Stability Of Polymeric Micelles Research Articles

Poly(Photosensitizer-Prodrug) Unimolecular Micelles for Chemo-Photodynamic Synergistic Therapy of Antitumor and Antibacteria.

It is crucial to use simple methods to prepare stable polymeric micelles with multiple functions for cancer treatment. Herein, via a "bottom-up" strategy, we reported the fabrication of β-CD-(PEOSMA-PCPTMA-PPEGMA)21 (βPECP) unimolecular micelles that could simultaneously treat tumors and bacteria with chemotherapy and photodynamic therapy (PDT). The unimolecular micelles consisted of a 21-arm β-cyclodextrin (β-CD) core as a macromolecular initiator, photosensitizer eosin Y (EOS-Y) monomer EOSMA, anticancer drug camptothecin (CPT) monomer, and a hydrophilic shell PEGMA. Camptothecin monomer (CPTMA) could achieve controlled release of the CPT due to the presence of responsively broken disulfide bonds. PEGMA enhanced the biocompatibility of micelles as a hydrophilic shell. Two βPECP with different lengths were synthesized by modulating reaction conditions and the proportion of monomers, which both were self-assembled to unimolecular micelles in water. βPECP unimolecular micelles with higher EOS-Y/CPT content exhibited more excellent 1O2 production, in vitro drug release efficiency, higher cytotoxicity, and superior antibacterial activity. Also, we carried out simulations of the self-assembly and CPT release process of micelles, which agreed with the experiments. This nanosystem, which combines antimicrobial and antitumor functions, provides new ideas for bacteria-mediated tumor clinical chemoresistance.

Abstract 2885: O-carborane-entrapped polymeric Micelles for Proton Boron Capture Therapy

Abstract Introduction: Proton boron capture therapy (PBCT) has the potential to enhance the biological effectiveness of proton therapy, based on proton-boron fusion reactions (11B + p → 3α + 8.7 MeV), which produce 3 α particles. In this study, we formulated o-carborane, a high boron content cage-like compound, into a polymeric micelle (M-carb) as a delivery tool to achieve effective delivery of the boronated compound to cancer cells and validated the enhancement of the biological effectiveness of proton therapy promoted by the uptake of o-carborane-entrapped in the micelle. Methods: O-carborane was effectively entrapped into an amphiphilic block copolymer to yield a stable polymeric micelle. The size and surface charge of the resulting M-carb were characterized by dynamic light scattering (DLS) and the uptake of M-carb in MIA PaCa-2 pancreatic cancer cells was measured by inductively coupled plasma mass spectrometry (ICP-MS). A colony formation assay was employed to assess the impact of M-carb on the survival of MIA PaCa-2 cells irradiated with a proton beam at the entrance and distal Spread-Out Bragg Peak (SOBP) positions at doses ranging from 0, 2, 5, and 8 Gy. The γH2AX foci were quantified by immunofluorescence to assess treatment-induced DNA double-strand breaks. Boron phenylalanine (BPA) was used as a control boron-carrying agent. Results: O-carborane-entrapped polymeric micelles (M-carb) had a diameter of about 60 nm and a relatively narrow size distribution (polydispersity index ~0.15) and possessed a slight negative charge. After 6 h incubated with M-carb at an equivalent concentration of 200 µM boron, MIA PaCa-2 cells were found to have taken up ~45 ng 11Boron per million cells. The colony formation assay demonstrated a significant decrease in the survival rate of MIA PaCa-2 cells after 8 Gy proton irradiation in the presence of 40 ppm of boron (corresponding to 4.61 µM BPA or 0.46 µM carborane) compared to irradiation treatment alone (p<0.05). At 8 Gy, the survival rates were 0.10, 0.07, and 0.04 for the following irradiation conditions: i) irradiation alone; ii) in the presence of BPA; in the presence of M-carb. At 2 and 5 Gy, these survival rate values were 0.78, 0.69, and 0.69 and 0.33, 0.19, and 0.16, respectively. Importantly, M-carb alone at the concentration used in proton irradiation experiments displayed no cytotoxicity. Immunofluorescence assays revealed that at both 2 Gy and 5 Gy, BPA and M-carb significantly increased γH2AX foci compared to irradiation alone (p<0.0001). Conclusion: M-carb was efficiently taken up by MIA PaCa-2 cells. PBCT mediated by M-carb or BPA enhanced the relative biological effectiveness of proton therapy with consequent improvement of its cell-killing efficacy in pancreatic cancer cells. This approach holds promise for advancing proton therapy as a new treatment modality for pancreatic cancer. Citation Format: Qiu-Xu Teng, Guodong Zhang, Haiyan Chen, Filipa Mendes, Narayan Sahoo, Célia Fernandes, António Paulo, Chun Li. O-carborane-entrapped polymeric Micelles for Proton Boron Capture Therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2885.

