Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery.

BACKGROUND: There are few effective medications for treating colorectal cancer and liver metastases (CRLM). The interactions among glycolysis, epithelial-mesenchymal transition (EMT), and immune microenvironment contribute to the progression of CRLM. A main glycolytic enzyme pyruvate Kinase M2 (PKM2) is highly expressed in colorectal cancer and CRLM, and thus can be a potential therapeutic target. METHODS: A therapeutic strategy was proposed and the shikonin-loaded and hyaluronic acid-modified MPDA nanoparticles (SHK@HA-MPDA) were designed for CRLM therapy via PKM2 inhibition for immunometabolic reprogramming. The treatment efficacy was evaluated in various murine models with liver metastasis of colorectal tumor. RESULTS: SHK@HA-MPDA achieved tumor-targeted delivery via hyaluronic acid-mediated binding with the tumor-associated CD44, and efficiently arrested colorectal tumor growth. The inhibition of PKM2 by SHK@HA-MPDA led to the remodeling of the tumor immune microenvironment and reversing EMT by lactate abatement and the suppression of TGFß signaling; the amount of cytotoxic effector CD8+ T cells was increased while the immunosuppressive MDSCs decreased. CONCLUSION: The work provided a promising targeted delivery strategy for CRLM treatment by regulating glycolysis, EMT, and anticancer immunity. An immunometabolic strategy for treating colorectal cancer liver metastases using the shikonin-loaded, hyaluronic acid-modified mesoporous polydopamine nanoparticles (SHK@HA-MPDA) via glycolysis inhibition, anticancer immunity activation, and EMT reversal. SHK@HA-MPDA can inhibit cytoplasmic PKM2 and glycolysis of the tumor and reduce lactate flux, and then activate the DCs and remodel the tumor immune microenvironment. The reduced lactate flux can reduce MDSC migration and suppress EMT.

Pharmaceutical liposomal delivery-specific considerations of innovation and challenges.

Liposomal technology has been widely used in the pharmaceutical field for the preparation of nano-sized drug delivery systems based on natural or synthetic lipids. Liposomes possess many attractive properties, such as easy processing, high biocompatibility, adaptable drug loading, and improved PK profiles. In recent decades, great efforts have been made in this field, and dozens of liposomal medicines have been marketed worldwide and many more are under preclinical or clinical investigations. Liposomes can enhance the aqueous dissolution and stability of the encapsulated drugs and modulate the in vivo fate of the drugs (e.g., prolonged half-life and increased drug accumulation in the pathological sites). Therefore, liposomal technology can improve the druggability of the candidates, enhance treatment efficacy and reduce side effects. This review discusses the prospects of liposomal delivery, including the specific considerations of innovation and challenges.

Enhanced storage stability of solid lipid nanoparticles by surface modification of comb-shaped amphiphilic inulin derivatives.

Solid lipid nanoparticles (SLNs) have been widely used as a vehicle for drug delivery. However, highly ordered lipid lattices and poor storage stability limit their practical application. Highly ordered crystal lattices may result from the low drug payload. In addition, the lipid matrix of SLNs may undergo a polymorphic transition from high energy and disordered modifications to low energy and ordered modifications during storage. This leads to drug expulsion and precipitation. Meanwhile, SLNs are susceptible to particle aggregation and size growth during storage. To improve the performance of SLNs, two comb-shaped amphiphilic macromolecular materials (CAMs), dodecyl inulin (Inu12) and octadecyl inulin (Inu18), were synthesized and utilized as emulsifiers to modify and stabilize SLNs (Inu12/Inu18-SLNs). The results indicated that Inu12 and Inu18 could more effectively reduce the lipid crystallinity and crystal lattice order of fresh SLNs versus Poloxamer 188 and Tween-80. Moreover, after six months of storage at 4 °C or 25 °C, both blank and Cyclosporine A (CsA)-loaded Inu12/Inu18-SLNs had a slower crystal transition than Tween/P188-SLNs. The particle size increases of Inu12/Inu18-SLNs were much smaller than those of Tween/P188-SLNs. The drug encapsulation efficiencies of CsA-loaded Inu12/Inu18-SLNs during storage decreased more slowly than Tween-SLNs. Therefore, Inu12 and Inu18 could more effectively inhibit lipid crystal transition and prevent particle aggregation during storage. This, in turn, leads to better storage physical stability of SLNs. Thus, the Inu12 and Inu18 CAMs were superior to Tween-80 and Poloxamer 188 (common straight-chain surfactants).

Improved gastrointestinal stability of solid lipid nanoparticles using comb-shaped amphiphilic inulin derivatives.

