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Introduction: Hyaluronic acid (HA) has emerged as a promising applicant for the tumor-targeted delivery of various therapeutic agents. Because of its biocompatibility, biodegradability and receptor-binding properties, HA has been extensively investigated as the drug delivery carrier. In this review, recent advances in HA-based nanomedicines are discussed., Areas Covered: This review focuses on HA-based nanomedicines for the diagnosis and treatment of cancer. In particular, recent advances in HA-drug conjugates and HA-based nanoparticles for small molecular drug delivery are discussed. The bioreducible HA conjugates for small interfering ribonucleic acid delivery have been also discussed., Expert Opinion: To develop a successful HA-based nanomedicine, it has to be prepared without significant deterioration of intrinsic property of HA. The chemical modification of HA with drugs or hydrophobic moieties may reduce the binding affinity of HA to the receptors. In addition, since the HA-based nanomedicines tend to accumulate in the liver after their systemic administration, new strategies to overcome this issue have to be developed.

For the effective diagnosis and therapy of atherosclerosis, there is a pressing need to develop the carrier which can specifically deliver the agents to the pathological site. Since the representative hallmark of atherosclerosis in its pathogenic process is the over-expression of the receptors for hyaluronic acid (HA) such as stabilin-2 and CD44, we herein investigated the potential of HA nanoparticles (HA-NPs) as the carrier for active targeting atherosclerosis. From in vitro cellular uptake tests, it was revealed that HA-NPs were selectively taken up by the cells over-expressing stabilin-2 or CD44. On the other hand, the cellular uptake of HA-NPs was drastically reduced when the cells were pre-treated with excess amount of free HA, implying that HA-NPs were taken up by the receptor-mediated endocytosis. Following systemic administration of Cy5.5-labeled NPs into the ApoE-deficient mice as the animal model, the atherosclerotic legion was assessed at 24 post-injection by using the optical imaging system. Interestingly, the fluorescent signal of the atherosclerotic lesion by HA-NPs was much stronger than that of the normal aorta. Three dimensional z-stack images of an atherosclerotic plaque indicated the even distribution of HA-NPs in the atherosclerotic legion. It was demonstrated by immunohistochemistry that HA-NPs were co-localized with the HA receptors including stabilin-2 and CD44. In addition, the amount of HA-NPs, accumulated in the atherosclerotic lesion, was much higher than that of HGC-NPs, known to reach the atherosclerotic lesion by the passive targeting mechanism. Overall, it was evident that HA-NPs could effectively reach the atherosclerotic lesion via the active targeting mechanism after systemic administration, implying their high potential as the carrier for diagnosis and therapy of atherosclerosis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Nanohybrid liposomes coated with amphiphilic hyaluronic acid-ceramide (HACE) was fabricated for targeted delivery of anticancer drug and in vivo cancer imaging. Nanohybrid liposomes including doxorubicin (DOX) and Magnevist, a contrast agent for magnetic resonance (MR) imaging, with 120-130nm mean diameter and a narrow size distribution were developed. DOX release from the developed formulation was improved at acidic pH (pH5.5 and 6.8) versus physiological pH (pH7.4). Cytotoxicity induced by the blank plain liposome was reduced by coating the outer surface of the nanohybrid liposome with HACE. Cellular uptake of DOX from the nanohybrid liposome was enhanced by HA and CD44 receptor interaction, versus the plain liposome. In vivo contrast-enhancing effects revealed that the nanohybrid liposome can be used as a tumor targeting MR imaging probe for cancer diagnosis. In a pharmacokinetic study in rats, in vivo clearance of DOX was decreased in the order DOX solution, plain liposome (F2), and nanohybrid liposome (F3), indicating prolonged circulation of the drug in the blood stream and improved therapeutic