Glutathione Reductase-Sensitive Polymeric Micelles for Controlled Drug Delivery on Arthritic Diseases.

Inflammation plays an essential role in arthritis development and progression. Despite the advances in the pharmaceutical field, current treatments still present low efficacy and severe side effects. Considering the high activity of the glutathione reductase (GR) enzyme in inflamed joints, a distinctive drug delivery system sensitive to the GR enzyme was designed for efficient drug delivery on arthritic diseases. A linear amphiphilic polymer composed of methoxypolyethylene glycol amine-glutathione-palmitic acid (mPEG-GSHn-PA) was synthesized and the intermolecular oxidation of the thiol groups from GSHs retain the drug inside the resulting micelles. Stable polymeric micelles of 100 nm of size presented a loading capacity of dexamethasone (Dex) up to 65%. Although in physiological conditions the Dex release presented slow and sustained kinetics, in the presence of the GR enzyme, there was a burst release (stimuli-responsive properties). Biological assays demonstrated their cytocompatibility in contact with human articular chondrocytes, macrophages, and endothelial cells as well as their hemocompatibility. Importantly, in an in vitro model of inflammation, the polymeric micelles promoted a controlled drug release in the presence of GR, exhibiting a higher efficacy than the free Dex while reducing the negative effects of the drug into normal cells. In conclusion, this formulation is a promising approach to treat arthritic diseases and other inflammatory conditions.

Exploring the feasibility of carbamoylethyl pullulan-g-palmitic acid polymeric micelles for the effective targeting of raloxifene to breast tumor: Optimization and preclinical evaluation

Carbamoylethyl pullulan-grafted palmitic acid (CP-g-PA), a novel self-assembled polymer was synthesized and examined for its efficacy in delivering the raloxifene (RA) to mammary carcinoma. The synthesized CP-g-PA was confirmed by evaluating through various spectral and morphological attributes. Further, the central composite design-response surface methodology with two factors at three levels was utilized to obtain the optimized and stable polymeric micelles. The optimized formulation was subjected to in vitro and in vivo evaluation. RA loaded polymeric micelles (RA-PMs) were spherical in shape with particle size less than 100 nm and high entrapment efficiency (77.02%). The developed formulation exhibited pH-dependent release profile of RA when loaded in polymeric micelles and provides substantial compatibility to erythrocytes. In vivo pharmacokinetic study demonstrates that RA-PMs offers higher mean residence time and volume of distribution as compared to pure RA. Besides, the biodistribution study manifested enhanced drug concentration in tumor and decreased concentration in other tissue as compared to pure drug. The treatment with RA-PMs also increases the median survival time, tumor inhibition rate and % increase in life span of the tumor bearing rats. Overall, the results pointed towards the overwhelming response of RA when loaded into micelles made from CP-g-PA.

