Near-infrared Light-Triggered Size-Shrinkable theranostic nanomicelles for effective tumor targeting and regression.

Most nanomedicines with suitable sizes (normally 100-200 nm) exhibit favorable accumulation in the periphery of tumors but hardly penetrate into deep tumors. Effective penetration of nanomedicines requires smaller sizes (less than 30 nm) to overcome the elevated tumor interstitial fluid pressure. Moreover, integrating an efficient diagnostic agent in the nanomedicines is in high demand for precision theranostics of tumors. To this end, a near-infrared light (NIR) -triggered size-shrinkable micelle system (Fe3O4@AuNFs/DOX-M) coloaded antitumor drug doxorubicin (DOX) and biomodal imaging agent magnetic gold nanoflower (Fe3O4@AuNFs) was developed to achieve efficient theranostic of tumors. Upon the accumulation of Fe3O4@AuNFs/DOX-M in the tumor periphery, a NIR laser was irradiated near the tumor site, and the loaded Fe3O4@Au NFs could convert the light energy to heat, which triggered the cleavage of DOX-M to the ultra-small micelles (∼5 nm), thus realizing the deep penetration of micelles and on-demand drug release. Moreover, Fe3O4@AuNFs in the micelles could also be used as CT/MRI dual-modal contrast agent to "visualize" the tumor. Up to 92.6 % of tumor inhibition was achieved for the developed Fe3O4@AuNFs/DOX-M under NIR irradiation. This versatile micelle system provided a promising drug carrier platform realizing efficient tumor dual-modal diagnosis and photothermal-chemotherapy integration.

An FOF1-ATPase motor-embedded chromatophore as a nanorobot for overcoming biological barriers and targeting acidic tumor sites.

Despite the booming progress of anticancer nanomedicines in the past two decades, precise tumor-targetability and sufficient tumor-accumulation are less successful and still require further research. To tackle this challenge, herein we present a biomolecular motor (FOF1-ATPase)-embedded chromatophore as nanorobot to efficiently overcome biological barriers, and thoroughly investigate its chemotactic motility, tumor-accumulation ability and endocytosis. Chromatophores embedded with FOF1-ATPase motors were firstly extracted from Thermus thermophilus, then their properties were fully characterized. Specifically, two microfluidic platforms (laminar flow microchip and tumor microenvironment (TME) microchip) were designed and developed to fully investigate the motility, tumor-accumulation ability and endocytosis of the chromatophore nanorobot (CN). The results from the laminar flow microchip indicated that the obtained CN possessed the strongly positive chemotaxis towards protons. And the TME microchip experiments verified that the CN had a desirable tumor-accumulation ability. Cellular uptake experiments demonstrated that the CN efficiently promoted the endocytosis of the fluorescence DiO into the HT-29 cells. And the in vivo studies revealed that the intravenously administered CN exhibited vigorous tumor-targetability and accumulation ability as well as highly efficient antitumor efficacy. All the results suggested that FOF1-ATPase motors-embedded CN could be promising nanomachines with powerful self-propulsion for overcoming physiological barriers and tumor-targeted drug delivery. STATEMENT OF SIGNIFICANCE: In this study, we demonstrated that FOF1-ATPase-embedded chromatophore nanorobots exhibit a strong proton chemotaxis, which not only plays a key role in tumor-targetability and accumulation, but also promotes tumor tissue penetration and internalization. The results of in vitro and in vivo studies indicated that drug-loaded chromatophore nanorobots are capable to simultaneously accomplish tumor-targeting, accumulation, penetration and internalization for enhanced tumor therapy. Our study provides a fundamental basis for further study on FOF1-ATPase-embedded chromatophore as tumor-targeting drug delivery systems that have promising clinical applications. It offers a new and more efficient delivery vehicle for cancer related therapeutics.

Targeted drug delivery systems for matrix metalloproteinase-responsive anoparticles in tumor cells: A review.

Nanodrug delivery systems based on tumor microenvironment responses have shown excellent performance in tumor-targeted therapy, given their unique targeting and drug-release characteristics. Matrix metalloproteinases (MMPs) have been widely explored owing to their high specificity and expression in various tumor microenvironments. The design of an enzyme-sensitive nanodelivery system using MMPs as targeted receptors could markedly improve the performance of drug targeting. The current review focuses on the development and application of MMP-responsive drug carriers, and summarizes the classification of single- and multi-target nanocarriers based on their MMP responsiveness. The potential applications and challenges of this nanodrug delivery system are discussed to provide a reference for designing high-performance nanodrug delivery systems.

