Targeting tumor highly-expressed LAT1 transporter with amino acid-modified nanoparticles: Toward a novel active targeting strategy in breast cancer therapy.

Designing active targeting nanocarriers with increased cellular accumulation of chemotherapeutic agents is a promising strategy in cancer therapy. Herein, we report a novel active targeting strategy based on the large amino acid transporter 1 (LAT1) overexpressed in a variety of cancers. Glutamate was conjugated to polyoxyethylene stearate as a targeting ligand to achieve LAT1-targeting PLGA nanoparticles. The targeting efficiency of nanoparticles was investigated in HeLa and MCF-7 cells. Significant increase in cellular uptake and cytotoxicity was observed in LAT1-targeting nanoparticles compared to the unmodified ones. More interestingly, the internalized LAT1 together with targeting nanoparticles could recycle back to the cell membrane within 3 h, guaranteeing sufficient transporters on cell membrane for continuous cellular uptake. The LAT1 targeting nanoparticles exhibited better tumor accumulation and antitumor effects. These results suggested that the overexpressed LAT1 on cancer cells holds a great potential to be a high-efficiency target for the rational design of active-targeting nanosystems.

Membrane-Loaded Doxorubicin Liposomes Based on Ion-Pairing Technology with High Drug Loading and pH-Responsive Property.

In order to achieve high drug loading and high entrapment efficiency, a doxorubicin-cholesteryl hemisuccinate ion-pair complex (DCHIP) was formed, and the ion-pair complex liposomes (DCHIP-Lip) were prepared based on conventional thin-film dispersion method. Firstly, DCHIP was fabricated and confirmed with FTIR, 1H-NMR, DSC, and XRD techniques. Afterwards, DCHIP-Lip were prepared and evaluated in terms of particle size, zeta potential, entrapment efficiency, and drug loading content. Finally, the in vitro and in vivo behavior of liposomes was further investigated. The DCHIP-Lip had a nanoscale particle size of about 120 nm with a negative zeta potential of about -22 mV. In addition, the entrapment efficiency and drug loading content of DOX reached 6.4 ± 0.05 and 99.29 ± 0.3%, respectively. Importantly, the release of DCHIP-Lip was pH sensitive and increased cell toxicity against MCF-7 cells was achieved. Upon dilution, the liposomes were fairly stable under physiological conditions. The in vivo pharmacokinetic study indicated that the AUC of DOX in DCHIP-Lip was 11.48-fold higher than that of DOX-HCl solution and the in vivo antitumor activity of DCHIP-Lip showed less body weight loss and a significant prohibition effect of tumor growth. Based on these findings, it can be seen that the ion-pairing technology combined with conventional liposome drug loading method could be used to achieve high drug loading and it could be valuable for the study of liposomal delivery system.

In vivo tailor-made protein corona of a prodrug-based nanoassembly fabricated by redox dual-sensitive paclitaxel prodrug for the superselective treatment of breast cancer.

Prodrug self-nanoassemblies have many advantages for anticancer drug delivery, including high drug loading rate, resistance to recrystallization, and on-demand drug release. However, few studies have focused on their protein corona, which is inevitably formed after entering the blood and determines their subsequent fates in vivo. To actively tune the protein corona of prodrug nanoassemblies, three maleimide-paclitaxel prodrugs were synthesized via different redox-sensitive linkers (ester bond, thioether bond and disulfide bond). After incubation with rat plasma, the surface maleimide groups effectively captured albumins, resulting in albumin-enriched protein corona. The recruited albumin corona enabled enhanced tumor accumulation and facilitated cellular uptake, ensuring the high-efficiency delivery of nanoassemblies to tumor cells. Surprisingly, we found that the traditionally reduction-sensitive disulfide bond could also be triggered by reactive oxygen species (ROS). Such a redox dual-responsive drug release property of the disulfide bond-containing prodrug nanoassemblies further increased the selectivity in cytotoxicity between normal and tumor cells. Moreover, the disulfide bond-containing prodrug nanoassemblies exhibited the highest antitumor efficacy in vivo compared to marketed Abraxane® and other prodrug nanoassemblies. Thus, the fabrication of the maleimide-decorated disulfide bond bridged prodrug nanoassembly, integrating a tunable protein corona and on-demand drug release, is a promising strategy for improved cancer chemotherapy.