efficacy of the nanohybrid liposome (F3). Based on these findings, the nanohybrid liposomal system may be a useful candidate for real-time cancer diagnosis and therapy., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The successful clinical translation of siRNA-based therapeutics requires efficient carrier systems that can specifically deliver siRNA within the cytosol of the target cells. Although numerous polymeric nanocarriers forming ionic complexes with siRNA have been investigated for cancer therapy, their poor stability and lack of tumor targetability have impeded their in vivo applications. To surmount these limitations, we synthesized a novel type of biodegradable hyaluronic acid-graft-poly(dimethylaminoethyl methacrylate) (HPD) conjugate that can form complexes with siRNA and be chemically crosslinked via the formation of the disulfide bonds under facile conditions. The crosslinked siRNA-HPD (C-siRNA-HPD) complexes exhibited high stability in a 50% serum solution, as compared to the uncrosslinked siRNA-HPD (U-siRNA-HPD) complexes and free siRNA. Both the C-siRNA-HPD and U-siRNA-HPD complexes were efficiently taken up by the CD44-overexpressing melanoma cells (B16F10), but not by the normal fibroblast cells (NIH3T3). When the RFP-expressing B16F10 cells were treated with the complexes or free siRNA, the C-siRNA-HPD complexes showed the highest decrease in RFP expression. In vivo studies demonstrated the selective accumulation of C-siRNA-HPD complexes at the tumor site after their systemic administration into tumor-bearing mice, resulting in an efficient gene silencing effect. Overall, these results suggest that the HPD conjugate could be used as an efficient carrier for the tumor-targeted delivery of siRNA., (© 2013.)

One of the major hurdles of the nanoparticles as drug carriers is the unintended burst release of loaded drugs during blood circulation. To surmount this issue, we developed photo-crosslinked hyaluronic acid nanoparticles (c-HANPs) with improved stability for tumor-targeted drug delivery. They were readily prepared via UV-triggered chemical crosslinking with the acrylate groups in the polymer backbone. The size of c-HANPs was not much different from that of uncrosslinked HANPs. However, c-HANPs exhibited significantly high stability in a physiological buffer and released the loaded drug, paclitaxel (PTX), in a sustained manner. It is noteworthy that the drug release rate from c-HANPs remarkably increased in the presence of hyaluronidase, an enzyme abundant at the intracellular compartments of the tumor cells. It was found from in vitro cellular uptake tests that c-HANPs were rapidly taken up by the tumor cells via the receptor (CD44)-mediated endocytosis, which was not inhibited by photo-crosslinking. In non-invasive animal imaging results, they showed higher tumor-targeting ability than uncrosslinked HANPs because high stability of c-HANPs enabled their long circulation in the body. Owing to the sustained release of the drug and enhanced tumor-targeting ability, c-HANPs showed higher therapeutic efficacy compared to free PTX and uncrosslinked HANPs. These data implied the promising potential of c-HANP as tumor-targeting drug carriers and demonstrated the remarkable effect of the improved stability upon the biodistribution and therapeutic efficacy of drug-loaded nanoparticles., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The in vivo stability and tumor targetability of self-assembled polymeric nanoparticles are crucial for effective drug delivery. In this study, to develop biostable nanoparticles with high tumor targetability, poly(ethylene glycol)-conjugated hyaluronic acid nanoparticles (PEG-HANPs) were mineralized through controlled deposition of inorganic calcium and phosphate ions on the nanoparticular shell via a sequential addition method. The resulting nanoparticles (M-PEG-HANPs) had a smaller size (153.7±4.5nm) than bare PEG-HANPs (265.1±9.5nm), implying that mineralization allows the formation of compact nanoparticles. Interestingly, when the mineralized nanoparticles were exposed to acidic buffer conditions (

