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To improve antitumor efficiency of chemotherapy and reduce side effect, according to the physiological characteristics of tumor tissues and tumor intracellular microenvironment, a multifunctional drug delivery system with properties of long circulation, active targeting, redox and pH triggered drug release was established based on the Generation 4 polyamidoamine dendrimer (PAMAM). First, the redox cleavable disulfide bonds (SS) were introduced for linking polyethylene glycol (PEG) with PAMAM to form PAMAM-S-S-PEG (PSSP). Then cRGD peptide was applied to the PEG end of PSSP to construct RGD-PSSP conjugates. Finally, encapsulating the antitumor chemotherapy drug doxorubicin (DOX) into the hydrophobic cavity of RGD-PSSP conjugates constructed the RGD-PSSP/DOX drug delivery system. The in vitro experiments displayed that RGD-PSSP/DOX NPs showed obviously redox and pH dual sensitive drug release profile. MTT and cell uptake observation elucidated cRGD modification could increase the cytotoxicity, and promote the uptake of B16 cells and HUVEC cells both overexpressing integrin ανβ3on cell membrane. Cell uptake mechanism investigation further revealed that RGD-PSSP/DOX interacted with plasma membrane via specific recognition of cRGD peptide with integrin ανβ3, and was subsequently internalized mainly through clathrin- and caveolin-mediated endocytosis. Remarkably, RGD-PSSP/DOX presented superior anticancer activity and lower heart and kidney toxicity in vivo, which could be regarded as a potential candidate for efficient antitumor chemotherapy drug delivery., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: A multifunctional redox- and pH-responsive polymeric drug delivery system is designed and investigated for targeted anticancer drug delivery to liver cancer., Methods: The nanocarrier (His-PAMAM-ss-PEG-Tf, HP-ss-PEG-Tf) is constructed based on generation 4 polyamidoamine dendrimer (G4 PAMAM). Optimized amount of histidine (His) residues is grafted on the surface of PAMAM to obtain enhanced pH-sensitivity and proton-buffering capacity. Disulfide bonds (ss) are introduced between PAMAM and PEG to reach accelerated intracellular drug release. Transferrin (Tf) was applied to achieve active tumor targeting. Doxorubicin (DOX) is loaded in the hydrophobic cavity of the nanocarrier to exert its anti-tumor effect., Results: The results obtained from in vitro and in vivo evaluation indicate that HP-ss-PEG-Tf/DOX complex has pH and redox dual-sensitive properties, and exhibit higher cellular uptake and cytotoxicity than the other control groups. Flow cytometry and confocal microscopy display internalization of HP-ss-PEG-Tf/DOX via clathrin mediated endocytosis and effective endosomal escape in HepG2 cancer cells. Additionally, cyanine 7 labeled HP-ss-PEG-Tf conjugate could quickly accumulate in the HepG2 tumor. Remarkably, HP-ss-PEG-Tf/DOX present superior anticancer activity, enhanced apoptotic activity and lower heart and kidney toxicity in vivo., Discussion: Thus, HP-ss-PEG-Tf is proved to be a promising candidate for effective targeting delivery of DOX into the tumor., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Hu et al.)

Aim: To develop a nanocarrier for targeted delivery of agents to the cartilage., Materials & Methods: Chondrocyte affinity peptide modified PEGylated polyamidoamine conjugates (CAP-PEG-PAMAM) were prepared and rhodamine B isothiocyanate (RB) fluorophore was linked on them for comparative biological tracing and profiling., Results: CAP4-PP-RB exhibited much more efficient cellular uptake in vitro than that of PEG-PAMAM-RB. Both the conjugates were likely internalized by chondrocytes via clathrin and caveolin co-mediated endocytosis, and delivered to lysosomes. In vivo imaging demonstrated the fluorescein-labeled nanocarrier was capable to persist in the joint cavity of rats for a prolonged time. Furthermore, the CAP4-PEG-PAMAM showed a good biocompatibility and enhanced penetration effects in vivo., Conclusion: CAP-PEG-PAMAM could be an effective nanocarrier for intra-articular delivery of agents to cartilage.

