Natural lignin nanoparticles target tumor by saturating the phagocytic capacity of Kupffer cells in the liver.

Ligand-receptor recognition serves as the fundamental driving force for active targeting, yet it is still constrained by off-target effects. Herein, we demonstrate that circumventing or blocking the mononuclear phagocyte system (MPS) are both viable strategies to address off-target effects. Naturally derived lignin nanoparticles (LNPs) show great potential to block MPS due to its good stability, low toxicity, and degradability. We further demonstrate the impact of LNPs dosage on in vivo tumor targeting and antitumor efficacy. Our results show that a high dose of LNPs (300 mg/kg) leads to significant accumulation at the tumor site for a duration of 14 days after intravenous administration. In contrast, the low-dose counterparts (e.g., 50, 150 mg/kg) result in almost all LNPs accumulating in the liver. This discovery indicates that the liver is the primary site of LNP capture, leaving only the surplus LNPs the chance to reach the tumor. In addition, although cell membrane-engineered LNPs can rapidly penetrate tumors, they are still prone to capture by the liver during subsequent circulation in the bloodstream. Excitingly, comparable therapeutic efficacy is obtained for the above two strategies. Our findings may offer valuable insights into the targeted delivery of drugs for disease treatment.

Versatile Supermolecular Inclusion Complex Based on Host-Guest Interaction for Targeted Gene Delivery.

A facile and targeted gene delivery system was prepared by conjugating ß-cyclodextrin modified polyethylenimine (PEI-CD) and adamantyl peptide (AdGRGDS) based on host-guest interaction. With the rational design between PEI-CD and AdGRGDS, the PEI-CD/AdGRGDS gene delivery system showed excellent DNA binding capability and exhibited good ability to compact DNA into uniform spherical nanoparticles. In vitro luciferase assay showed that gene expression transfected by PEI-CD/AdGRGDS was stronger than that by PEI-CD in HeLa cells, whereas gene expression transfected by PEI-CD/AdGRGDS and PEI-CD was similar to each other in COS7 cells. Internalization of complexes was qualitatively studied using a confocal laser scanning microscope (CLSM) and quantitatively analyzed by flow cytometry, respectively, and targeting specificity was also evaluated by CLSM. Results of CLSM and flow cytometry indicated that PEI-CD/AdGRGDS had good targeting specificity to tumor cells with integrin αvß3 overexpression. To further evaluate the targeting specificity and transfection efficiency in vivo, a rat model with murine hepatic carcinoma cell line H22 was used. PEI-CD/AdGRGDS showed stronger gene expression efficiency than PEI-CD via in vivo transfection of pORF-LacZ and pGL-3 plasmids after subcutaneous injection. Interestingly, PEI-CD/AdGRGDS also showed high targeting specificity and transfection distribution to tumor xenograft after tail-vein injection. In vitro and in vivo assays highlighted the importance of GRGDS targeting specificity to tumor cells with integrin αvß3 overexpression and demonstrated that the PEI-CD/AdGRGDS gene delivery system would have great potential for targeted tumor therapy.

A surface charge-switchable and folate modified system for co-delivery of proapoptosis peptide and p53 plasmid in cancer therapy.

To improve the tumor therapeutic efficiency and reduce undesirable side effects, ternary FK/p53/PEG-PLL(DA) complexes with a detachable surface shielding layer were designed. The FK/p53/PEG-PLL(DA) complexes were fabricated by coating the folate incorporated positively charged FK/p53 complexes with charge-switchable PEG-shield (PEG-PLL(DA)) through electrostatic interaction. At the physiological pH 7.4 in the bloodstream, PEG-PLL(DA) could extend the circulating time by shielding the positively charged FK/p53 complexes. After the accumulation of the FK/p53/PEG-PLL(DA) complexes in tumor sites, tumor-acidity-triggered charge switch led to the detachment of PEG-PLL(DA) from the FK/p53 complexes, and resulted in efficient tumor cell entry by folate-mediated uptake and electrostatic attraction. Stimulated by the high content glutathione (GSH) in cytoplasm, the cleavage of disulfide bond resulted in the liberation of proapoptosis peptide C-KLA(TPP) and the p53 gene, which exerted the combined tumor therapy by regulating both intrinsic and extrinsic apoptotic pathways. Both in vitro and in vivo studies confirmed that the ternary detachable complexes FK/p53/PEG-PLL(DA) could enhance antitumor efficacy and reduce adverse effects to normal cells. These findings indicate that the tumor-triggered decomplexation of FK/p53/PEG-PLL(DA) supplies a useful strategy for targeting delivery of different therapeutic agents in synergetic anticancer therapy.

A pH-responsive drug nanovehicle constructed by reversible attachment of cholesterol to PEGylated poly(l-lysine) via catechol-boronic acid ester formation.

The present work reports the construction of a drug delivery nanovehicle via a pH-sensitive assembly strategy for improved cellular internalization and intracellular drug liberation. Through spontaneous formation of boronate linkage in physiological conditions, phenylboronic acid-modified cholesterol was able to attach onto catechol-pending methoxypoly(ethylene glycol)-block-poly(l-lysine). This comb-type polymer can self-organize into a micellar nanoconstruction that is able to effectively encapsulate poorly water-soluble agents. The blank micelles exhibited negligible in vitro cytotoxicity, yet doxorubicin (DOX)-loaded micelles could effectively induce cell death at a level comparable to free DOX. Owing to the acid-labile feature of the boronate linkage, a reduction in environmental pH from pH 7.4 to 5.0 could trigger the dissociation of the nanoconstruction, which in turn could accelerate the liberation of entrapped drugs. Importantly, the blockage of endosomal acidification in HeLa cells by NH4Cl treatment significantly decreased the nuclear uptake efficiency and cell-killing effect mediated by the DOX-loaded nanoassembly, suggesting that acid-triggered destruction of the nanoconstruction is of significant importance in enhanced drug efficacy. Moreover, confocal fluorescence microscopy and flow cytometry assay revealed the effective internalization of the nanoassemblies, and their cellular uptake exhibited a cholesterol dose-dependent profile, indicating the contribution of introduced cholesterol functionality to the transmembrane process of the nanoassembly.

One-step preparation and pH-tunable self-aggregation of amphoteric aliphatic polycarbonates bearing plenty of amine and carboxyl groups.

This paper reports a novel amphoteric aliphatic polycarbonate bearing both amine and carboxyl groups. In the absence of protection-deprotection chemistry, the multi-functionalized copolymer is synthesized by one-step enzymatic copolymerization. The influences of the reaction conditions including monomer feed ratio and polymerization time are explored. The simultaneous incorporation of amine and carboxyl functionalities provides the copolymer with a pH-tunable self-aggregation feature, leading to various aggregation states including precipitated agglomerate, well-dispersed positively or negatively charged nanoparticles in a controlled manner. The copolymer displays minimal cytotoxicity to 293T and HeLa cells.