Conjugate Micelles Research Articles

Oral Curcumin-Thioketal-Inulin Conjugate Micelles against Radiation-Induced Enteritis.

Radiation-induced enteritis is an unavoidable complication associated with pelvic tumor radiotherapy, significantly influencing the prognosis of cancer patients. The limited availability of commercial gastrointestinal radioprotectors in clinical settings poses a substantial challenge in preventing radiation enteritis. Despite the inherent radioprotective characteristics of Cur in vitro, its poor solubility in water, instability, and low bioavailability lead to inferior therapeutic effects in vivo. Herein, we developed novel ROS-responsive micelles (CTI) from inulin and curcumin, aimed at mitigating radiation enteritis. CTI micelles had excellent solubility and stability. Importantly, CTI improved the cytotoxicity and bioavailability of curcumin, thereby showing enhanced effectiveness in neutralizing ROS induced by radiation, safeguarding against DNA damage, and reducing radiation-induced cellular mortality. Moreover, in a radiation enteritis mice model, CTI not only alleviated severe radiation-induced intestinal injury but also improved redox-related indicators and reduced inflammatory cytokine expression. Furthermore, CTI effectively increased gut microbiota abundance and maintained gut homeostasis. In conclusion, CTI could be a promising candidate for the clinical management of radiation enteritis. Our study provides a new perspective for radioprotection using natural antioxidants.

Chondroitin Sulfate-Derived Micelles for Adipose Tissue-Targeted Delivery of Celastrol and Phenformin to Enhance Obesity Treatment.

Adipose tissue macrophages (ATMs) are crucial in maintaining a low-grade inflammatory microenvironment in adipose tissues (ATs). Modulating ATM polarization to attenuate inflammation represents a potential strategy for treating obesity with insulin resistance. This study develops a combination therapy of celastrol (CLT) and phenformin (PHE) using chondroitin sulfate-derived micelles. Specifically, CLT-loaded 4-aminophenylboronic acid pinacol ester-modified chondroitin sulfate micelle (CS-PBE/CLT) and chondroitin sulfate-phenformin conjugate micelles (CS-PHE) were synthesized, which were shown to actively target ATs through CD44-mediated pathways. Furthermore, the dual micellar systems significantly reduced inflammation and lipid accumulation via protein quantification and Oil Red O staining. In preliminary in vivo studies, we performed H&E staining, immunohistochemical staining, insulin tolerance test, and glucose tolerance test, and the results showed that the combination therapy using CS-PBE/CLT and CS-PHE micelles significantly reduced the average body weight, white adipose tissue mass, and liver mass of high-fat diet-fed mice while improving their systemic glucose homeostasis. Overall, this combination therapy presents a promising alternative to current treatment options for diet-induced obesity.

Visible light and pH-responsive star copolymer and doxorubicin-polymer conjugate micelles for combination drug delivery and bioimaging

Amphiphilic 3-arm star copolymer containing visible light-cleavable BODIPY group and pH-responsive imine bonds at the junction of hydrophilic poly(ethylene glycol) (PEG) and two poly(ε-caprolactone) (PCL) arms was synthesized by the combination of ring-opening polymerization (ROP) and click chemistry. The formation and stimuli-responsive disruption of micelles were analyzed using dynamic light scattering and transmission electron microscopy. Dual stimuli-responsive release of anticancer drugs Doxorubicin (Dox) and Camptothecin (CPT) from the micelles was studied. Micellar assemblies containing Dox conjugated to PEG-BODIPY through imine bonds were prepared and controlled release of Dox in response to visible light and pH was shown. CPT and Dox-loaded star copolymer micelles as well as CPT loaded Dox-conjugated micelles were used in cellular uptake studies on MDA-MB 231 cells, and the synergistic effect of the two stimuli on the release of the two drugs was demonstrated inside the cells. Micellar assemblies also showed excellent bioimaging properties in the cellular uptake studies.