Partly PEGylated polyamidoamine (PAMAM) dendrimer was used as the nanocarrier for the cytoplasmic delivery of kartogenin (KGN) to induce chondrogenic differentiation of mesenchymal stem cells (MSCs). Here, KGN was conjugated to the surface of PAMAM and the end group of polyethylene glycol (PEG) to obtain PEG-PAMAM-KGN (PPK) and KGN-PEG-PAMAM (KPP) conjugate, respectively. The effects of PPK and KPP on the in vitro chondrogenic differentiation of MSCs were evaluated. KPP induced higher expression of chondrogenic markers than PPK and free KGN. In particular, after treatment of KPP, CBF β nuclear localization intensity was significantly increased, indicating enhanced efficacy of chondrogenesis. The fluorescein labeled PEG-PAMAM was capable to persist in the joint cavity for a prolonged time of both healthy and osteoarthritis (OA) rats. Thus, PEG-PAMAM could be a useful nanocarrier for intra-articular (IA) delivery of drug to treat OA., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Unlabelled: To solve the contradiction between long circulation time and effective intracellular drug release, redox and pH-responsive drug delivery system was developed by incorporated redox-sensitive disulfide linkage between poly(amidoamine) dendrimers (PAMAM) and poly(ethylene glycol) (PEG). Doxorubicin (DOX) was loaded into the hydrophobic core of the conjugates to prepare PAMAM-SS-PEG/DOX complexes (PSSP/DOX). In vitro release studies suggested that DOX release from PSSP/DOX complexes followed an redox and acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PSSP/DOX complexes against B16 tumor cells increased with, while cellular uptake decreased with increasing PEGylation degree. Further, intracellular DOX release observation and measurement indicate that the intracellular DOX release played a critical role for the cytotoxicity of DOX-loaded PSSP conjugates. In addition, cellular entry mechanism of the PSSP/DOX study demonstrated that both clathrin- and caveolae-mediated endocytosis were the primary pathways for cellular entry of PSSP/DOX. Finally, in vivo study of PSSP/DOX complexes in B16 tumor-bearing mice indicate that PSSP/DOX could significantly improve antitumor efficiency and present a good safety. The redox and pH-responsive drug delivery system has been demonstrated to be a promising candidate for solid tumor therapy., Statement of Significance: In previous research, pH-sensitive diblock polymer of poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate) (PEG-PTMBPEC) was synthesized to facilitate the intracellular anticancer drug release. However, the nanoparticles based on PEG-PTMBPEC get into the tumor cells just relying on the EPR-mediated passive targeting resulting in the low drug accumulation. Therefore, cRGD peptide modified PEG-PTMBPEC polymeric micelles were developed for specific targeted delivery of doxorubicin (DOX) to neovascular cells and tumor cells simultaneously. The precise intracellular target site and effective drug concentration will contribute to enhancing the antitumor toxicity and reducing the systematic toxicity of DOX. The cRGD modified pH-sensitive micellar system is a promising vehicle for intracellular drug delivery to αvβ3 integrin receptor overexpressed tumor cells and neovascular cells., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

An ideal drug delivery system for cancer therapy should be equipped with extended circulation, improved tumor targeting and controlled drug release, as well as low toxicity from the carrier. In this study, a multifunctional drug delivery system based on the PEGylated poly(amidoamine) (PAMAM) dendrimer was designed, and folate-PEGylation was applied to modify the dendrimer in order to enhance tumor selectivity. A series of acid-labile PAMAM-DOX conjugates (FPP-hyd-DOX) with different FA ligand ratios were successfully constructed. (1)H NMR, FTIR, DLS and TEM were used to describe the physicochemical characterization of PAMAM-DOX conjugates. Both in vitro drug release assay and subcellular localization, the conjugates exhibited an obvious pH-triggered drug release. The FPP-hyd-DOX 16/1 displayed much lower IC50 value than that of non-targeted PP-hyd-DOX. Through fluorescence microscopy and flow cytometry investigations, the cellular uptake of FPP-hyd-DOX 16/1 was obviously enhanced, compared with that of PP-hyd-DOX. The cellular uptake mechanism and subcellular localization study revealed that the conjugates were internalized by KB cells via FA receptor and clathrin co-mediated endocytosis, delivered to acidic lysosomes and triggered the release of DOX into nuclei to exert its cytotoxicity. These obtained results showed that FPP-hyd-DOX conjugations would be a promising drug delivery carrier for targeted cancer therapy., (Copyright © 2015. Published by Elsevier B.V.)