Synergistic effects of multidrug/material combination deliver system for anti-mutidrug-resistant tumor.

Multidrug resistance (MDR) is a public health issue of particular concern, for which nanotechnology-based multidrug delivery systems are considered among the most effective suppressive strategies for such resistance in tumors. However, for such strategies to be viable, the notable shortcomings of reduced loading efficiency and uncontrollable drug release ratio need to be addressed. To this end, we developed a novel "multidrug/material" co-delivery system, using d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS, P-gp efflux pump inhibitor) and poly(amidoamine) (PAMAM) to fabricate a precursor material with the properties of reversing MDR and having a long-cycle. Further, to facilitate multidrug co-delivery, we loaded doxorubicin(Dox) and curcumin(Cur, cardiotoxicity modifier and P-gp inhibitor) into PAMAM-TPGS nano-micelles respectively, and mixed in appropriate proportions. The multidrug/material co-delivery system thus obtained was characterized by high drug loading and a controllable drug release ratio in the physiological environment. More importantly, in vitro and in vivo pharmacodynamic studies indicated that the multidrug/material co-delivery system facilitated the reversal of MDR. Moreover, the system has increased anti-tumor activity and is biologically safe. We accordingly propose that the "multidrug/material" co-delivery system developed in this study could serve as a potential platform for reversing MDR and achieving safe and effective clinical treatment.

Photopolymerizable, immunomodulatory hydrogels of gelatin methacryloyl and carboxymethyl chitosan as all-in-one strategic dressing for wound healing.

Microenvironment regeneration in wound tissue is crucial for wound healing. However, achieving desirable wound microenvironment regeneration involves multiple stages, including hemostasis, inflammation, proliferation, and remodeling. Traditional wound dressings face challenges in fully manipulating all these stages to achieve quick and complete wound healing. Herein, we present a VEGF-loaded, versatile wound dressing hydrogel based on gelatin methacryloyl (GelMA) and carboxymethyl chitosan (CMCS), which could be easily fabricated using UV irradiation. The newly designed GelMA-CMCS@VEGF hydrogel not only exhibited strong tissue adhesion capacity due to the interactions between CMCS active groups and biological tissues, but also possessed desirable extensible properties for frequently moving skins and joints. Furthermore, the hydrogel demonstrates exceptional abilities in blood cell coagulation, hemostasis and cell recruitment, leading to the promotion of endothelial cells proliferation, adhesion, migration and angiogenesis. Additionally, in vivo studies demonstrated that the hydrogel drastically shortened hemostatic time, and achieved satisfactory therapeutic efficacy by suppressing inflammation, modulating M1/M2 polarization of macrophages, significantly promoting collagen deposition, stimulating angiogenesis, epithelialization and tissue remodeling. This work contributes to the design of versatile hydrogel dressings for rapid and complete wound healing therapy.

Escherichia coli Nissle 1917-driven microrobots for effective tumor targeted drug delivery and tumor regression.