The Influence of PEG Chain Length on the in vivo Tumor Accumulation of Self-assembled Amphiphilic Drug-PEG Polymeric Micelles

The integration of a drug and polyethylene glycol (PEG) into an amphiphilic polymer to form self-assembled micelles with high drug loading for self-delivery to tumors is recently reported, which has showed high clinical availability. However, the effect of PEG chain length on cell internalization efficiency and tumor targeting efficiency in this PEG-drug conjugate micelle self-delivery system has yet to be studied. Herein, pyropheophorbide-a (PhA) was used as a model drug and a fluorescent tracer to synthesize amphiphilic polymers with varying PEG chain lengths, which self-assembled into PhA-PEG2000 NPs and PhA-PEG5000 NPs with high drug loading (21.2% and 9.7%, respectively, according to calculation). The results showed that PhA-PEG2000 NPs had higher cell internalization in vitro than PhA-PEG5000 NPs, but much lower tumor accumulation in vivo than PhA-PEG5000 NPs. This was attributed to the longer in vivo blood circulation time of the latter. Furthermore, the in vitro and in vivo examinations revealed negligible side effects, indicating the intrinsic safety of the micelles. This study provides insight into the influence of PEG chain length on biodistribution of organs and tumor accumulation after intravenous administration of PEG-drug conjugate micelle and guides the design of drug incorporated amphiphilic polymer-based micelles.

Ultra-stable dextran conjugated prodrug micelles for oxidative stress and glycometabolic abnormality combination treatment of Alzheimer's disease

Sophisticated nanomedicines are continually being developed, but big obstacles remain before they finish the drug release mission. The first challenge is rupture possibility of structure when infinite dilution, competitive reaction of electrolytes and protein in blood circulation. In addition, low responsive drug release efficiency in the lesion site remains the major challenge for clinical application of nanomedicine combination treatment. In this study, we discussed the opportunities for Alzheimer's disease (AD) combination therapy based on the thermodynamically ultra-stable dextran conjugated prodrug micelles. Dextran-nateglinide conjugated prodrug micelles (NA) and dextran-vitamin E succinate conjugated prodrug micelles (VES) presented ultra-low critical micelle concentration of ~10−5 mM and high physiological stability when challenged by NaCl, sodium dodecyl sulphate (SDS), dodecyl dimethyl benzyl ammonium chloride (DDBAC) and no rupture of structure happened. The NA/insulin polymer-drug conjugate micelles (NA/INS PDC) and VES/insulin polymer-drug conjugate micelles (VES/INS PDC) efficiently cleaved by reactive oxygen species (ROS), leading to over 80% release of the encapsulated and conjugated drugs. The combination of nateglinide and insulin, vitamin E succinate and insulin improved the glucose metabolism, reduced oxidative stress, improved the mitochondrial function and recovered the cognitive capacity of mice. This work demonstrated a paradigm for specific and high efficacy AD combination therapy.

Oxaliplatin delivery via chitosan/vitamin E conjugate micelles for improved efficacy and MDR-reversal in breast cancer

A bioinspired chitosan/vitamin E conjugate (Ch/VES, 1:4) was synthesized, optimized based on chitosan's molecular weight (15, 300 kDa), and was assembled to entrap oxaliplatin (OXPt). 1H NMR, infrared spectroscopy, chromatography, X-ray photoelectron spectroscopy, X-ray diffraction, drug release, hemolysis, and stability studies were performed to characterize OXPt@Ch/VES micelles. The therapeutic efficacy of the micelles was tested in vitro in ER+/PR+/HER2− and triple-negative sensitive/resistant breast cancer cells, MCF-7 and MDA-MB-231 via cellular uptake, cytotoxicity, nuclear staining, DNA fragmentation, mitochondrial membrane potential, ROS generation, apoptosis, and cell cycle assays and in vivo using 4T1(Luc)-tumor-bearing mice. OXPt@Ch/VES Ms exhibited decreased IC50 towards MCF-7, MDA-MB-231 (sensitive/resistant) than OXPt. OXPt@Ch/VES Ms caused extensive DNA damage, mitochondrial depolarization, apoptosis, and cell-growth arrest (G2/M). OXPt@Ch/VES Ms treatment retarded tumor growth significantly, prolonged survival, and decreased nephrotoxicity than OXPt. The OXPt@Ch/VES Ms could serve as a potential nanomedicine to overcome conventional OXPt-mediated drug resistance/nephrotoxicity in breast cancer.

GE11 peptide-decorated acidity-responsive micelles for improved drug delivery and enhanced combination therapy of metastatic breast cancer.