Interface crosslinked mPEG-b-PAGE-b-PCL triblock copolymer micelles with high stability for anticancer drug delivery

The stability of polymeric micelles is a key property for anticancer drug delivery. In this study, a novel amphiphilic triblock copolymer, methoxy poly(ethylene glycol)-b-poly(allyl glycidyl ether)-b-poly(ε-caprolactone) (mPEG-b-PAGE-b-PCL), with different hydrophobic lengths was designed and synthesized using the combination of two successive ring-opening polymerizations. The products were characterized using 1H NMR and gel permeation chromatography (GPC). The triblock copolymers could self-assemble into micelles to encapsulate doxorubicin (DOX). The diameter of the DOX-loaded micelles increased from 63 to 92 nm with increasing PCL block length in the copolymer composition. The interface of the mPEG-b-PAGE-b-PCL micelles was crosslinked by a thiol-ene reaction with 1,4-butanedithiol. The stability, drug release and in vitro cytotoxicity of the DOX-loaded micelles were studied. The results showed that the DOX-loaded micelles could be effectively endocytosed by cancer cells and have good antitumor efficacy. In addition, the crosslinked micelles (CLMs) had better tumor accumulation than the noncrosslinked micelles (NCLMs) after intravenous injection using the lipophilic dye DiR.

The effect of π-Conjugation on the self-assembly of micelles and controlled cargo release

Here we presented a novel micelle self-assembled from amphiphiles with π-conjugated moieties (OEG-DPH). The π-conjugated structural integrity of the micelles enabled stable encapsulation of Nile Red (NR, model drug). The self-assembly behaviour of the amphiphiles and the release profile of NR loaded micelles were investigated. Spherical core-shell structured NR loaded micelles with low CMC of 57 μg/mL and the efficient intracellular delivery process was monitored. This research provided a way to fabricate stable polymeric micelles and develop a practical nanocarrier for therapeutics delivery.

Novel thymoquinone loaded chitosan-lecithin micelles for effective wound healing: Development, characterization, and preclinical evaluation

While the wound healing activity of thymoquinone (TQ) is well known, its clinical effectiveness remains limited due to the inherently low aqueous solubility, resulting in suboptimal TQ exposure in the wound sites. To address these problems, TQ loaded chitosan-lecithin micelles for wound healing were prepared and its efficacy was determined in vivo in the excision wound model. Firstly, the co-block polymer of chitosan and soya lecithin was synthesized which has low critical micelle concentration (CMC). Its employment in the development of TQ loaded polymeric micelles by Self-assembly method resulted in the stable polymeric micelle composition having requisite small particle size (<100 nm), narrow size distribution (close to zero) and high entrapment efficiency (98.77 %) of TQ. The designed nano-carriers not only substantially entrapped the drug but also controlled the release rate of TQ. The TQ-polymeric micelle hydrogel exhibited superior wound healing efficacy to the native TQ and Silver Sulphadiazine.

Brush-shaped RAFT polymer micelles as nanocarriers for a ruthenium (II) complex photodynamic anticancer drug

Amphiphilic polymers containing brush-shaped poly(polyethylene glycol methyl ether acrylate) (PEGA) as a hydrophilic segment may form a stable hydrophilic shell for a polymeric micelle due to a strong interaction among the brush shaped molecules. In this paper, polymeric micelles with brush-shaped poly(PEGA) as hydrophilic shell were designed and formulated as nanocarriers for a new ruthenium (II) complex anticancer drug to address its poor water solubility. Well defined brush-shaped poly(PEGA)-containing amphiphilic block polymers were synthesised by reversible addition-fragmentation chain transfer (RAFT) polymerisation. The as-prepared amphiphilic polymers formed stable polymeric micelle nanocarriers for the hydrophobic ruthenium (II) complex, resulting in greatly increased solubility of the drug by inhibiting its aggregation in aqueous environment. Cytotoxicity studies demonstrated that the use of polymeric micelle nanocarriers increased the drug’s toxicity to human liver cancer cells (SK-HEP-1) by 3 fold under dark and 12 fold under light conditions. However, both bare drug and encapsulated drug showed no toxicity to the normal cells, demonstrating the drug’s potential targeting capacity to cancer cells.

