Cleavable-Branched Polymer-Modified Liposomes Reduce Accelerated Blood Clearance and Enhance Photothermal Therapy.

In recent years, cationic liposomes have been successfully used as delivery platforms for mRNA vaccines. Poly(ethylene glycol) (PEG)-lipid derivatives are widely used to enhance the stability and reduce the toxicity of cationic liposomes. However, these derivatives are often immunogenic, triggering the rise of anti-PEG antibodies. Understanding the role and impact of PEG-lipid derivatives on PEGylated cationic liposomes is key to solving the PEG dilemma. In this study, we designed linear, branched, and cleavable-branched cationic liposomes modified with PEG-lipid derivatives and investigated the effect of the liposome-induced accelerated blood clearance (ABC) phenomenon on photothermal therapy. Our study indicated that the linear PEG-lipid derivatives mediated the effect of photothermal therapy by stimulating splenic marginal zone (MZ) B cells to secrete anti-PEG antibodies and increasing the level of IgM expression in the follicular region of the spleen. However, the cleavable-branched and branched PEG-lipid derivatives did not activate the complement system and avoided the ABC phenomenon by inducing noticeably lower levels of anti-PEG antibodies. The cleavable-branched PEGylated cationic liposomes improved the effect of photothermal therapy by reversing the charge on the liposome surface. This detailed study of PEG-lipid derivatives contributes to the further development and clinical application of PEGylated cationic liposomes.

A novel micellar carrier to reverse multidrug resistance of tumours: TPGS derivatives with end-grafted cholesterol.

D-α-tocopherol polyethylene glycol succinate (TPGS) has good biocompatibility, low immunogenicity, prolonged circulation time, and it can reverse multidrug resistance of tumours. However, the micelle concentration (CMC) of TPGS is too high (0.2 mg/mL) to develop the formulation of the micelle. In this study, TPGS was modified with cholesterol to obtain a new carrier material, TPGS-CHMC. The CMC of TPGS-CHMC was 2 µg/mL, which was extremely lower than that of TPGS. Docetaxel (DTX)-loaded TPGS-CHMC micelles (TPGS-CHMC/DTX) exhibited an average size of approximately 13 nm, a zeta potential of approximately -4.66 mV, and high encapsulation efficiency (99.2 ± 0.6%). TPGS-CHMC reduced mitochondrial membrane potential and cell membrane fluidity in paclitaxel-resistant ovarian cancer cells (A2780/T). In vivo, DiR-loaded TPGS-CHMC micelles were selectively distributed in A2780/T tumour-bearing nude mice. In A2780/T tumour-bearing nude mice, TPGS-CHMC/DTX micelles displayed significantly higher anti-tumour activity and less toxicity than the free DTX solution. In summary, TPGS-CHMC has various advantages and provides a new option for developing functional polymeric micelles.

Blockade of neutrophil recruitment to tumor sites based on sialic acid-modified nanoplatforms enhances the efficacy of checkpoint blockade immunotherapy.

Checkpoint inhibitors are designed to rejuvenate depleted or suppressed T cells in the tumor microenvironment, relying on the immune system to control and kill tumors. However, accumulating evidence indicates that tumor-infiltrating neutrophils impede the proliferation and activation of T cells and determine the resistance to checkpoint blockade and chemotherapy. In this study, sialic acid ligand-modified colchicine derivative phospholipid complexes specifically targeted tumor-associated neutrophils in the peripheral blood, blocked neutrophil accumulation in tumors, and attenuated the inhibitory effect of infiltrating neutrophils on T cells. Neutrophil blocking therapy enhanced the immunotherapy effect of the PD-L1 antibody in S180 advanced tumors and 4T1 breast cancer. Our study found that PD-L1 antibody monotherapy increased the tumor infiltration of immunosuppressive neutrophils. Combination therapy with neutrophil blocking can greatly reduce tumor-infiltrating neutrophils and increase the proliferation of cytotoxic CD8+ T lymphocytes in the tumor. The combination therapy significantly improved the survival rate of mice with advanced S180 tumors and increased the sensitivity of immune checkpoint inhibitors to 4T1 cold tumors.