Colon cancer is the second leading cause of cancer-related death in the United States. The considerable mortality from colon cancer is due to metastasis to other organs, mainly the liver. In the management of colon cancer, early detection and targeted therapy are crucial. In this study, we aimed to establish a versatile theranostic system for early tumor detection and targeted tumor therapy by using poly(ethylene glycol)-conjugated hyaluronic acid nanoparticles (P-HA-NPs) which can selectively accumulate in tumor tissue. For the diagnostic application, a near-infrared fluorescence (NIRF) imaging dye (Cy 5.5) was chemically conjugated onto the HA backbone of P-HA-NPs. After intravenous injection of Cy5.5-P-HA-NPs into the tumor-bearing mice, small-sized colon tumors as well as liver-implanted colon tumors were effectively visualized using the NIRF imaging technique. For targeted therapy, we physically encapsulated the anticancer drug, irinotecan (IRT), into the hydrophobic cores of P-HA-NPs. Owing to their notable tumor targeting capability, IRT-P-HA-NPs exhibited an excellent antitumor activity while showing a reduction in undesirable systemic toxicity. Importantly, we demonstrated the theranostic application using Cy5.5-P-HA-NPs and IRT-P-HA-NPs in orthotopic colon cancer models. Following the systemic administration of Cy5.5-P-HA-NPs, neoplasia was clearly visualized, and the tumor growth was effectively suppressed by intravenous injection of IRT-P-HA-NPs. It should be emphasized that the therapeutic responses could be simultaneously monitored by Cy5.5-P-HA-NPs. Our results suggest that P-HA-NPs can be used as a versatile theranostic system for the early detection, targeted therapy, and therapeutic monitoring of colon cancer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Hyaluronic acid-ceramide (HACE)-based nanoprobes for magnetic resonance (MR) and optical imaging were developed for cancer diagnosis. Diethylenetriaminepentaacetic dianhydride (DTPA) was conjugated to HACE for the chelation of gadolinium (Gd) as an MR contrast agent. Cy5.5 was also conjugated to the HACE backbone as a near-infrared fluorescence (NIRF) imaging dye. The self-assembled HACE-based nanoprobe, Cy5.5-HACE-DTPA-Gd, exhibited a uniformly distributed particle size and morphological shape. The HACE-based nanoprobe did not induce serious cytotoxicity in U87-MG (low expression of CD44 receptor) and SCC7 (high expression of CD44 receptor) cells. The cellular uptake efficiency of the HACE-based nanoprobe was higher in SCC7 cells than in U87-MG cells, indicating an HA-CD44 receptor interaction. In vitro MR signal enhancement of the HACE-based nanoprobe was confirmed compared with a commercial formulation (Magnevist). Moreover, in vivo MR contrast enhancement of the HACE-based nanoprobe in the tumor region was verified in an SCC7 tumor xenograft mouse model. The tumor targetability of the developed nanoprobe was monitored by an NIRF imaging study, and improved accumulation of the nanoprobe in the tumor region was observed. Therefore, this HACE-based dual-imaging nanoprobe can be used to make a more accurate diagnosis of cancer based on its passive and active tumor targeting strategies., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Tumor-targeted imaging and therapy have been the challenging issue in the clinical field. Herein, we report tumor-targeting hyaluronic acid nanoparticles (HANPs) as the carrier of the hydrophobic photosensitizer, chlorin e6 (Ce6) for simultaneous photodynamic imaging and therapy. First, self-assembled HANPs were synthesized by chemical conjugation of aminated 5β-cholanic acid, polyethylene glycol (PEG), and black hole quencher3 (BHQ3) to the HA polymers. Second, Ce6 was readily loaded into the HANPs by a simple dialysis method resulting in Ce6-loaded hyaluronic acid nanoparticles (Ce6-HANPs), wherein in the loading efficiency of Ce6 was higher than 80%. The resulting Ce6-HANPs showed stable nano-structure in aqueous condition and rapid uptake into tumor cells. In particular Ce6-HANPs were rapidly degraded by hyaluronidases abundant in cytosol of tumor cells, which may enable intracellular release of Ce6 at the tumor tissue. After an intravenous injection into the tumor-bearing mice, Ce6-HANPs could efficiently