Nanotechnology-mediated drug delivery systems suffer from insufficient retention in tumor tissues and unreliable drug release at specific target sites. Herein, we developed an epidermal growth factor receptor-targeted multifunctional micellar nanoplatform (GE11-DOX+CEL-M) by encapsulating celecoxib into polymeric micelles based on the conjugate of GE11-poly(ethylene glycol)-b-poly(trimethylene carbonate) with doxorubicin to suppress tumor growth and metastasis. The polymeric micelles maintained stable nanostructures under physiological conditions but quickly disintegrated in a weakly acidic environment, which is conducive to controlled drug release. Importantly, GE11-DOX+CEL-M micelles effectively delivered the drug combination to tumor sites and enhanced tumor cell uptake through GE11-mediated active tumor targeting. Subsequently, GE11-DOX+CEL-M micelles dissociated in response to intracellular slightly acidic microenvironmental stimuli, resulting in rapid release of celecoxib and doxorubicin to synergistically inhibit the proliferation and migration of tumor cells. Systemic administration of GE11-DOX+CEL-M micelles into mice bearing subcutaneous 4T1 tumor models resulted in higher tumor growth suppression and decreased lung metastasis of tumor cells compared with micelles without GE11 decoration or delivering only doxorubicin. Furthermore, the micelles effectively reduced the systemic toxicity of the chemotherapy drugs. This nanotherapeutic system provides a promising strategy for safe and effective cancer therapy.

Dimeric artesunate-choline conjugate micelles coated with hyaluronic acid as a stable, safe and potent alternative anti-malarial injection of artesunate

Artesunate (ARS) is the only artemisinin-based intravenous drug approved for treatment of malaria in the clinic. ARS is rapidly metabolized in vivo to short lived (∼30–45 min) but fast acting, dihydroartemisinin (DHA). The short half-life of DHA necessitates multiple dose administration to circumvent the risk of recrudescence and development of artemisinin resistance. In this work, we report a stable, safe and potent alternative artemisinin-based injectable nanocomplex consisting of dimeric artesunate-choline conjugate (dACC) micelles coated with hyaluronic acid (HA). Firstly, dACC was synthesized by one-step esterification of two artesunate molecules with 3-(dimethylamino)-1,2-propanediol followed by quaternization. After that, dACC was self-assembled into cationic nanomicelles and further coated with anionic small molecular weight HA. The HA-coated dACC nanocomplex (dACC/HA nanocomplex) has a narrow size distribution of about 30 nm. Hemolytic toxicity and cytotoxicity studies revealed a favorable bio-safety profile. Finally, in vitro and in vivo studies showed the dACC/HA nanocomplex possess superior safety and antimalarial efficacy compared to ARS. Taken together, the dACC/HA nanocomplex is a promising injectable alternative to the traditional clinically used artesunate.

Enhancing the anticancer efficacy of a LL-37 peptide fragment analog using peptide-linked PLGA conjugate micelles in tumor cells

LL-37, a well-known antimicrobial human peptide, is a cationic peptide that provides an important antimicrobial defense mechanism in damaged skin. Accumulating evidence indicates that LL-37 also displays an anticancer effect in colon cancer, gastric cancer, hematologic malignancy and oral squamous cell carcinoma. However, anticancer activity of LL-37 peptide fragment analogs has not been reported. Poor intercellular translocation may be one of the causes for this lack of observed anticancer activity. In this study, a LL-37 peptide fragment analog with cysteine at the N-terminus was conjugated with the biodegradable polymer, lactic acid/glycolic acid copolymer (PLGA), using the thiol group of cysteine. The purpose of this study was to improve the cell permeability of the peptide using a micellar system and then evaluate the anticancer activity. Cell proliferation, migration, and invasion assays were performed to evaluate the anticancer activity in four cancer cell lines with high metastasis, HM-1, B16/BL6, HeLa, and HepG2. The LL-37 fragment peptide analog-linked PLGA conjugate was shown to effectively inhibit cell proliferation, migration, and invasion and had increased cell permeability in all the cancer cell lines, compared with the peptide alone. These results suggested that LL-37 fragment peptide analog (CKR12)-linked PLGA conjugate micelles could be useful in the development of cancer therapeutics.