A potential platform of combining sialic acid derivative-modified paclitaxel cationic liposomes with antibody-drug conjugates inspires robust tumor-specific immunological memory in solid tumors.

The recent approvals for antibody-drug conjugates (ADCs) in multiple malignancies in the past few years have fueled the ongoing development of this class of drug. However, the limitation of ADCs is selectivity toward cancer cells especially overexpressing the antigen of interest. To broaden the anti-cancer spectrum of ADCs, combinatorial strategies of ADCs with chemotherapy have become a central focus of the current preclinical and clinical research. Here, we used the microtubule stabilizer paclitaxel and enfortumab vedotin-ejfv (EV), an ADC carrying the microtubule inhibitor payload monomethyl auristatin E (MMAE), for co-administration under the consideration of their mechanism of action associated with microtubules. We designed a sialic acid-cholesterol (SA-CH) conjugate-modified cationic liposome platform loaded with PTX (PTX-SAL) for efficiently targeting tumor-associated immune cells. Compared with monotherapy, PTX-SAL-mediated combination therapy with ADCs significantly inhibited S180 tumor growth in mice, with complete tumor regression occurring. The formation of a durable tumor-specific immunological memory response in mice that experienced complete tumor regression was assessed by secondary tumor cell rechallenge, and the production of memory T cells in the spleen was detected as related to the increased CD4+T memory cells and the enhanced serum IFN-γ. All our preliminary results throw light on the tremendous application potential for the application of this combination therapy regimen capable of mounting a durable immune response and stimulating a robust T cell-mediated tumor-specific immunological memory.

Sialic acid-mediated photochemotherapy enhances infiltration of CD8+ T cells from tumor-draining lymph nodes into tumors of immunosenescent mice.

Immunoscenescence plays a key role in the initiation and development of tumors. Furthermore, immunoscenescence also impacts drug delivery and cancer therapeutic efficacy. To reduce the impact of immunosenescence on anti-tumor therapy, this experimental plan aimed to use neutrophils with tumor tropism properties to deliver sialic acid (SA)-modified liposomes into the tumor, kill tumor cells via SA-mediated photochemotherapy, enhance infiltration of neutrophils into the tumor, induce immunogenic death of tumor cells with chemotherapy, enhance infiltration of CD8+ T cells into the tumor-draining lymph nodes and tumors of immunosenescent mice, and achieve SA-mediated photochemotherapy. We found that CD8+ T cell and neutrophil levels in 16-month-old mice were significantly lower than those in 2- and 8-month-old mice; 16-month-old mice exhibited immunosenescence. The anti-tumor efficacy of SA-mediated non-photochemotherapy declined in 16-month-old mice, and tumors recurred after scabbing. SA-mediated photochemotherapy enhanced tumor infiltration by CD8+ T cells and neutrophils, induced crusting and regression of tumors in 8-month-old mice, inhibited metastasis and recurrence of tumors and eliminated the immunosenescence-induced decline in antitumor therapeutic efficacy in 16-month-old mice via the light-heat-chemical-immunity conversion.

Deuterated colchicine liposomes based on oligomeric hyaluronic acid modification enhance anti-tumor effect and reduce systemic toxicity.

Deuterated drugs are produced by substituting hydrogen atoms with deuterium atoms at specific sites in a drug molecule to prolong its metabolic cycle and reduce the production of toxic metabolites. Deuterated drugs have recently attracted increasing attention from the pharmaceutical industry. Colchicine exhibits a strong anti-tumor activity but has a short half-life, rapid attenuated drug concentration, narrow treatment window, and lack of tumor-specific targeting in vivo, resulting in toxicity and side effects. In this study, we explored whether deuteration could reduce the toxicity of colchicine. We prepared deuterated colchicine liposomes coated with oligo-hyaluronic acid, which can bind to the tumor-specific CD44 receptor and reduce the clearance of immune cells from the blood, resulting in a long blood circulation time and active targeting. We observed that deuteration of the colchicine B ring reduced drug toxicity and improved the anti-tumor response in 4 T1 breast cancer. Liposomes modified with oligo-hyaluronic acid exhibited increased tumor accumulation, further improving the anti-tumor effect of the drugs. Our results provide a basis for the development and application of deuterated drugs in the field of nano-preparations.