Combining chemotherapeutics is a promising method of improving cancer treatment; however, the clinical success of combination therapy is limited by the distinct pharmacokinetics of combined drugs, which leads to nonuniform distribution. In this study, we report a new robust approach to load two drugs with different hydrophilicities into a single cross-linked multilamellar liposomal vesicle (cMLV) to precisely control the drug ratio that reaches the tumor in vivo. The stability of cMLVs improves the loading efficiency and sustained release of doxorubicin (Dox) and paclitaxel (PTX), maximizing the combined therapeutic effect and minimizing the systemic toxicity. Furthermore, we show that the cMLV formulation maintains specific drug ratios in vivo for over 24 h, enabling the ratio-dependent combination synergy seen in vitro to translate to in vivo antitumor activity and giving us control over another parameter important to combination therapy. This combinatorial delivery system may provide a new strategy for synergistic delivery of multiple chemotherapeutics with a ratiometric control over encapsulated drugs to treat cancer and other diseases.
Liposomes constitute one of the most popular nanocarriers for the delivery of cancer therapeutics. However, since their potency is limited by incomplete drug release and inherent instability in the presence of serum components, their poor delivery occurs in certain circumstances. In this study, we address these shortcomings and demonstrate an alternative liposomal formulation, termed crosslinked multilamellar liposome (CML). With its properties of improved sustainable drug release kinetics and enhanced vesicle stability, CML can achieve controlled delivery of cancer therapeutics. CML stably encapsulated the anticancer drug doxorubicin (Dox) in the vesicle and exhibited a remarkably controlled rate of release compared to that of the unilamellar liposome (UL) with the same lipid composition or Doxil-like liposome (DLL). Our imaging study demonstrated that the CMLs were mainly internalized through a caveolin-dependent pathway and were further trafficked through the endosome-lysosome compartments. Furthermore, in vivo experiments showed that the CML-Dox formulation reduced systemic toxicity and significantly improved therapeutic activity in inhibiting tumor growth compared to that of UL-Dox or DLL-Dox. This drug packaging technology may therefore provide a new treatment option to better manage cancer and other diseases.
Encapsulating anticancer protein therapeutics in nanocarriers is an attractive option to minimize active drug destruction, increase local accumulation at the disease site, and decrease side effects to other tissues. Tumor-specific ligands can further facilitate targeting the nanocarriers to tumor cells and reduce nonspecific cellular internalization. Rationally designed non-covalent protein nanocapsules incorporating copper-free "click chemistry" moieties, polyethylene glycol (PEG) units, redox-sensitive cross-linker, and tumor-specific targeting ligands were synthesized to selectively deliver intracellular protein therapeutics into tumor cells via receptor-mediated endocytosis. These nanocapsules can be conjugated to different targeting ligands of choice, such as anti-Her2 antibody single-chain variable fragment (scFv) and luteinizing hormone releasing hormone (LHRH) peptide, resulting in specific and efficient accumulation within tumor cells overexpressing corresponding receptors. LHRH-conjugated nanocapsules selectively delivered recombinant human tumor suppressor protein p53 and its tumor-selective supervariant into targeted tumor cells, which led to reactivation of p53-mediated apoptosis. Our results validate a general approach for targeted protein delivery into tumor cells using cellular-responsive nanocarriers, opening up new opportunities for the development of intracellular protein-based anticancer treatment.
Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cellular therapy by harvesting infiltrated lymphocytes from tumors, culturing and amplifying them in vitro and then infusing back to treat patients. Its diverse TCR clonality, superior tumor-homing ability, and low off-target toxicity endow TIL therapy unique advantages in treating solid tumors compared with other adoptive cellular therapies. Nevertheless, the successful application of TIL therapy currently is still limited to several types of tumors. Herein in this review, we summarize the fundamental work in the field of TIL therapy and the current landscape and advances of TIL clinical trials worldwide. Moreover, the limitations of the current TIL regimen have been discussed and the opportunities and challenges in the development of next-generation TIL are highlighted. Finally, the future directions of TIL therapy towards a broader clinical application have been proposed.
The unique spectral properties of semiconductor quantum dots (QDs) enable long-term live-cell imaging and ultrasensitive detection of viral particles, which in turn can potentially provide a practical means for detailed analysis of the underlying molecular mechanisms of virus entry. In this study, we report a general method of labeling adeno-associated virus serotype 2 (AAV2) with QDs for enhanced visualization of the intracellular behavior of viruses in living target cells. It was found that the mild condition required for this QD conjugation reaction allowed for the retention of viral infectivity of AAV2. Furthermore, quantitative analysis of viral motility in living cells suggested that QD-labeling had no significant effect on the intracellular transport properties of AAV2 particles compared to those of conventional organic dye-labeled AAV2. Our imaging study demonstrated that QD-AAV2 was internalized mainly through a clathrin-dependent pathway and then trafficked through various endosomes. It was also observed that QD-AAV2 particles exploit the cytoskeleton network to facilitate their transport within cells, and the labeling study provided evidence that the ubiquitin-proteasome system was likely involved in the intracellular trafficking of AAV2, at least at the level of nuclear transport. Taken together, our findings reveal the potential of this QD-labeling method for monitoring the intracellular dynamics of virus-host cell interactions and interrogating the molecular mechanisms of viral infection in greater detail.
Adeno-associated virus type 2 (AAV2) is considered a promising gene delivery vector and has been extensively applied in several disease models; however, inefficient transduction in various cells and tissues has limited its widespread application in many areas of gene therapy. In this study, we have developed a general, but efficient, strategy to enhance viral transduction, both in vitro and in vivo, by incubating viral particles with cell-permeable peptides (CPPs). We show that CPPs increase internalization of viral particles into cells by facilitating both energy-independent and energy-dependent endocytosis. Moreover, CPPs can significantly enhance the endosomal escape process of viral particles, thus enhancing viral transduction to those cells that have exhibited very low permissiveness to AAV2 infection as a result of impaired intracellular viral processing. We also demonstrated that this approach could be applicable to other AAV serotypes. Thus, the membrane-penetrating ability of CPPs enables us to generate an efficient method for enhanced gene delivery of AAV vectors, potentially facilitating its applicability to human gene therapy.
One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment (TME), which inactivates the function of tumor-infiltrating lymphocytes (TIL) through the production of immunosuppressive molecules, such as adenosine. Adenosine inhibits the function of CD4 and CD8 T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the TME. To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLV) to tumor-infiltrating T cells deep within the immune suppressive TME. Through and studies, we have demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CAR-T cells within the TME. .
Exploring functional substrates and precisely regulating the electronic structures of atomic metal active species with moderate spin state are of great importance yet remain challenging. Hereon, we provide an axial Fe‐O‐Ti ligand regulated spin‐state transition strategy to improve the oxygen reduction reaction (ORR) activity of Fe centers. Theoretical calculations indicate that Fe‐O‐Ti ligands in FeN3O‐O‐Ti can induce a low‐to‐medium spin‐state transition and optimize O2 adsorption by FeN3O. As a proof‐of‐concept, the oriented catalyst was prepared from atomic‐Fe‐doped polymer‐like quantum dots and ultrathin o‐terminated MXene. The optimal catalyst exhibits an intrinsic activity that is almost 5 times higher than the control sample (without axial Fe‐O‐Ti ligands). It also delivers a superior performance in Zn‐air batteries and H2/O2 anion exchange membrane fuel cells in a wide‐temperature range.
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