Vitamin-anticancer drug conjugates: a new era for cancer therapy

Background: Following cardiovascular diseases, cancer is the world's second leading cause of death. Chemotherapy is the conventional gold technique for successful treatment of cancer. There are some drawbacks associated with traditional chemotherapy, namely, low aqueous solubility, limited biological half-life, production of multidrug resistance and non-specificity (lack of targeting ability) or dose-limiting cellular toxicity. To develop a targeted drug delivery for its anticancer effect is still a challenging task. Methods: We developed literature review methods which included inclusion and exclusion criteria for identifying potentially relevant articles, articles search strategies, abstract review protocols and a comprehensive scoring system for published studies. This study contains a detailed survey of various reported methods such as folic acid-drug conjugates, CobalaminDrug Conjugate, Vitamin B12-Conjugated and Paclitaxel-Loaded Micelles etc., all of which were studied for their methods of preparation and possible impact on biological activity. Results: Due to its specific ability to carry anticancer drugs directly to tumours, vitamin-mediated drug targeting has recently emerged as a novel concept. Solid tumour cancer has an unquenchable appetite for various essential vitamins, resulting in over-expression of the receptors involved in cell internalization of vitamins on the surface of cancer cells. So, the vitamin drug conjugates are specifically important for carrying the anticancer drugs directly to the tumour cells. Biotin, folic acid, vitamin B12 and riboflavin, the vitamin necessary for the division of all cells, especially cancer cells, have recently been examined as targeting agents. Conclusion: Vitamin-Drug Conjugate methods were found to be the most suitable methods amongst all the other reported methods and they can be applied for current therapy against cancer.

Podophyllotoxin-polyacrylic acid conjugate micelles: improved anticancer efficacy against multidrug-resistant breast cancer

BackgroundPodophyllotoxin (PPT) is a naturally occurring compound obtained from the roots of Podophyllum species, indicated for a variety of malignant tumors such as breast, lung, and liver tumors. This toxic polyphenol (PPT) exhibited significant activity against P-glycoprotein (P-gp) mediated multidrug-resistant (MDR) cancer cells. However, extremely poor water solubility, a narrow therapeutic window, and high toxicity have greatly restricted the clinical uses of PPT. Therefore, the present research was aimed to synthesize the water-soluble ester prodrug of PPT with polyacrylic acid (PAA), a water-soluble polymer by Steglich esterification reaction, and to screen it for assay, solubility, in vitro hemolysis, in vitro release, and in vitro anticancer activity.ResultsThe Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy results revealed the successful synthesis of podophyllotoxin-polyacrylic acid conjugate (PPC). The assay and saturation solubility of the prodrug is found to be 64.01 ± 4.5% and 1.39 ± 0.05 mg/mL (PPT equivalent) respectively. The PPC showed CMC (critical micelle concentration) of 0.430 mg/mL in distilled water at room temperature. The PPC micelles showed a mean particle size of 215 ± 11 nm with polydispersity index (PDI) of 0.193 ± 0.006. Further, the transmission electron microscope (TEM) results confirmed the self-assembling character of PPC into micelles. The PPC caused significantly less hemolysis (18.6 ± 2.9%) than plain PPT solution. Also, it demonstrated significantly (p < 0.01) higher in vitro cytotoxicity against both sensitive as well as resistance human breast cancer cells (MCF-7 and MDA MB-231) after 48 h of treatment.ConclusionThe obtained study results clearly revealed the notable in vitro anticancer activity of PPT following its esterification with PAA. However, further in vivo studies are needed to ascertain its efficacy against a variety of cancers.

Lapatinib-loaded acidity-triggered charge switchable polycarbonate-doxorubicin conjugate micelles for synergistic breast cancer chemotherapy

Stimulus-responsive nanosystem is a powerful method to improve the bioavailability and reduce the side effects of anticancer agents. In the present study, a customized dual pH-responsive micellar nanoplatform (DOX+LAP-M) based on polycarbonate-doxorubicin conjugate micelles was prepared to co-deliver the chemotherapeutic agent lapatinib for inhibiting tumor growth and metastasis. DOX+LAP-M micelles with spherical morphology had a size of ~112 nm and had an initial negative surface charge, which are favorable characteristics for long-term circulation in the blood. Once the micelles accumulated in tumor tissues, the intrinsic tumor extracellular acidity triggered the charge switch of DOX+LAP-M micelles from -1 to 9 mV, thereby facilitating cell internalization and tumor penetration. Subsequently, the pH-sensitive micellar core accelerated the release of doxorubicin and lapatinib in the acidic intracellular environment. DOX+LAP-M micelles effectively inhibited the proliferation, migration, and invasion of 4T1 cells in vitro; furthermore, the administration of DOX+LAP-M micelles in 4T1 xenograft-bearing mice suppressed solid tumor growth with an inhibitory rate of 90.2% and significantly decreased pulmonary metastatic nodules, without significant systemic toxicity. This multifunctional micellar system has high potential for clinical cancer therapy.

