimer-based multifunctional cancer therapeutic conjugates have been designed and synthesized. The primary amino groups on the surface of the generation 5 (G5) PAMAM dendrimer were neutralized through partial acetylation, providing enhanced solubility of the dendrimer (in conjugation of FITC (fluorescein isothiocyanate)) and preventing nonspecific targeting interactions (in vitro and in vivo) during delivery. The functional molecules fluorescein isothiocyanate (FITC, an imaging agent), folic acid (FA, targets overexpressed folate receptors on specific cancer cells), and paclitaxel (taxol, a chemotherapeutic drug) were conjugated to the remaining nonacetylated primary amino groups. The appropriate control dendrimer conjugates have been synthesized as well. Characterization of the G5 PAMAM dendrimer and its nanosize conjugates, including the molecular weight and number of primary amine groups, has been determined by multiple analytical methods such as gel permeation chromatography (GPC), nuclear magnetic resonance spectroscopy (NMR), potentiometric titration, high-performance liquid chromatography (HPLC), and UV spectroscopy. These multifunctional dendrimer conjugates have been tested in vitro for targeted delivery of chemotherapeutic and imaging agents to specific cancer cells. We present here the synthesis, characterization, and functionality of these dendrimer conjugates.     

Bioreducible block copolymers based on poly(ethylene glycol) and poly(γ-benzyl L-glutamate) for intracellular delivery of camptothecin

Poly(ethylene glycol)-b-poly(γ-benzyl L-glutamate)s bearing the disulfide bond (PEG-SS-PBLGs), which is specifically cleavable in intracellular compartments, were prepared via a facile synthetic route as a potential carrier of camptothecin (CPT). Diblock copolymers with different lengths of PBLG were synthesized by ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of a PEG macroinitiator (PEG-SS-NH(2)). Owing to their amphiphilic nature, the copolymers formed spherical micelles in an aqueous condition, and their particle sizes (20-125 nm in diameter) were dependent on the block length of PBLG. Critical micelle concentrations of the copolymers were in the range 0.005-0.065 mg/mL, which decreased as the block length of PBLG increased. CPT, chosen as a model anticancer drug, was effectively encapsulated up to 12 wt % into the hydrophobic core of the micelles by the solvent casting method. It was demonstrated by the in vitro optical imaging technique that the fluorescence signal of doxorubicin, quenched in the PEG-SS-PBLG micelles, was highly recovered in the presence of glutathione (GSH), a tripeptide reducing disulfide bonds in the cytoplasm. The micelles released CPT completely within 20 h under 10 mM GSH, whereas only 40% of CPT was released from the micelles in the absence of GSH. From the in vitro cytotoxicity test, it was found that CPT-loaded PEG-SS-PBLG micelles showed higher toxicity to SCC7 cancer cells than CPT-loaded PEG-b-PBLG micelles without the disulfide bond. Microscopic observation demonstrated that the disulfide-containing micelle could effectively deliver the drug into nuclei of SCC7 cells. These results suggest that PEG-SS-PBLG diblock copolymer is a promising carrier for intracellular delivery of CPT.     