Self-assembly and drug release control of dual-responsive copolymers based on oligo(ethylene glycol)methyl ether methacrylate and spiropyran

To compare the synthesis and drug release of random and block copolymers, random and block copolymerizations of oligo(ethylene glycol)methyl ether methacrylate (OEGMA) and 1′-(2-methacryloxyethyl)-3′,3′-dimethyl-6-nitrospiro-(2H-1-benzopyran-2,2′-indoline) (SPMA) were carried out by atom transfer radical polymerization. The 1H NMR and GPC results indicated the targeted random and block copolymers were successfully synthesized. Critical micelle concentrations of random and block copolymers were determined as 0.0178 mg/mL and 0.0265 mg/mL, and the micelle aggregation numbers of the random and block copolymers were calculated as approximately 17 and 13, respectively, indicating that more molecular chains were required to form a stable polymeric micelle for a random than its block copolymer. A lower critical solution temperature of 37 °C, the human body temperature, was obtained for two copolymer samples, suggesting that they might have potential application in the biomedical field. During the self-assembly, the morphology of block copolymer micelles was more regular than that of random copolymer, and both copolymers exhibited the exchange of hydrophilic and hydrophobic segments called as “Schizophrenic” behavior under UV light irradiation at 50 °C. With doxorubicin as a model molecule in drug release control, heating and ultraviolet light irradiation could accelerate the drug release process to some extent, indicating the potential application of the resulting random and block copolymers in drug release and bioengineering.

Reduction-responsive interlayer-crosslinked micelles prepared from star-shaped copolymer via click chemistry for drug controlled release

To improve the stability of polymeric micelles, here we describe interlayer-crosslinked micelles prepared from star-shaped copolymer via click chemistry. The formation of interlayer-crosslinked micelles was investigated and confirmed by proton nuclear magnetic resonance, Fourier-transform infrared spectroscopy, and fluorescence spectroscopy. The morphology of un-crosslinked micelles and crosslinked micelles observed by transmission electron microscope is both uniform nano-sized spheres (approximately 20 nm). The crosslinking enhances the stability of polymeric micelles and improves the drug loading capacity of polymeric micelles. The interlayer-crosslinked micelles prepared from star-shaped copolymer and a crosslinker containing a disulfide bond are reduction-responsive and can release the drug quickly in the presence of the reducing agents such as glutathione (GSH).

Design of theranostic nanomedicine (II): synthesis and physicochemical properties of a biocompatible polyphosphazene&amp;ndash;docetaxel conjugate

To prepare an efficient theranostic polyphosphazene–docetaxel (DTX) conjugate, a new drug delivery system was designed by grafting a multifunctional lysine ethylester (LysOEt) as a spacer group along with methoxy poly(ethylene glycol) (MPEG) to the polyphosphazene backbone ([NP]n), and then DTX was conjugated to the carrier polymer using acid-cleavable cis-aconitic acid (AA) as a linker. The resultant polyphosphazene–DTX conjugate, formulated as [NP(MPEG550)3(Lys-OEt)(AA)(DTX)]n and named “Polytaxel”, exhibited high water solubility and stability by forming stable polymeric micelles as shown in its transmission electron microscopy image and dynamic light scattering measurements. Another important aspect of Polytaxel is that it can easily be labeled with various imaging agents using the lysine amino group, enabling studies on various aspects, such as its organ distribution, tumor-targeting properties, pharmacokinetics, toxicity, and excretion. The pharmacokinetics of Polytaxel was remarkably improved, with prolonged elimination half-life and enhanced area under the curve. Ex vivo imaging study of cyanine dye-labeled Polytaxel showed that intravenously injected Polytaxel is long circulating in the blood stream and selectively accumulates in tumor tissues. Polytaxel distributed in other organs was cleared from all major organs at ~6 weeks after injection. The in vitro study of DTX release from the carrier polymer showed that >95% of conjugated DTX was released at pH 5.4 over a period of 7 days. Xenograft trials of Polytaxel using nude mice against the human gastric tumor cell line MKN-28 showed complete tumor regression, with low systemic toxicity. Polytaxel is currently in preclinical study.