Temperature-triggered micellization of interferon alpha-diblock copolypeptide conjugate with enhanced stability and pharmacology

Polypeptides are useful in designing protein-polypeptide conjugates for therapeutic applications; however, they are not satisfactory in improving the stability of therapeutic proteins and extending their in vivo half-life. Here we show that thermally-induced self-assembly (TISA) of elastin-like polypeptide diblock copolymer fused interferon alpha (IFNα-ELPdiblock) into a spherical micelle can dramatically enhance the proteolytic stability of IFNα. Notably, the circulation half-life of IFNα-ELPdiblock micelle (54.7 h) is 124.3-, 5.7-, and 1.4-time longer than those of free IFNα (0.44 h), freely soluble IFNα-ELP (9.6 h), and PEGylated IFNα (39.0 h), respectively. Importantly, in a mouse model of ovarian tumor, IFNα-ELPdiblock micelle exhibited significantly enhanced tumor retention and antitumor efficacy over free IFNα, freely soluble IFNα-ELP, and even PEGylated IFNα. These findings provide a thermoresponsive supramolecular strategy of TISA to design protein-diblock copolypeptide conjugate micelles with enhanced stability and pharmacology.

Fenretinide-polyethylene glycol (PEG) conjugate with improved solubility enhanced cytotoxicity to cancer cell and potent in vivo efficacy

Fenretinide (4-HPR), a synthetic retinoid, has shown its antitumor activity in many tumor types with low cytotoxicity to normal cells and high clinical safety. However, the low water solubility limits its further biological applications. To increase solubility, 4-HPR was conjugated with methoxy polyethylene glycol carboxylic acid (mPEG2K-COOH) by an ester linkage between the phenol hydroxyl of 4-HPR and the carboxyl of mPEG2K-COOH. The 4-HPR-PEG2K conjugate micelles had mean size of 76.70 ± 1.248 nm with a narrow distribution and a low critical micelle concentration. In vitro cytotoxicity studies showed the micelles have higher cytotoxicity to A2780s and MCF-7 cells. Its IC50 was 4.7 and 4.1-fold lower than the free 4-HPR, respectively. Importantly, in vivo pharmacokinetic studies, the AUC of 4-HPR was found to be 2.3-fold higher in 4-HPR-PEG2K micelles compared to free 4-HPR. And the 4-HPR-PEG2K micelles had higher antitumor activity. Meanwhile, the histopathology analysis exhibited that the micellar treatment decreased the viability of A2780s cells and increased the level of induced apoptosis. Therefore, the enhanced activity of 4-HPR by the method of conjugation with mPEG2K-COOH could hopefully provide new insights into the matter of ovarian cancer and breast cancer treatment.

Self-assembly of oxidation-responsive polyethylene glycol-paclitaxel prodrug for cancer chemotherapy

Amphiphilic drug conjugates can self-assemble into nanovehicles for cancer drug delivery, but the key is to design stable yet intracellular labile drug linkers for drug retention during blood circulation but fast intracellular drug release. The conjugation of paclitaxel (PTX) is generally via the ester of its 2′-hydroxyl group, but the ester is either too stable to release PTX in the cytosol or so labile that hydrolyzes during circulation. Herein, we report a p-(boronic ester)benzyl-based tumor-specifically cleavable linker for preparing PTX-conjugate with polyethylene glycol (PEG, Mw = 5000 Da) (PEG-B-PTX). The amphiphilic PEG-B-PTX self-assembled into micelle with an average size of ~50 nm and a PTX loading content of 13.3 wt%. The PEG-B-PTX micelles were very stable at the normal physiological environment and thus circulated long in the blood compartment, but fast dissociated and released PTX in response to the elevated reactive‑oxygen species (ROS) level in tumors. The conjugate micelles showed significantly improved antitumor efficiency in vitro and in vivo against human glioma and breast cancer cells, and reduced toxicity compared to the clinically used Taxol. Thus, the PTX-conjugate micelles were characteristic of well-characterized chemical structure and nanostructure, precise and reproducible drug loading efficiency (i.e., 100%) and fixed loading content, high PTX loading content due to PTX itself as part of the carrier, no burst drug release, and easy and reproducible fabrication of the micelles, which are all essential for clinical translation.