Novel anticancer polymeric conjugates of activated nucleoside analogues

Inherent or therapy-induced drug resistance is a major clinical setback in cancer treatment. The extensive usage of cytotoxic nucleobases and nucleoside analogues in chemotherapy also results in the development of specific mechanisms of drug resistance, such as nucleoside transport or activation deficiencies. These drugs are prodrugs; and being converted into the active mono-, di-, and triphosphates inside cancer cells following administration, they affect nucleic acid synthesis, nucleotide metabolism, or sensitivity to apoptosis. Previously, we actively promoted the idea that the nanodelivery of active nucleotide species, e.g., 5'-triphosphates of nucleoside analogues, can enhance drug efficacy and reduce nonspecific toxicity. In this study, we report the development of a novel type of drug nanoformulations, polymeric conjugates of nucleoside analogues, which are capable of the efficient transport and sustained release of phosphorylated drugs. These drug conjugates have been synthesized, starting from cholesterol-modified mucoadhesive polyvinyl alcohol or biodegradable dextrin, by covalent attachment of nucleoside analogues through a tetraphosphate linker. Association of cholesterol moieties in aqueous media resulted in intramolecular polymer folding and the formation of small nanogel particles containing 0.5 mmol/g of a 5'-phosphorylated nucleoside analogue, e.g., 5-fluoro-2'-deoxyuridine (floxuridine, FdU), an active metabolite of anticancer drug 5-fluorouracyl (5-FU). The polymeric conjugates demonstrated rapid enzymatic release of floxuridine 5'-phosphate and much slower drug release under hydrolytic conditions (pH 1.0-7.4). Among the panel of cancer cell lines, all studied polymeric FdU-conjugates demonstrated an up to 50× increased cytotoxicity in human prostate cancer PC-3, breast cancer MCF-7, and MDA-MB-231 cells, and more than 100× higher efficacy against cytarabine-resistant human T-lymphoma (CEM/araC/8) and gemcitabine-resistant follicular lymphoma (RL7/G) cells as compared to free drugs. In the initial in vivo screening, both PC-3 and RL7/G subcutaneous tumor xenograft models showed enhanced sensitivity to sustained drug release from polymeric FdU-conjugate after peritumoral injections and significant tumor growth inhibition. All these data demonstrate a remarkable clinical potential of novel polymeric conjugates of phosphorylated nucleoside analogues, especially as new therapeutic agents against drug-resistant tumors.     

Redox-responsive polyphosphate nanosized assemblies: a smart drug delivery platform for cancer therapy

Novel redox-responsive polyphosphate nanosized assemblies based on amphiphilic hyperbranched multiarm copolyphosphates (HPHSEP-star-PEP(x)) with backbone redox-responsive, good biocompatibility, and biodegradability simultaneously have been designed and prepared successfully. The hydrophobic core and hydrophilic multiarm of HPHSEP-star-PEP(x) are composed of hyperbranched and linear polyphosphates, respectively. Benefiting from the amphiphilicity, HPHSEP-star-PEP(x) can self-assemble into spherical micellar nanoparticles in aqueous media with tunable size from about 70 to 100 nm via adjusting the molecular weight of PEP multiarm. Moreover, HPHSEP-star-PEP(x) micellar structure can be destructed under reductive environment and result in a triggered drug release behavior. The glutathione-mediated intracellular drug delivery was investigated against a HeLa human cervical carcinoma cell line, and the results indicate that doxorubicin-loaded (DOX-loaded) HPHSEP-star-PEP(x) micelles show higher cellular proliferation inhibition against glutathione monoester pretreated HeLa cells than that of the nonpretreated ones. In contrast, the DOX-loaded micelles exhibit lower inhibition against buthionine sulfoximine pretreated HeLa cells. These results suggest that such redox-responsive polyphosphate micelles can rapidly deliver anticancer drugs into the nuclei of tumor cells enhancing the inhibition of cell proliferation and provide a favorable platform to construct excellent drug delivery systems for cancer therapy.     

Short oligonucleotide prodrug having 5-fluoro and 5-iodouracil inhibits the proliferation of cancer cells in a photo-responsive manner

Photo-induced C1′ hydrogen abstraction of 5-fluoro-2′-deoxyuridine was adopted as the key reaction for releasing 5-fluorouracil (5-FU) anticancer drug from oligonucleotide strands. After photoirradiation following 5-FU release, anticancer activity was expected. We demonstrated that oligonucleotide tetramer, d(A^FU^IUA), can release 5-FU under physiological conditions in a photo-responsive manner thorough photo-induced C1′ hydrogen abstraction, and that the 5-FU released from d(A^FU^IUA) having a phosphorothioate backbone clearly suppresses the proliferation of HeLa cells in a photo-responsive manner.     

Combinatorial anticancer effects of curcumin and 5-fluorouracil loaded thiolated chitosan nanoparticles towards colon cancer treatment

Background

Evaluation of the combinatorial anticancer effects of curcumin/5-fluorouracil loaded thiolated chitosan nanoparticles (CRC-TCS-NPs/5-FU-TCS-NPs) on colon cancer cells and the analysis of pharmacokinetics and biodistribution of CRC-TCS-NPs/5-FU-TCS-NPs in a mouse model.