Nanocarriers with low toxicity, high stability, long circulation in blood and triggered drug release at target sites are extremely needed for cancer therapy. In this study, different molar ratios of poly (ethylene glycol) (PEG) were conjugated to poly (amidoamine) dendrimer (PAMAM) by cleavable disulfide bonds, yielding redox and pH dual-responsive nanocarriers (PSSP). The redox sensitivity of the PSSP conjugates was confirmed by measuring the change in particle size and zeta potential under reductive environment by dynamic light scattering (DLS). Meanwhile, all conjugates showed slight hemolytic ratio and high stability in 10% FBS for 24h. Phagocytosis experiments indicated that the PSSP conjugates could effectively escape the engulfment of macrophage. Doxorubicin (DOX) was loaded into the hydrophobic core of the conjugates with loading content of 10%. In vitro release studies suggested that release rate as well as cumulative release amount of DOX from the PSSP conjugates were pronouncedly enhanced in reductive environment as compared with the non-cleavable counterparts. Besides, all conjugates exhibited excellent acid-triggered release performance. Significantly, PEGylation degree of the conjugates had critical impact on drug release. Cytotoxicity tests displayed that DOX-loaded PSSP conjugates were more potent in killing B16 and A549 tumor cells than the non-cleavable counterparts. Curiously, PSSP conjugate with the highest PEGylation degree showed the best antitumor effect despite the somewhat less cell uptake. Therefore, the dual-responsive PSSP conjugates seem promising candidates for efficient intracellular release of antitumor drugs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this study, pH-sensitive biomaterials coated polymer/DNA nanocomplexes containing a high mobility group box 1 (HMGB1) were developed as an efficient non-viral gene delivery system. HMGB1 is a family of endogenous molecules that contains nuclear locating sequences (NSL). Polyethylene glycol tethered carboxylated chitosan modified with folic acid (FA-PEG-CCTS) was synthesized and its buffering capacity was determined by acid-base titration. A pH-sensitive core-shell system FA-PEG-CCTS/PAMAM/HMGB1/pDNA nanocomplexes (FPCPHDs), was prepared and characterized. Electrophoresis showed that FPCPHDs were resistant to heparin replacement and DNase I digestion. FPCPHDs exhibited only minor toxic effects on HepG2 and KB cells. The results of both luciferase activity assay and RFP fluorescence intensity analysis showed that FPCPHDs enhanced gene transfection and expression in KB cells. Moreover, gene transfection and expression in KB cells were inhibited by free folic acid. Intracellular trafficking of FPCPHDs in KB cells showed that FPCPHDs could rapidly escape from endo-lysosomes and become exclusively located in the nucleus at 3 h post transfection. In addition, FPCPHDs exhibited increased red fluorescence protein (RFP) expression at the tumor site of S180 xenograft nude mice. All results suggest that FPCPHDs is an efficient approach to improve the transfection and expression efficiency in most FR-positive cancer cells., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Partly PEGylated polyamidoamine (PAMAM) dendrimer was used as the nanocarrier for the cytoplasmic delivery of kartogenin (KGN) to induce chondrogenic differentiation of mesenchymal stem cells (MSCs). Here, KGN was conjugated to the surface of PAMAM and the end group of polyethylene glycol (PEG) to obtain PEG-PAMAM-KGN (PPK) and KGN-PEG-PAMAM (KPP) conjugate, respectively. The effects of PPK and KPP on the in vitro chondrogenic differentiation of MSCs were evaluated. KPP induced higher expression of chondrogenic markers than PPK and free KGN. In particular, after treatment of KPP, CBF β nuclear localization intensity was significantly increased, indicating enhanced efficacy of chondrogenesis. The fluorescein labeled PEG-PAMAM was capable to persist in the joint cavity for a prolonged time of both healthy and osteoarthritis (OA) rats. Thus, PEG-PAMAM could be a useful nanocarrier for intra-articular (IA) delivery of drug to treat OA. [ABSTRACT FROM AUTHOR]