Potent tumor regression remains challenging due to the lack of effective targeted drug delivery into deep tumors as well as the reduced susceptibility of cancer cells to anticancer agents in hypoxic environments. Bacteria-driven drug-delivery systems are promising carriers in overcoming targeting and diffusion limits that are inaccessible for conventional antitumor drugs. In this study, probiotic facultative anaerobe Escherichia coli Nissle 1917 (EcN) was functionalized and formed self-propelled microrobots to actively deliver therapeutic drug and photosensitizer to the deep hypoxic regions of tumors. Doxorubicin (Dox) was firstly modified with cis-aconityl anhydride (CA) and terminal thiol-decorated hydrazone derivative (Hyd-SH) through dual pH-sensitive amide and imine bonds, respectively. The functionalized CA-Dox-Hyd-SH was further coordinated with photosensitizer gold nanorods (AuNRs) and then conjugated to the surface of EcN. The resulting microrobots (EcN-Dox-Au) inherited the mobility characteristics and bioactivity of native EcN. Upon the irradiation of NIR laser, the microrobots exhibited enhanced tumor accumulation and penetration into the deep hypoxia tumor site. Strikingly, after 21 days of treatment with EcN-Dox-Au formulations, complete tumor regression was achieved without relapse for at least 53 days. This self-propelled strategy utilizing bacteria-driven microrobots provides a promising paradigm for enhancing drug penetration and elevating chemosensitivity, resulting in a superior antitumor effect. STATEMENT OF SIGNIFICANCE: Self-propelled Escherichia coli Nissle 1917 (EcN) - mediated microrobots are functionalized to co-deliver therapeutic drugs and photosensitizers to the deep tumor site. Anti-tumor drug doxorubicin (Dox) was modified through dual pH-sensitive bonds on both terminals and then linked with EcN and photosensitizer gold nanorods (AuNRs) to realize tumor microenvironment acidic pH-responsive drug release. Upon irradiation with a NIR laser near the tumor site, AuNRs produced a photothermal effect which realized the superficial tumor thermal ablation and increased the permeability of the tumor cell membrane to facilitate the penetration of microrobots. Moreover, the deep penetration of microrobots also enhanced the susceptibility of the cancer cells to Dox, and realized the complete tumor regression in the established breast cancer-bearing mice without recurrence using a lower dose of drug regimen.

FOF1-ATPase Motor-Embedded Chromatophore as Drug Delivery System: Extraction, Cargo Loading Ability and Mucus Penetration Ability.

Mucosal drug delivery permits direct and prompt drug absorption, which is capable of reducing undesirable decomposition that occurs before absorption. However, mucus clearance of those mucosal drug delivery systems strongly retards their actual application. Herein, we propose chromatophore nanoparticles embedded with FOF1-ATPase motors to promote mucus penetration. The FOF1-ATPase motor-embedded chromatophores were firstly extracted from Thermus thermophilus by using a gradient centrifugation method. Then, the model drug (curcumin) was loaded onto the chromatophores. The drug loading efficiency and entrapment efficiency were optimized by using different loading approaches. The activity, motility, stability and mucus permeation of the drug-loaded chromatophore nanoparticles were thoroughly investigated. Both the in vitro and in vivo studies revealed that the FOF1-ATPase motor-embedded chromatophore successfully enhanced mucus penetration glioma therapy. This study indicates that the FOF1-ATPase motor-embedded chromatophore is a promising alternative as a mucosal drug delivery system.

FOF1-ATP synthase molecular motor biosensor for miRNA detection of colon cancer.

AIMS: To establish a FOF1-ATP synthase molecular motor biosensor to accurately identify colon cancer miRNAs. MAIN METHODS: The FOF1-ATP synthase molecular motor is extracted by fragmentation-centrifugation and connected to the colon cancer-specific miR-17 capture probe in the manner of the ε subunit-biotin-streptavidin-biotin system. Signal probes are designed for dual-signal characterization to increase detection accuracy. The FOF1-ATPase rotation rate decreases when the signaling and capture probes are combined with the target miRNA, resulting in a decrease in ATP synthesis. miR-17 concentrations are determined by changes in ATP-mediated chemiluminescence intensity and signal probe-mediated OD450nm. KEY FINDINGS: The chemiluminescence intensity and OD450nm show a good linear relationship with the miR-17 concentration in the range of 5 to 200 nmol L-1 (R2 = 0.9985, 0.9989). The colon cancer mouse model is established for the blood samples, and miR-17 in serum and RNA extracts is quantitatively determined using the constructed sensor. SIGNIFICANCE: The results are consistent with colon cancer progression, and the low concentration of miR-17 detecting accuracy is comparable to the PCR assay. In conclusion, the developed method is a direct, rapid, and promising method for miRNA detection of colon cancer.

Tumor microenvironment responded naturally extracted FOF1-ATPase loaded chromatophores for antitumor therapy.