Methods

CRC-TCS-NPs/5-FU-TCS-NPs were developed by ionic cross-linking. The in vitro combinatorial anticancer effect of the nanomedicine was proven by different assays. Further the pharmacokinetics and biodistribution analyses were performed in Swiss Albino mouse using HPLC.

Results

The 5-FU-TCS-NPs (size: 150 ± 40 nm, zeta potential: + 48.2 ± 5 mV) and CRC-TCS-NPs (size: 150 ± 20 nm, zeta potential: + 35.7 ± 3 mV) were proven to be compatible with blood. The in vitro drug release studies at pH 4.5 and 7.4 showed a sustained release profile over a period of 4 days, where both the systems exhibited a higher release in acidic pH. The in vitro combinatorial anticancer effects in colon cancer (HT29) cells using MTT, live/dead, mitochondrial membrane potential and cell cycle analysis measurements confirmed the enhanced anticancer effects (2.5 to 3 fold). The pharmacokinetic studies confirmed the improved plasma concentrations of 5-FU and CRC up to 72 h, unlike bare CRC and 5-FU.

Conclusions

To conclude, the combination of 5-FU-TCS-NPs and CRC-TCS-NPs showed enhanced anticancer effects on colon cancer cells in vitro and improved the bioavailability of the drugs in vivo.

General significance

The enhanced anticancer effects of combinatorial nanomedicine are advantageous in terms of reduction in the dosage of 5-FU, thereby improving the chemotherapeutic efficacy and patient compliance of colorectal cancer cases.     

Immobilization and intracellular delivery of an anticancer drug using mussel-inspired polydopamine capsules

We report a facile approach to immobilize pH-cleavable polymer-drug conjugates in mussel-inspired polydopamine (PDA) capsules for intracellular drug delivery. Our design takes advantage of the facile PDA coating to form capsules, the chemical reactivity of PDA films, and the acid-labile groups in polymer side chains for sustained pH-induced drug release. The anticancer drug doxorubicin (Dox) was conjugated to thiolated poly(methacrylic acid) (PMA(SH)) with a pH-cleavable hydrazone bond, and then immobilized in PDA capsules via robust thiol-catechol reactions between the polymer-drug conjugate and capsule walls. The loaded Dox showed limited release at physiological pH but significant release (over 85%) at endosomal/lysosomal pH. Cell viability assays showed that Dox-loaded PDA capsules enhanced the efficacy of eradicating HeLa cancer cells compared with free drug under the same assay conditions. The reported method provides a new platform for the application of stimuli-responsive PDA capsules as drug delivery systems.     

Light-induced cleavage of model phenylalanine conjugates based on coumarins and quinolones

In order to evaluate the application of quinolone as a new photocleavable protecting group, in comparison with coumarin, a series of model phenylalanine conjugates were prepared by reaction with chloromethylated O and N heterocycles. The photophysical properties of the resulting ester conjugates were evaluated as well as the photosensitivity under irradiation at 250, 300, 350, and 419 nm. The results obtained showed that the quinolone conjugates were readily photolysed, with complete release of the amino acid in short irradiation times and could be considered a new addition to the family of photocleavable protecting groups for the carboxylic acid function of amino acids.     

Study on drug release behaviors of poly-alpha,beta-[n-(2-hydroxyethyl)-L-aspartamide]-g-poly(epsilon-caprolactone) nano- and microparticles

Biodegradable amphiphilic graft copolymers poly-alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide]-g-poly(epsilon-caprolactone) (PHEA-g-PCL) with different branch lengths were synthesized through the ring-opening polymerization of epsilon-caprolactone initiated by the macroinitiator PHEA bearing hydroxyl groups. With use of the graft copolymers with different compositions, nanoparticle drug delivery systems with sizes smaller than 100 nm were prepared by a dialysis method, and microparticle drug delivery systems with sizes smaller than 5 microm were fabricated by a melting-emulsion method. The regularly spherical shapes of the drug-loaded nano- and microparticles were verified by transmission electron microscopy and scanning electron microscopy. In vitro drug release properties of nano- and microparticle drug delivery systems were investigated, with the emphasis on the effects of polymer composition, particle size, and drug-loading content on the release behaviors.