Dipeptide-modified nanoparticles to facilitate oral docetaxel delivery: new insights into PepT1-mediated targeting strategy.

Oligopeptide transporter 1 (PepT1) has been a striking prodrug-designing target. However, the underlying mechanism of PepT1 as a target to facilitate the oral absorption of nanoparticles (NPs) remains unclear. Herein, we modify Poly (lactic-co-glycolic acid) (PLGA) NPs with the conjugates of dipeptides (L-valine-valine, L-valine-phenylalanine) and polyoxyethylene (PEG Mw: 1000, 2000) stearate to facilitate oral delivery of docetaxel (DTX) to investigate the oral absorption mechanism and regulatory effects on PepT1 of the dipeptide-modified NPs. The cellular uptake of the dipeptide-modified NPs is more efficient than that of the unmodified NPs in the stably transfected hPepT1- Hela cells and Caco-2 cells, suggesting the involvement of PepT1 in the endocytosis of NPs. The internalization of the dipeptide-modified NPs is proved to be a proton-dependent process. Moreover, the L-valine-valine modified NPs with shorter PEG chain exhibit distinct advantages in terms of intestinal permeability and oral absorption, resulting in significantly improved oral bioavailability of DTX. In summary, PepT1 could serve as a desirable target for oral nanoparticulate drug delivery and the dipeptide-modified NPs represent a promising nanoplatform to facilitate oral delivery of hydrophobic drugs with low bioavailability.

In situ low-immunogenic albumin-conjugating-corona guiding nanoparticles for tumor-targeting chemotherapy.

Nanoparticles (NPs) are unavoidably covered by a layer of immunogenic proteins upon injection into blood, such as immunoglobins and complements, which buries the active-targeting ligands and triggers the rapid clearance of NPs by the mononuclear phagocytic system. Low antifouling polyethylene glycol is used to inhibit the formation of the immunogenic corona but it leads to poor cellular uptake and the immunogen-related accelerated blood clearance (ABC) phenomenon in multiple administrations. Here, we develop surface maleimide-modified NPs that covalently conjugate in vivo plasma albumin in its corona upon exposure to blood. The in situ recruited low-immunogenic albumin-enriching corona is capable of protecting maleimide-decorated NPs from phagocytosis in the bloodstream, preventing the ABC phenomenon in the second administration, facilitating NP accumulation in the tumor site/cells by the passive EPR effect and albumin receptor-mediated active targeting, and finally improving the antitumor activity. Such findings suggest that the facile strategy, based on the in situ anchored albumin-enriching corona, is efficient at enabling maleimide-decorated NPs to acquire stealth and tumor-targeting ability.

Large amino acid transporter 1 mediated glutamate modified docetaxel-loaded liposomes for glioma targeting.

The therapeutic outcome of glioma treatment is rigorously limited by blood-brain barrier (BBB) and infiltrating growth of glioma. To tackle the dilemma, more and more attentions were focused on developing nutrient transporters-mediated dual-targeted drug delivery system, in one side for BBB penetration, another for intracranial glioma targeting. Herein, Large amino acid transporter 1 (LAT1), overexpressed both on BBB and glioma cells, was selected as a target. Docetaxel-loaded glutamate-d-α-tocopherol polyethylene glycol 1000 succinate copolymer (Glu-TPGS) functionalized LAT1-targeting liposomes (DTX-TGL) were applied to enhance the BBB penetration and glioma therapy. The in vivo results of the fluorescent image indicated that TGL possessed an effective BBB penetration than that of unmodified ones in mice. The LAT1 targeting effcicacy and cell cytotoxicity of TGL were investigated in C6 glioma cells. Compared with unmodified liposomes, a significant higher cellular uptake and cell cytotoxicity was found in TGL treated group. Our results indicated that LAT1-targeting docetaxel-loaded liposome paves up a new direction using LAT1 transporter as a good target in designing brain glioma-targeting nanosystems.