Reduction-sensitive poly(ethylene glycol)–polypeptide conjugate micelles for highly efficient intracellular delivery and enhanced antitumor efficacy of hydroxycamptothecin

The non-specific biodistribution of traditional chemotherapeutic drugs against tumors is the key factor that causes systemic toxicity and hinders their clinical application. In this study, a reduction-sensitive polymer conjugate micelle was manufactured to achieve tumor-specific targeting, reduce toxic side-effects and improve anti-tumor activity of a natural anti-cancer drug, hydroxycamptothecin (HCPT). Therefore, HCPT was conjugated with methoxy-poly(ethylene glycol)-poly(β-benzyl-L-aspartate) (mPEG-PBLA) by a disulfide bond or succinate bond for the first time to obtain the mPEG-PBLA-SS-HCPT (PPSH) and mPEG-PBLA-CC-HCPT (PPCH) that would form micelles after high-speed agitation and dialysis. The PPSH micelles showed an average particle size of 126.3 nm, a low polydispersity index of 0.209, and a negative surface charge of −21.1 mV zeta potential. Transmission electron microscopy showed the PPSH micelles to have spherical morphology. PPSH had a low critical micelle concentration of 1.29 μg ml−1 with high dilution stability, storage stability and reproducibility. Moreover, the particle size of the PPSH micelles had no significant change after incubation with rat plasma for 72 h, probably resulting in high long circulation in the blood. The PPSH micelles showed significant reduction sensitivity to glutathione. Their sizes increased by 403.2 nm after 24 h post-incubation, and 87.6% drug release was achieved 48 h post-incubation with 40 mM glutathione solutions. The PPSH micelles showed stronger inhibition of HepG2 cells in vitro and growth of H-22 tumor in vivo than the PPCH and HCPT solutions after intravenous injection. The accumulation of PPSH micelles in the tumor tissue contributed to the high anti-tumor effect with little side-effect on the normal tissues. The reduction-sensitive PPSH micelles were a promising carrier of HCPT and other poorly soluble anti-cancer drugs.

Multi pH-sensitive polymer-drug conjugate mixed micelles for efficient co-delivery of doxorubicin and curcumin to synergistically suppress tumor metastasis.

Combination therapy has been proved to be an effective strategy to inhibit metastasis, however, its efficacy is always compromised by the poor delivery efficiency of drugs. In this study, multi pH-sensitive polymer-drug conjugate mixed micelles were fabricated by the self-assembly of PEOz-PLA-ace-Cur, a conjugate of curcumin (Cur) with poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA) through the linkage of the pH-cleavable acetal bond, and PEOz-PLA-imi-DOX, a conjugate of doxorubicin (DOX) with PEOz-PLA through the linkage of the pH-cleavable benzoic imine bond. The mixed conjugate micelles (PP-Cur/PP-DOX-Mix-PMs) with accurately and conveniently controlled mass ratio of the two drugs were demonstrated to have a small particle size (40-128 nm), high drug loading capacity and pH-dependent drug release behavior. Notably, PP-Cur5/PP-DOX1-Mix-PMs exhibited slower DOX release under physiological conditions compared with PEOz-PLA-imi-DOX micelles, resulting in deeply reduced side effects in vivo. Furthermore, the mixed conjugate micelles showed synergistically enhanced inhibition of MDA-MB-231 cell growth and metastasis evidenced by the results of in vitro anti-invasion, wound healing and anti-migration assessment, and in vivo bioluminescence imaging in nude mice, and significant reduction of the side effects of DOX compared with dual drug physically loaded polymeric micelles. Mechanistic studies demonstrated that the possible inhibitory mechanism of PP-Cur5/PP-DOX1-Mix-PMs on tumor metastasis could be assigned to their inhibition of the invasion, migration, intravasation and extravasation of tumor cells. In conclusion, the multi pH-sensitive polymer-drug conjugate mixed micelles with synergistically enhanced anti-tumor and anti-metastasis activity are potential candidates for safe and effective cancer combination therapy.