Polymeric micelle nanocarriers in cancer research

Amphiphilic block copolymers (ABCs) assemble into a spherical nanoscopic supramolecular core/shell nanostructure termed a polymeric micelle that has been widely researched as an injectable nanocarrier for poorly water-soluble anticancer agents. The aim of this review article is to update progress in the field of drug delivery towards clinical trials, highlighting advances in polymeric micelles used for drug solubilization, reduced off-target toxicity and tumor targeting by the enhanced permeability and retention (EPR) effect. Polymeric micelles vary in stability in blood and drug release rate, and accordingly play different but key roles in drug delivery. For intravenous (IV) infusion, polymeric micelles that disassemble in blood and rapidly release poorly water-soluble anticancer agent such as paclitaxel have been used for drug solubilization, safety and the distinct possibility of toxicity reduction relative to existing solubilizing agents, e.g., Cremophor EL. Stable polymeric micelles are long-circulating in blood and reduce distribution to non-target tissue, lowering off-target toxicity. Further, they participate in the EPR effect in murine tumor models. In summary, polymeric micelles act as injectable nanocarriers for poorly water-soluble anticancer agents, achieving reduced toxicity and targeting tumors by the EPR effect.

The effect of photoisomerization on the enzymatic hydrolysis of polymeric micelles bearing photo-responsive azobenzene groups at their cores.

The design of stable polymeric micelles that can respond to specific stimuli is crucial for the development of smart micellar nanocarriers that can release their active cargo selectively at the target site, thus diminishing the therapeutic limitations due to non-selective damage to healthy tissues. Here we report the design and synthesis of photo- and enzyme-responsive amphiphilic PEG-dendron hybrids bearing one, two or four enzymatically cleavable azobenzene end-groups. These dual-responsive hybrids can respond to light through the reversible isomerization of the azobenzene end-groups from the non-polar trans isomer to the highly polar cis isomer and vice versa, upon UV and visible irradiation, respectively. The high structural precision of these hybrids, which emerges from the dendritic architecture, enabled a detailed study of the photoisomerization of the azobenzene end-groups with high molecular resolution. Remarkably, although the transition from trans-to-cis led to a significant increase in the polarity of the micellar cores, the micelles remained stable. Our kinetic studies show that although the trans isomer is a better substrate for the activating enzyme, the UV induced formation of the cis azobenzene end-groups led to significant acceleration of the enzymatic hydrolysis of the end-groups. These results provide strong indication that the enzyme cannot reach the core of the micelles and instead the end-groups have to leave the hydrophobic core in order to be exposed on the micelle's surface or even leave the micelle in order to allow their cleavage by the activating enzymes.

Non-invasive topical drug delivery to spinal cord with carboxyl-modified trifunctional copolymer of ethylene oxide and propylene oxide

In this study the effect of oxidative modification on micellar and drug delivery properties of copolymers of ethylene oxide (EO) and propylene oxide (PO) was investigated. Carboxylated trifunctional copolymers were synthesized in the reaction with chromium(VI) oxide. We found that carboxylation significantly improved the uniformity and stability of polymeric micelles by inhibiting the microphase transition. The cytotoxicity of copolymers was studied in relation to their aggregative state on two cell types (cancer line vs. primary fibroblasts). The accumulation of rhodamine 123 in neuroblastoma SH-SY5Y cells was dramatically increased in the presence of the oxidized block copolymer with the number of PO and EO units of 83.5 and 24.2, respectively. The copolymer was also tested as an enhancer for topical drug delivery to the spinal cord when applied subdurally. The oxidized copolymer facilitated the penetration of rhodamine 123 across spinal cord tissues and increased its intraspinal accumulation. These results show the potential of using oxidized EO/PO based polymers for non-invasive delivery of protective drugs after spinal cord injury.