reach the tumor tissue via the passive targeting mechanism and specifically enter tumor cells through the receptor-mediated endocytosis based on the interactions between HA of nanoparticles and CD44, the HA receptor on the surface of tumor cells. Upon laser irradiation, Ce6 which was released from the nanoparticles could generate fluorescence and singlet oxygen inside tumor cells, resulting in effective suppression of tumor growth. Overall, it was demonstrated that Ce6-HANPs could be successfully applied to in vivo photodynamic tumor imaging and therapy simultaneously., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Polyethylene glycol (PEG)-conjugated hyaluronic acid-ceramide (HACE) was synthesized for the preparation of doxorubicin (DOX)-loaded HACE-PEG-based nanoparticles, 160 nm in mean diameter with a negative surface charge. Greater uptake of DOX from these HACE-PEG-based nanoparticles was observed in the CD44 receptor highly expressed SCC7 cell line, compared to results from the CD44-negative cell line, NIH3T3. A strong fluorescent signal was detected in the tumor region upon intravenous injection of cyanine 5.5-labeled nanoparticles into the SCC7 tumor xenograft mice; the extended circulation time of the HACE-PEG-based nanoparticle was also observed. Pharmacokinetic study in rats showed a 73.0% reduction of the in vivo clearance of DOX compared to the control group. The antitumor efficacy of the DOX-loaded HACE-PEG-based nanoparticles was also verified in a tumor xenograft mouse model. DOX was efficiently delivered to the tumor site by active targeting via HA and CD44 receptor interaction and by passive targeting due to its small mean diameter (<200 nm). Moreover, PEGylation resulted in prolonged nanoparticle circulation and reduced DOX clearance rate in an in vivo model. These results therefore indicate that PEGylated HACE nanoparticles represent a promising anticancer drug delivery system for cancer diagnosis and therapy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Tumor targetability and site-specific drug release of therapeutic nanoparticles are key factors for effective cancer therapy. In this study, poly(ethylene glycol) (PEG)-conjugated hyaluronic acid nanoparticles (P-HA-NPs) were investigated as carriers for anticancer drugs including doxorubicin and camptothecin (CPT). P-HA-NPs were internalized into cancer cells (SCC7 and MDA-MB-231) via receptor-mediated endocytosis, but were rarely taken up by normal fibroblasts (NIH-3T3). During in vitro drug release tests, P-HA-NPs rapidly released drugs when incubated with cancer cells, extracts of tumor tissues, or the enzyme Hyal-1, which is abundant in the intracellular compartments of cancer cells. CPT-loaded P-HA-NPs (CPT-P-HA-NPs) showed dose-dependent cytotoxicity to cancer cells (MDA-MB-231, SCC7, and HCT 116) and significantly lower cytotoxicity against normal fibroblasts (NIH-3T3) than free CPT. Unexpectedly, high concentrations of CPT-P-HA-NPs demonstrated greater cytotoxicity to cancer cells than free CPT. An in vivo biodistribution study indicated that P-HA-NPs selectively accumulated into tumor sites after systemic administration into tumor-bearing mice, primarily due to prolonged circulation in the blood and binding to a receptor (CD44) that was overexpressed on the cancer cells. In addition, when CPT-P-HA-NPs were systemically administrated into tumor-bearing mice, we saw no significant increases in tumor size for at least 35 days, implying high antitumor activity. Overall, P-HA-NPs showed promising potential as a drug carrier for cancer therapy., (© 2011 American Chemical Society)