In order to reduce enzymatic degradation and thereby enhance the stability of solid lipid nanoparticles (SLNs) in the gastrointestinal tract, comb-shaped amphiphilic macromolecular material (CAM) of dodecyl inulin (Inu12) and octadecyl inulin (Inu18) were designed as the emulsifier and stabilizer to modify SLNs (Inu12/Inu18-SLNs). Inu12-SLNs and Inu18-SLNs had similar particle size as the control SLNs (P188-SLNs and Tween-SLNs) prepared with the straight chain surfactants, poloxamer 188 and tween-80 as the emulsifier, which ranged from 220 nm to 270 nm. The zeta potentials of all the SLNs formulations were slightly negative. Cyclosporine A (CsA)-loaded Inu12-SLNs and Inu18-SLNs showed a much lower drug release than CsA-loaded Tween-SLNs at pH 6.8 PBS containing 0.1% sodium dodecylsulfate and all the three SLNs exhibited biphasic release profiles. The results of cytotoxicity test showed that the toxic effects of Inu12-SLNs and Inu18-SLNs on cell viability had no significant difference in comparison to P188-SLNs and Tween-SLNs. Both CAM-modified SLNs (Inu12/Inu18-SLNs) showed a significant reduced lipolysis in vitro. As compared to P188-SLNs and Tween-SLNs, the total lipolysis of Inu18-SLNs during 4 h was decreased by 31.51 % and 45.67 % and that of Inu12-SLNs was decreased by 24.13 % and 38.29 %, respectively. Besides, the cumulative drug precipitations for CsA-loaded Inu12-SLNs and Inu18-SLNs during 4 h lipolysis were dramatically declined, which were 64% and 42% of that for Tween-SLNs, respectively. Therefore, it can be concluded that both alkylated inulin-derived CAM-modified SLNs, especially the Inu18-SLNs had the improved gastrointestinal stability to resist the lipid degradation by lipase enzyme.

Enhanced oral absorption of insulin using colon-specific nanoparticles co-modified with amphiphilic chitosan derivatives and cell-penetrating peptides.

In this study, amphipathic chitosan derivative (ACS) and cell-penetrating peptide (CPP) co-modified colon-specific nanoparticles (CS-CPP NPs) were prepared and evaluated to improve the oral bioavailability of protein and peptide drugs. ACS modification was harnessed to protect CPPs from degradation in the stomach and small intestine after oral administration and achieve colon-specific drug delivery. After CS-CPP NPs reached the colon, ACSs on the surface of the NPs were gradually degraded and CPPs were exposed to bring into play the penetration efficacy in the colon epithelium. Herein, we synthesized four types of ACSs (TOCS, TDCS, TPCS and TSCS) and adopted three types of CPPs (Tat, Penetratin and R8) to prepare NPs (TOCS-Tat NPs, TDCS-Tat NPs, TPCS-Tat NPs, TSCS-Tat NPs, TDCS-Pen NPs and TDCS-R8 NPs). The study of the protective effects of ACS upon Tat showed that the modification of ACS exerted favourable protection upon Tat in the stomach and small intestine. ACS degradation in the colon was indirectly determined in the viscosity method, which indicated that ACS could be gradually degraded in the colon. Using Caco-2 cell monolayers as cell models, it was found that the cellular uptake amount and transcellular transportation performance of CS-CPP NPs were much enhanced compared with those of TDCS NPs and PVA NPs. With Bama mini-pigs as animal models, the pharmacodynamic study demonstrated that the hypoglycemic effect for insulin-loaded TDCS-Tat NPs was more significant than that for TDCS NPs, lowering the blood glucose by 40%. The pharmacokinetic study indicated that the AUC and Cmax for TDCS-Tat NPs were respectively increased by 1.45 times and 1.82 times compared with those of TDCS NPs. In conclusion, CS-CPP NPs as vehicles for colon-specific drug delivery systems may be an efficient approach to improve the oral absorption of protein and peptide drugs.

Vitamin E-based redox-sensitive salinomycin prodrug-nanosystem with paclitaxel loaded for cancer targeted and combined chemotherapy.

Cancer stem cells (CSCs) can resist conventional chemotherapy to lead to cancer recurrence. For complete eradication of cancers, an effective CSCs therapeutic strategy should be developed to combine with conventional chemotherapy. In this work, a novel vitamin E-based redox-sensitive salinomycin (SAL, an inhibitor for CSCs) prodrug nanoparticles (TS NPs) and hyaluronic acid (HA)-coated TS NPs (HTS NPs) were fabricated to deliver paclitaxel (PTX) for cancer-targeted and combined chemotherapy. Both TS and HTS prodrug NPs had mean diameter of about 200 nm with uniform size distribution, excellent drug loading capacity for PTX, and glutathione-triggered SAL and PTX release profiles. The HTS prodrug NPs had enhanced cellular uptake efficiency over TS NPs due to CD44 receptor-mediated endocytosis, hence exerting stronger potency of SAL upon CSCs-enriched mammospheres formation and G0/G1 cell phase arresting. Cytotoxicity and 3D tumor spheroids assays demonstrated that both TS and HTS prodrug NPs themself can synergize with loaded PTX to maximize the chemotherapeutic effect. Obviously, the latter demonstrated a more potent anticancer efficacy due to improved intracellular drug delivery efficiency. These results suggested that the designed TS prodrug NPs, especially the coated HTS NPs can serve as an effective anti-CSCs strategy for cancer targeted and combination treatments.