Molecular Self-Assembly of Bioorthogonal Aptamer-Prodrug Conjugate Micelles for Hydrogen Peroxide and pH-Independent Cancer Chemodynamic Therapy.

Chemodynamic therapy (CDT) has demonstrated new possibilities for selective and logical cancer intervention by specific manipulation of dysregulated tumorous free radical homeostasis. Current CDT methods largely rely on conversion of endogenous hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals via classical Fenton or Haber-Weiss chemistry. However, their anticancer efficacies are greatly limited by the requirement of strong acidity for efficient chemical reactions, insufficient tumorous H2O2, and upregulated antioxidant defense to counteract free radical-caused oxidative damage. Here, we present a new concept whereby bioorthogonal chemistry and prodrug are combined to create a new type of aptamer drug conjugate (ApDC): aptamer-prodrug conjugate (ApPdC) micelle for improved and cancer-targeted CDT. The hydrophobic prodrug bases can not only promote self-assembly of aptamers but also act as free radical generators via bioorthogonal chemistry. In depth mechanistic studies reveal that, unlike traditional CDT systems, ApPdC micelles enable in situ activation and self-cycling generation of toxic C-centered free radicals in cancer cells through cascading bioorthogonal reactions, with no dependence on either H2O2 or pH, yet concurrently with diminished cancerous antioxidation by GSH depletion for a synergistic CDT effect. We expect this work to provide new insights into the design of targeted cancer therapies and studies of free radical-related molecular mechanisms.

Site-Selective in Situ Growth-Induced Self-Assembly of Protein-Polymer Conjugates into pH-Responsive Micelles for Tumor Microenvironment Triggered Fluorescence Imaging.

Self-assembly of site-selective protein-polymer conjugates into stimuli-responsive micelles is interesting owing to their potential biomedical applications, ranging from molecular imaging to drug delivery, but remains a significant challenge. Herein we report a method of site-selective in situ growth-induced self-assembly (SIGS) to synthesize site-specific human serum albumin-poly(2-(diisopropylamino)ethyl methacrylate) (HSA-PDPA) conjugates that can in situ self-assemble into pH-responsive micelles with tunable morphologies. Indocyanine green (ICG) was selectively loaded into the core of sphere-like HSA-PDPA micelles to form pH-responsive fluorescence nanoprobes. The nanoprobes rapidly dissociated into protonated individual unimers at a transition pH of around 6.5, that is the extracellular pH of tumors, which resulted in a sharp fluorescence increase and markedly enhanced cellular uptake. In a tumor-bearing mouse model, they exhibited greatly enhanced tumor fluorescence imaging as compared to ICG alone and pH-nonresponsive nanoprobes. These findings suggest that pH-responsive and site-selective protein-polymer conjugate micelles synthesized by SIGS are promising as a new class of tumor microenvironment-responsive nanocarriers for enhanced tumor imaging and therapy.

Pluronic F127-cyclodextrin conjugate micelles for encapsulation of honokiol

To overcome honokiol’s poor water solubility and investigate its antifungal activity and pharmacokinetic property, Pluronic® F-127 (F127)-cyclodextrin conjugate was synthesized and employed to prepare honokiol-loaded micelles through emulsion-solvent evaporation method. The drug-loaded micelles were obtained with 92.30 ± 3.28% of encapsulation efficiency being higher than that obtained from F127 due to additional cyclodextrin inclusion. Fourier transformation infrared spectrometry and diffraction scanning calorimetry analysis tests demonstrated that honokiol was successfully encapsulated into the conjugate micelles in the amorphous or solid solution state because of their interactions. Meanwhile, in vitro antifungal activity experiment indicated that the MIC90 of drug-loaded micelles was 64 μg/mL, showing the same antifungal activity as pure honokiol although it obviously retarded honokiol’s release. In vivo pharmacokinetic results confirmed that in vivo area under curve and apparent distribution volume of honokiol in drug-loaded micelles were 2- and 1.69-folds higher than that for pure honokiol, with its obvious prolonged mean retention time and half-life period, respectively. The clearance rate of honokiol was also shortened about 2-fold in comparison with pure honokiol when encapsulated into the micelles. These results suggest that the developed F127-cyclodextrin micellar formulation is a promising drug delivery system for antifungal drugs.