Tumor microenvironment (TME) plays an important role in the growth, invasion, and metastasis of tumor cells. The pH of TME is more acidic in solid tumors than in normal tissues. Although targeted delivery in TME has progressed, the complex and expensive construction of delivery systems has limited their application. FOF1-ATP synthase (FOF1-ATPase) is a rotation molecular motor found in bacteria, chloroplasts, and mitochondria. Here, FOF1-ATPase loaded chromatophores (chroma) isolated from thermophilic bacteria were extracted and utilized as a new delivery system targeting TME for the first time. Curcumin as model drug was successfully loaded by a filming-rehydration ultrasonic dispersion method to prepare a curcumin-loaded chroma delivery system (Cur-Chroma). The mobility and propensity distributions of Cur-Chroma reveal its specific pH-sensitive targeting driven by the transmembrane proton kinetic potential, demonstrating its distinct distribution in the TME and more favorable targeting delivery. Cellular uptake experiments indicated that Cur-Chroma entered cells through grid pathway-mediated endocytosis. In vivo studies have shown that Cur-Chroma can specifically target tumor tissue and effectively inhibit tumor growth with good safety. Curcumin's bioavailability and anti-tumor effects were significantly improved. These studies demonstrate that ATPase-loaded chromatophores are potentially ideal vehicles for anti-tumor drug delivery and have promising applications.

Gold nanorods-loaded chitosan-based nanomedicine platform enabling an effective tumor regression in vivo.

The clinical utility of 7-ethyl-10-hydroxycamptothecin (SN-38) is hampered by its low water solubility and reduced bioactivity at neutral or alkaline conditions. The rational design of an effective drug delivery system that can significantly enhance the therapeutic index of SN-38 and achieve complete tumor regression still remains a challenge. Herein, chitosan-based hybrid nanoparticles system co-loading with chemotherapeutic drug SN-38 and gold nanorods (AuNRs) was engineered for effective combinational photothermal-chemotherapy. To increase the solubility of SN-38, soluble polymeric prodrug poly (l-glutamic acid)-SN38 (l-PGA-SN38) was firstly synthesized and then complexed with chitosan to form stable nanomedicine via a mild and facile way without using any organic solvent or surfactant. Upon introducing AuNRs into chitosan-based nanomedicine by coordination interaction between the amine group of chitosan and AuNRs, the hybrid nanoparticles exhibited distinct synergistic therapeutic effect compared with single chemotherapy or photothermal treatment in vitro and in vivo. Almost complete tumor regression was achieved after 21-day treatment of the developed hybrid nanoparticles and showed no recurrence for at least 60 days.

Enzyme-responsive nano-drug delivery system for combined antitumor therapy.

Efficient drug loading, tumor targeting, intratumoral penetration, and cellular uptake are the main factors affecting the effectiveness of drug delivery systems in oncotherapy. Based on the tumor microenvironment, we proposed to develop Curcumin (Cur)-loaded matrix metalloproteinase (MMP)-responsive nanoparticles (Cur-P-NPs) by static electricity, to enhance tumor targeting, cellular uptake, and drug loading efficiency. These nanoparticles combine the properties of both PEG-peptides (cleaved peptide + penetrating peptide) and star-shaped polyester (DPE-PCL) nanoparticles. Cur-P-NPs displayed good entrapment efficiency, drug loading and biocompatibility. Additionally, they showed an enhanced release rate, cellular uptake, and anti-proliferative activity by activating peptides under the simulated tumor microenvironment. Furthermore, intraperitoneal injection of losartan (LST) successfully enhanced intratumoral drug penetration by collagen I degradation. In vivo studies based on the systematic administration of the synergistic LST + Cur-P-NPs combination to mice confirmed that combined antitumor therapy with LST and Cur-P-NPs could further improve intratumor distribution, enhance anticancer efficacy, and reduce the toxicity and side effects. Therefore, LST + Cur-P-NPs represent a new and efficient system for clinical oncotherapy.

A biocompatible superparamagnetic chitosan-based nanoplatform enabling targeted SN-38 delivery for colorectal cancer therapy.