Hyaluronic acid-ceramide (HA-CE)-based self-assembled nanoparticles were developed for intravenous docetaxel (DCT) delivery. In this study, physicochemical properties, cellular uptake efficiency, and in vivo targeting capability of the nanoparticles developed were investigated. DCT-loaded nanoparticles composed of HA-CE and Pluronic 85 (P85) with a mean diameter of 110-140 nm were prepared and their morphological shapes were assessed using transmission electron microscopy (TEM). DCT release from nanoparticle was enhanced with increasing P85 concentrations in our in vitro model. Blank nanoparticles exhibited low cytotoxicity in U87-MG, MCF-7 and MCF-7/ADR cell lines. From cellular uptake studies, the nanoparticles developed enhanced the intracellular DCT uptake in the CD44-overexpressing cell line (MCF-7). The nanoparticles were shown to be taken up by the HA-CD44 interaction according to DCT and coumarin 6 (C6) cellular uptake studies. The multidrug resistance (MDR)-overcoming effects of DCT-loaded HA-CE/P85-based nanoparticles were also observed in cytotoxicity tests in MCF-7/ADR cells. Following the intravenous injection of DCT-loaded cyanine 5.5 (Cy5.5)-conjugated nanoparticles in MCF-7/ADR tumor-bearing mice, its in vivo targeting for CD44-overexpressing tumors was identified by non-invasive near-infrared (NIR) fluorescence imaging. These results indicate that the HA-CE-based nanoparticles prepared may be a promising anti-cancer drug delivery system through passive and active tumor targeting., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A major drawback of hyaluronic acid (HA)-based drug conjugates or nanoparticles for cancer therapy is their preferential accumulation in the liver after systemic administration. In an attempt to investigate the physicochemical characteristics and in vivo fates of poly(ethylene glycol) (PEG)-conjugated HA nanoparticles (HA-NPs), amphiphilic HA derivatives were prepared by varying the degree of PEGylation. The PEGylated HA-NPs formed self-assembled nanoparticles (217-269 nm in diameter) with the negatively charged surfaces in the physiological condition. Although PEGylation of HA-NPs reduced their cellular uptake in vitro, larger amounts of nanoparticles were taken up by cancer cells over-expressing CD44, an HA receptor, than by normal fibroblast cells. The ex vivo images of the organs using an optical imaging technique after the intravenous injection of Cy5.5-labeled nanoparticles into normal mice demonstrated that PEGylation could effectively reduce the liver uptake of HA-NPs and increase their circulation time in the blood. When the nanoparticles were systemically administered into tumor-bearing mice for in vivo real-time imaging, the strongest fluorescence signals were detected at the tumor site of the mice for the whole period of time studied, indicating their high tumor targetability. Interestingly, PEGylated HA-NPs were more effectively accumulated into the tumor tissue up to 1.6-fold higher than bare HA-NPs. The high tumor targetability of PEGylated HA-NPs was further supported by the intravital tumor imaging, in which their rapid extravasation into the tumor tissue was clearly observed. These results suggest that PEGylated HA-NPs can be useful as a means for cancer therapy and diagnosis., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Amphiphilic hyaluronic acid conjugates were synthesized as a potential drug carrier by chemical conjugation of an amine-terminated hydrotropic oligomer, which has a unique ability to enhance the solubility of paclitaxel (PTX), to a hyaluronic acid (HA) backbone using carbodiimide chemistry. The physicochemical properties of the hydrotropic hyaluronic acid (HydroHA) conjugates were investigated using (1)H NMR, dynamic light scattering, transmission electron microscopy (TEM), and fluorescence spectroscopy. HydroHA conjugates could form self-assembled nanoparticles in an aqueous medium because of hydrophobic interactions among hydrotropic oligomers. Their particle sizes were in the range of 274-356nm, depending on the degree of substitution (DS) of the hydrotropic oligomer. TEM images showed that particle morphology was spherical in shape. Critical aggregation concentrations of HydroHA conjugates ranged from 0.034 to 0.125mg/mL, which decreased with an increase in the DS of the hydrotropic oligomer. The HydroHA conjugates were selectively taken up by the cancer cell line (SCC-7) over-expressing CD44, a hyaluronic receptor. The nanoparticles could encapsulate PTX up to 20.7wt.