Long circulating and stable polymeric micelles for targeted delivery of paclitaxel

Long circulating and stable polymeric micelles for targeted delivery of paclitaxel

Self-assembled polymeric nanocarriers for the targeted delivery of retinoic acid to the hair follicle.

Acne vulgaris is a highly prevalent dermatological disease of the pilosebaceous unit (PSU). An inability to target drug delivery to the PSU results in poor treatment efficacy and the incidence of local side-effects. Cutaneous application of nanoparticulate systems is reported to induce preferential accumulation in appendageal structures. The aim of this work was to prepare stable polymeric micelles containing retinoic acid (RA) using a biodegradable and biocompatible diblock methoxy-poly(ethylene glycol)-poly(hexylsubstituted lactic acid) copolymer (MPEG-dihexPLA) and to evaluate their ability to deliver RA to skin. An innovative punch biopsy sample preparation method was developed to selectively quantify follicular delivery; the amounts of RA present were compared to those in bulk skin, (i.e. without PSU), which served as the control. RA was successfully incorporated into micelle nanocarriers and protected from photoisomerization by inclusion of Quinoline Yellow. Incorporation into the spherical, homogeneous and nanometer-scale micelles (dn < 20 nm) increased the aqueous solubility of RA by >400-fold. Drug delivery experiments in vitro showed that micelles were able to deliver RA to porcine and human skins more efficiently than Retin-A(®) Micro (0.04%), a marketed gel containing RA loaded microspheres, (7.1 ± 1.1% vs. 0.4 ± 0.1% and 7.5 ± 0.8% vs. 0.8 ± 0.1% of the applied dose, respectively). In contrast to a non-colloidal RA solution, Effederm(®) (0.05%), both the RA loaded MPEG-dihexPLA polymeric micelles (0.005%) and Retin-A(®) Micro (0.04%) displayed selectivity for delivery to the PSU with 2-fold higher delivery to PSU containing samples than to control samples. Moreover, the micelle formulation outperformed Retin-A(®) Micro in terms of delivery efficiency to PSU presenting human skin (10.4 ± 3.2% vs. 0.6 ± 0.2%, respectively). The results indicate that the polymeric micelle formulation enabled an increased and targeted delivery of RA to the PSU, potentially translating to a safer and more efficient clinical management of acne.

Anticancer efficacy of a supramolecular complex of a 2-diethylaminoethyl-dextran-MMA graft copolymer and paclitaxel used as an artificial enzyme.

The anticancer efficacy of a supramolecular complex that was used as an artificial enzyme against multi-drug-resistant cancer cells was confirmed. A complex of diethylaminoethyl–dextran–methacrylic acid methylester copolymer (DDMC)/paclitaxel (PTX), obtained with PTX as the guest and DDMC as the host, formed a nanoparticle 50–300 nm in size. This complex is considered to be useful as a drug delivery system (DDS) for anticancer compounds since it formed a stable polymeric micelle in water. The resistance of B16F10 melanoma cells to PTX was shown clearly through a maximum survival curve. Conversely, the DDMC/PTX complex showed a superior anticancer efficacy and cell killing rate, as determined through a Michaelis–Menten-type equation, which may promote an allosteric supramolecular reaction to tubulin, in the same manner as an enzymatic reaction. The DDMC/PTX complex showed significantly higher anticancer activity compared to PTX alone in mouse skin in vivo. The median survival times of the saline, PTX, DDMC/PTX4 (particle size 50 nm), and DDMC/PTX5 (particle size 290 nm) groups were 120 h (treatment (T)/control (C), 1.0), 176 h (T/C, 1.46), 328 h (T/C, 2.73), and 280 h (T/C, 2.33), respectively. The supramolecular DDMC/PTX complex showed twice the effectiveness of PTX alone (p < 0.036). Above all, the DDMC/PTX complex is not degraded in cells and acts as an intact supramolecular assembly, which adds a new species to the range of DDS.

Role of non-covalent and covalent interactions in cargo loading capacity and stability of polymeric micelles.