7-Ethyl-10-hydroxycamptothecin (SN-38) as a potent anti-tumor candidate, suffers the constraints from its poor water solubility, pH-dependent lactone ring stability and the lack of efficient delivery system without losing its activity. Herein, biocompatible superparamagnetic chitosan-based nanocomplexes complexing with water-soluble polymeric prodrug poly(L-glutamic acid)-SN-38 (PGA-SN-38) was engineered for efficient delivery of SN-38. The manufacturing process of colloidal complexes was green, expeditious and facile, with one-shot addition of PGA-SN-38 into chitosan solution without using any organic solvent or surfactant. Upon introducing ultra-small-size superparamagnetic nanoparticles (~10 nm), the developed magnetic nanocomplexes exhibited significantly boosted tumor-targeted accumulation and efficient cellular internalization under a local magnetic field. Notably, the magnetic nanocomplexes achieved distinctly superior targeting and anti-tumor efficacy in the established xenograft colorectal cancer model of mice, with high tumor suppression rate up to 81%. Therefore, this superparamagnetic chitosan-based nanocomplex system could provide a promising platform for the targeted delivery of SN-38 in colorectal cancer therapy.

Star polyester-based folate acid-targeting nanoparticles for doxorubicin and curcumin co-delivery to combat multidrug-resistant breast cancer.

Chemotherapeutic treatments are indispensable in the treatment of breast cancer. However, the emergence of multidrug-resistance, strong cell toxicity, and poor targeting selection has inhibited their clinical application. In this study, two synergistic drugs, doxorubicin (DOX) and curcumin (CUR), were co-administered to overcome multidrug resistance (MDR). Based on the characteristics of the tumor microenvironment, we developed folic acid-modified nanoparticles ((DOX + CUR)-FA-NPs) based on a star-shaped polyester (FA-TRI-CL) to enhance the tumor targeting selectivity and drug loading (DL) capacity. The (DOX + CUR)-FA-NPs displayed a characteristic spheroid morphology with an ideal diameter (186.52 nm), polydispersity index (0.024), zeta potential (-18.87 mV), and good entrapment efficiency (97.64%/78.13%, DOX/CUR) and DL (20.27%/11.29%, DOX/CUR) values. In vitro pharmacokinetic and pharmacodynamic experiments demonstrated that the (DOX + CUR)-FA-NPs were gradually released, and they displayed the highest cell apoptosis and cellular uptake in MCF-7/ADR cells. Additionally, in vivo results illustrated that (DOX + CUR)-FA-NPs not only displayed significant tumor targeting and anticancer efficacy, but also induced less pathological damage to the normal tissue. In summary, co-administered DOX and CUR appeared to reverse MDR, and this targeted combinational nanoscale delivery system could thus be a promising carrier for tumor therapies in the future.

A Novel Folic Acid Receptor-Targeted Drug Delivery System Based on Curcumin-Loaded ß-Cyclodextrin Nanoparticles for Cancer Treatment.

PURPOSE: A novel folate receptor-targeted ß-cyclodextrin (ß-CD) drug delivery vehicle was constructed to improve the bioavailability, biosafety, and drug loading capacity of curcumin. Controlled release and targeted delivery was achieved by modifying the nanoparticles with folic acid (FA). METHODS: Folate-conjugated ß-CD-polycaprolactone block copolymers were synthesized and characterized. Curcumin-loaded nanoparticles (FA-Cur-NPs) were structured by self-assembly. The physicochemical properties, stability, release behavior and tumor-targeting ability of the fabricated nanoparticles were studied. RESULTS: The average particle size and drug loading of FA-Cur-NPs was 151.8 nm and 20.27%, respectively. Moreover, the FA-Cur-NPs exhibited good stability in vitro for 72 h. The drug release profiles showed that curcumin from FA-Cur-NPs was released significantly faster in a pH 6.4 phosphate buffered solution (PBS) than in pH 7.4, indicating that curcumin can be enriched around the tumor site compared with normal cells. Additionally, the internalization of FA-Cur-NPs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. Furthermore, in vivo studies confirmed that FA-Cur-NPs exhibited marked accumulation in the tumor site and excellent antitumor activity. CONCLUSION: These findings suggest that FA-Cur-NPs are a promising approach for improving cancer therapy through active targeting and controllable release.

Curcumin-Loaded Hybrid Nanoparticles: Microchannel-Based Preparation and Antitumor Activity in a Mouse Model.