% by the dialysis method. The in vitro release pattern of PTX from nanoparticles was significantly dependent on drug loading content, in which the release rate was lower for the nanoparticles that contained larger amounts of the drug. From the cytotoxicity test, it was found that the drug-loaded HydroHA nanoparticles exhibited stronger cytotoxicity to SCC-7 than to normal fibroblast cell (CV-1). These results suggest that HydroHA nanoparticles have potential as the carrier of PTX for cancer therapy., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Hyaluronic acid nanoparticles (HA-NPs), which are formed by the self-assembly of hydrophobically modified HA derivatives, were prepared to investigate their physicochemical characteristics and fates in tumor-bearing mice after systemic administration. The particle sizes of HA-NPs were controlled in the range of 237-424 nm by varying the degree of substitution of the hydrophobic moiety. When SCC7 cancer cells over-expressing CD44 (the receptor for HA) were treated with fluorescently labeled Cy5.5-HA-NPs, strong fluorescence signals were observed in the cytosol of these cells, suggesting efficient intracellular uptake of HA-NPs by receptor-mediated endocytosis. In contrast, no significant fluorescence signals were observed when Cy5.5-labeled HA-NPs were incubated with normal fibroblast cells (CV-1) or with excess free-HA treated SCC7 cells. Following systemic administration of Cy5.5-labeled HA-NPs with different particle sizes into a tumor-bearing mouse, their biodistribution was monitored as a function of time using a non-invasive near-infrared fluorescence imaging system. Irrespective of the particle size, significant amounts of HA-NPs circulated for two days in the bloodstream and were selectively accumulated into the tumor site. The smaller HA-NPs were able to reach the tumor site more effectively than larger HA-NPs. Interestingly, the concentration of HA-NPs in the tumor site was dramatically reduced when mice were pretreated with an excess of free-HA. These results imply that HA-NPs can accumulate into the tumor site by a combination of passive and active targeting mechanisms.

The key issues, associated with nanocarriers for small interfering RNAs (siRNAs), are their poor stability and lack of tumor targetability in vivo. To address these issues, we developed gold-installed polyethyleneimine/siRNA complexes with a corona of PEGylated hyaluronic acid. [ABSTRACT FROM AUTHOR]

Antigen-specific CD8 + cytotoxic T lymphocytes (CTLs) are key elements of immunological rejection in transplantation as well as cancer immunotherapy. Most tumors, however, are not immunologically rejected because they have self antigens, which are not recognized as the foreigner by CTLs. In this study, we hypothesized that “foreignizing” tumor cells by delivering non-self foreign antigens into the tumors would result in rejection by foreign antigen-reactive CTLs. As the model system to foreignize the tumors, we prepared a polymeric conjugate consisting of hyaluronic acid as the CD44 + tumor-targeting ligand and ovalbumin (OVA) as a foreign antigen. When the conjugate was treated with CD44 high TC-1 tumor cells, it was effectively taken up and allowed for displaying of antigenic OVA 257–264 peptide at MHC class I on the surface of the cells. In addition, the conjugate was effectively accumulated into tumor tissue after its systemic administration to mice which are immunized with a vaccine for a vaccinia virus expressing OVA to generate OVA 257–264 specific CTLs, resulting in substantial inhibition of tumor growth. Overall, these results suggest that the polymeric conjugates bearing foreign antigens may be innovative and promising cancer immunotherapeutic agents by foreignizing tumor cells, leading to immunological rejection. [ABSTRACT FROM AUTHOR]