Polymeric micelles self-assembled from biodegradable amphiphilic block copolymers have been proven to be effective drug delivery carriers that reduce the toxicity and enhance the therapeutic efficacy of free drugs. Several reviews have been reported in the literature to discuss the importance of size/size distribution, stability and drug loading capacity of polymeric micelles for successful in vivo drug delivery. This review is focused on non-covalent and covalent interactions that are employed to enhance cargo loading capacity and in vivo stability, and to achieve nanosize with narrow size distribution. In particular, this review analyzes various non-covalent and covalent interactions and chemistry applied to introduce these interactions to the micellar drug delivery systems, as well as the effects of these interactions on micelle stability, drug loading capacity and release kinetics. Moreover, the factors that influence these interactions and the future research directions of polymeric micelles are discussed.

Synthesis and properties of a new micellar polyphosphazene–platinum(II) conjugate drug

Aiming at tumor targeting delivery of oxaliplatin using polymer therapy, a new monomeric platinum(II) complex (dach)Pt[HEDM] (dach: trans-(±)-1,2-diaminocyclohexane; HEDM: 2-hydroxyethoxydiethylmalate) was designed to include the antitumor moiety (dach)Pt and HEDM as a linker to the polyphosphazene backbone. This monomeric Pt-complex could easily be grafted to the PEGylated polyphosphazene backbone to prepare a novel polyphosphazene–Pt conjugate, [NP(MPEG550)(dach)Pt(EM)]n [MPEG550: methoxy poly(ethylene glycol) with an average molecular weight of 550; EM: ethoxymalate]. This amphiphilic polyphosphazene–Pt conjugate was found to self-assemble into stable polymeric micelles of a mean diameter of 130nm, which is suitable for passive tumor targeting by enhanced permeability and retention (EPR) effect. Pharmacokinetic study of this polymer conjugate exhibited long blood circulation as expected and longer half-life (t1/2β=9.52h) compared with oxaliplatin (3.47h), and much larger AUC (area under the curve) value (25,831ng·h/mL) compared with oxaliplatin (1194ng·h/mL). Biodistribution study of the polymer conjugate has shown excellent tumor selectivity with the tumor to tissue ratio of 3.84 at 2h post injection and 11.7 at 24h post injection probably due to the EPR effect of the polymer conjugate while no tumor selectivity was observed for monomeric oxaliplatin. Furthermore, accumulation of this polymer conjugate in kidney was much lower compared with oxaliplatin. Also the nude mouse xenograft trial of the polymer conjugate has shown higher antitumor efficacy compared with oxaliplatin.

In vitro evaluation of pH-sensitive cholesterol-containing stable polymeric micelles for delivery of camptothecin

Two novel amphiphilic statistical copolymers poly(cholesteryl acrylate-co-methoxypoly(ethylene glycol) methacrylate), poly[CHOLy-co-mPEGn,x] (for n=5, x=110 and y=15, and for n=23, x=22 and y=3) with copolymer composition (x:y) of 7:1 were designed and synthesized as a delivery system for water-insoluble anticancer agent, S-(+)-camptothecin (CPT). The polymers were synthesized using reversible addition fragmentation chain transfer (RAFT) polymerization technique and they were found to form stable polymeric micelles in water above a relatively low critical concentration. The polymeric micelles (PMs) were characterized by a number of techniques including surface tension, fluorescence, dynamic light scattering, and electron microscopy. Incorporation of CPT into the micelles and the stability of CPT-loaded micelles were studied by spectrophotometric method. Sustained release of an encapsulated fluorescent guest triggered by hydrolysis of the ester linkages in acidic pH is demonstrated. The polymers are not only hemocompatible and nontoxic in the allowed concentration range, but also they can easily permeate into the cancer cells (MCF7 and HeLa). The in vitro drug delivery assay of CPT-loaded polymeric micelles on cancer cells (HeLa) showed very good chemotherapeutic activity in the biocompatible concentration range of the copolymers.