PURPOSE: To develop microchannel-based preparation of curcumin (Cur)-loaded hybrid nanoparticles using enzyme-targeted peptides and star-shaped polycyclic lipids as carriers, and to accomplish a desirable targeted drug delivery via these nanoparticles, which could improve the bioavailability and antitumor effects of Cur. METHODS: The amphiphilic tri-chaintricarballylic acid-poly (ε-caprolactone)-methoxypolyethylene glycol (Tri-CL-mPEG) and the enzyme-targeted tetra-chain pentaerythritol-poly (ε-caprolactone)-polypeptide (PET-CL-P) were synthesized. The Cur-loaded enzyme-targeted hybrid nano-delivery systems (Cur-P-NPs) were prepared by using the microfluidic continuous granulation technology. The physicochemical properties, release behavior in vitro, and stability of these Cur-P-NPs were investigated. Their cytotoxicity, cellular uptake, anti-proliferative efficacy in vitro, biodistribution, and antitumor effects in vivo were also studied. RESULTS: The particle size of the prepared Cur-P-NPs was 146.1 ± 1.940 nm, polydispersity index was 0.175 ± 0.014, zeta potential was 10.1 ± 0.300 mV, encapsulation rate was 74.66 ± 0.671%, and drug loading capacity was 5.38 ± 0.316%. The stability of Cur-P-NPs was adequate, and the in vitro release rate increased with the decrease of the environmental pH. Seven days post incubation, the cumulative release values of Cur were 52.78%, 67.39%, and 98.12% at pH 7.4, pH 6.8 and pH 5.0, respectively. Cur-P-NPs exhibited better cell entry and antiproliferation efficacy against U251 cells than the Cur-solution and Cur-NPs and were safe for use. Cur-P-NPs specifically targeted tumor tissues and inhibited their growth (78.63% tumor growth inhibition rate) with low toxic effects on normal tissues. CONCLUSION: The enzyme-targeted hybrid nanoparticles prepared in the study clearly have the tumor-targeting ability. Cur-P-NPs can effectively improve the bioavailability of Cur and have potential applications in drug delivery and tumor management.

A Near-Infrared Laser-Triggered Size-Shrinkable Nanosystem with In Situ Drug Release for Deep Tumor Penetration.

The development of smart size-tunable drug delivery nanoplatform enables the solving of the paradox of inconsistent size-dependence of high tumor accumulation and deep penetration during its delivery process, thus achieving superior cancer treatment efficacy. Herein, we report a size-shrinkable nanomicelle complex system with an initial size of 101 nm enabling effective retention around the tumor periphery and could destruct to ultrasmall nanomicelles triggered by a near-infrared (NIR) laser to realize the deep tumor penetration. The nanomicelle system is consisted of an upper critical solution temperature (UCST)-type block copolymer poly(acrylamide-acrylonitrile)-polyethylene glycol-lipoic acid (p(AAm-co-AN)-g-PEG-LA) encapsulating gold nanorods. Upon the irradiation of the NIR laser at the tumor site, gold nanorods could convert the light energy to heat energy, realizing the photothermal ablation of superficial tumor tissue. Concurrently, the large micelles split into a cascade of ultrasmall micelles (∼7 nm), which could easily penetrate into the deep site of the tumor and achieve the in situ "on-demand" release of the loaded drug to exert superior combined photothermal-chemotherapy of cancer. By the precise manipulation of laser, the micelle complex system realized the hierarchical killing from the superficial-to-deep tumor and achieved almost complete tumor growth inhibition on the established xenograft liver tumor mice model.

RACK7 recognizes H3.3G34R mutation to suppress expression of MHC class II complex components and their delivery pathway in pediatric glioblastoma.

Histone H3 point mutations have been identified in incurable pediatric brain cancers, but the mechanisms through which these mutations drive tumorigenesis are incompletely understood. Here, we provide evidence that RACK7 (ZMYND8) recognizes the histone H3.3 patient mutation (H3.3G34R) in vitro and in vivo. We show that RACK7 binding to H3.3G34R suppresses transcription of CIITA, which is the master regulator of MHC (major histocompatibility complex) class II molecules and genes involved in vesicular transport of MHC class II molecules to the cell surface, resulting in suppression of MHC class II molecule expression and transport. CRISPR-based knock-in correction of the H3.3G34R mutation in human pediatric glioblastoma (pGBM) cells significantly reduces overall RACK7 chromatin binding and derepresses the same set of genes as does knocking out RACK7 in the H3.3G34R pGBM cells. By demonstrating that H3.3G34R and RACK7 work together, our findings suggest a potential molecular mechanism by which H3.3G34R promotes cancer.