With the increasing demand for instant real-time ultrasound (US) imaging of a specific organ, target-specific and long-circulating ultrasound contrast agents are of special interest. A new species of echogenic hyaluronic acid nanoparticles is presented as an ultralong-acting, liver-specific, US contrast agent that is distinct from conventional gas-filled microbubbles. Using an oil-in-water (O/W) emulsification method, bioinert and hydrophobic perfluoropentane (PFP) is encapsulated as an ultrasound gas precursor into hyaluronic acid nanoparticles (HANPs) using hydrophobic interactions. HANPs are formulated by self-assembly, with amphiphilic hyaluronic acid-5β-cholanic acid (HA-CA) conjugating in aqueous conditions. The resulting echogenic PFP-encapsulated HANPs (Echo-NPs) show solid nanostructures, differentiated from core-empty conventional microbubbles, and exhibiting outstanding physical properties as an ultrasound contrast agent. They are more stable and robust echogenic solid bodies with an in vivo favorable hydrodynamic size and because PFPs vaporize gradually, their expansion process is very slow in body conditions. After several systemic circulations, echo-NPs generated intense and ultralong echo signals for US imaging at the target site. The echogenic properties of Echo-NPs show a significantly increased half-life and echo persistence, compared with conventional microbubbles. The results clearly show that echo-NPs outperform conventional microbubbles in terms of both physical and echogenic in vitro and in vivo properties. [ABSTRACT FROM AUTHOR]

Abstract: Hyaluronic acid-ceramide (HA-CE)-based self-assembled nanoparticles were developed for intravenous docetaxel (DCT) delivery. In this study, physicochemical properties, cellular uptake efficiency, and in vivo targeting capability of the nanoparticles developed were investigated. DCT-loaded nanoparticles composed of HA-CE and Pluronic 85 (P85) with a mean diameter of 110–140nm were prepared and their morphological shapes were assessed using transmission electron microscopy (TEM). DCT release from nanoparticle was enhanced with increasing P85 concentrations in our in vitro model. Blank nanoparticles exhibited low cytotoxicity in U87-MG, MCF-7 and MCF-7/ADR cell lines. From cellular uptake studies, the nanoparticles developed enhanced the intracellular DCT uptake in the CD44-overexpressing cell line (MCF-7). The nanoparticles were shown to be taken up by the HA–CD44 interaction according to DCT and coumarin 6 (C6) cellular uptake studies. The multidrug resistance (MDR)-overcoming effects of DCT-loaded HA-CE/P85-based nanoparticles were also observed in cytotoxicity tests in MCF-7/ADR cells. Following the intravenous injection of DCT-loaded cyanine 5.5 (Cy5.5)-conjugated nanoparticles in MCF-7/ADR tumor-bearing mice, its in vivo targeting for CD44-overexpressing tumors was identified by non-invasive near-infrared (NIR) fluorescence imaging. These results indicate that the HA-CE-based nanoparticles prepared may be a promising anti-cancer drug delivery system through passive and active tumor targeting. [Copyright &y& Elsevier]

Many preclinically tested nanoparticles in existing animal models fail to be directly translated into clinical applications because of their poor resemblance to human cancer. Herein, the enhanced permeation and retention (EPR) effect of glycol chitosan nanoparticles (CNPs) in different tumor microenvironments (TMEs) was compared using different pancreatic tumor models, including pancreatic cancer cell line (BxPC3), patient-derived cancer cell (PDC), and patient-derived xenograft (PDX) models. CNPs were intravenously injected into different tumor models, and their accumulation efficiency was evaluated using non-invasive near-infrared fluorescence (NIRF) imaging. In particular, differences in angiogenic vessel density, collagen matrix, and hyaluronic acid content in tumor tissues of the BxPC3, PDC, and PDX models greatly affected the tumor-targeting efficiency of CNPs. In addition, different PDX models were established using different tumor tissues of patients to predict the clinical EPR effect of CNPs in inter-patient TMEs, wherein the gene expression levels of PECAM1, COL4A1, and HAS1 in human tumor tissues were observed to be closely related to the EPR effect of CNPs in PDX models. The results suggested that the PDX models could mimic inter-patient TMEs with different blood vessel structures and extracellular matrix (ECM) content that critically affect the tumor-targeting ability of CNPs in different pancreatic PDX models. This study provides a better understanding of the heterogeneity and complexity of inter-patient TMEs that can predict the response of various nanoparticles in individual tumors for personalized cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]