Superparamagnetic chitosan nanocomplexes for colorectal tumor-targeted delivery of irinotecan.

Conventional chemotherapy is effective for metastatic tumors widely present in colorectal cancer patients; however, chemotherapy may cause severe systemic toxicity due to a lack of specificity towards cancer cells. Effective delivery systems that can enhance targeted drug delivery to the desired tumor site and simultaneously protect the activity of drugs are in high demand. To that end, this study developed chitosan-based polyelectrolyte complexes (PECs) with the orientation of superparamagnetic nanoparticles, which enables the targeting delivery of the first-line model drug irinotecan (IRT) to the tumor area under a magnetic field. Colloidal PECs were mildly and facilely fabricated with chitosan and poly(glutamic acid) (PGA) via an all-in-water process, excluding the use of any potentially toxic chemicals. Iso-dispersed superparamagnetic Fe3O4 nanoparticles with relatively small particle diameters (~10 nm) were embedded into the IRT-loaded nano-PECs. The optimized nano-PECs showed high drug encapsulation capacity and improved anti-colon cancer cell efficacy compared with the free drug. Furthermore, the magnetic nano-PECs exhibited effective internalization by colon tumor cells, and favorable tumor-targeting ability was demonstrated via in vivo biodistribution study. Therefore, this magnetic targeted drug delivery nano-PECs system provides a promising platform to overcome the side effects of conventional chemotherapy for colorectal cancer.

Chitosan-based Colloidal Polyelectrolyte Complexes for Drug Delivery: A Review.

Polyelectrolyte complexes (PECs) as safe drug delivery carriers, are spontaneously formed by mixing the oppositely charged polyelectrolyte solutions in water without using organic solvents nor chemical cross-linker or surfactant. Intensifying attentions on the PECs study are aroused in academia and industry since the fabrication process of PECs is mild and they are ideal vectors for the delivery of susceptible drugs and macromolecules. Chitosan as the unique natural cationic polysaccharide, is a good bioadhesive material. Besides, due to its excellent biocompatibility, biodegradability, abundant availability and hydrophilic nature, chitosan-based PECs have been extensively applied for drug delivery, particularly after administration through mucosal and parenteral routes. The purpose of this review is to compile the recent advances on the biomedical applications of chitosan-based PECs, with specific focuses on the mucosal delivery, cancer therapy, gene delivery and anti-HIV therapy. The challenges and the perspectives of the chitosan-based PECs are briefly commented as well.

The Opposed Effects of Polyvinylpyrrolidone K30 on Dissolution and Precipitation for Indomethacin Supersaturating Drug Delivery Systems.

Amorphous solid dispersions (ASD) are one of the most important supersaturating drug delivery systems (SDDS) for poorly water-soluble drugs to improve their bioavailability. As a result of thermodynamic instability, drug molecules tend to precipitate during storage and dissolution in gastrointestinal tract. Various precipitation inhibitors (PI) have been widely used to improve the stability in the past decade. However, most studies have investigated the inhibiting capability of PI on drug precipitation, rarely considering their potential hindering effect on the drug dissolution. The present study designed an ASD of Indomethacin (IND) and Eudragit® EPO by hot melt extrusion to investigate the influence of the added PI (PVP-K30) into ASD both on dissolution and precipitation. The precipitation study by solvent shift method indicated PVP-K30 could inhibit the precipitation of IND significantly. The dissolution study in different concentrations of PVP-K30 showed when the concentration increased above 50 µg/mL, PVP-K30 displayed an acceptable precipitation inhibition without drug concentration decline but an unexpected dissolution impediment with the reduction of maximum concentration platform. The dissolution tests of physical mixtures (PMs) of ASD and PVP-K30 also showed the precipitation inhibition and dissolution impediment when more than 2% PVP-K30 in PMs. This opposed effect of PVP-K30 was strengthen in ternary systems prepared by hot melt extruding the mixtures of IND, Eudragit® EPO and PVP-K30. All of these results proved the PI may be a double-edged sword for the opposed effects of precipitation inhibition and dissolution impediment, which should be carefully considered in the design and development of SDDS.