Co-Delivery of Doxorubicin and Anti-PD-L1 Peptide in Lipid/PLGA Nanocomplexes for the Chemo-Immunotherapy of Cancer.

The combined delivery of chemotherapeutics with checkpoint inhibitors of the PD-1/PD-L1 pathway provides a new approach for cancer treatment. Small-molecule peptide inhibitors possess short production cycle, low immunogenicity, and fewer side effects; however, their potential in cancer therapy is hampered by the rapid biodegradation and a nanocarrier is needed for efficient drug delivery. Herein, anticancer drug doxorubicin (DOX) and PD-L1 inhibitor peptide P-12 are co-loaded by a lipid polymer nanocomplex based on poly(lactic-co-glycolic acid) (PLGA) and DSPE-PEG. Octaarginine (R8)-conjugated DSPE-PEG renders the LPN efficient internalization by cancer cells. The optimal nanomedicine LPN-30-R82K@DP shows a diameter of 125 nm and a DOX and P-12 loading content of 5.0 and 6.2%, respectively. LPN-30-R82K@DP exhibits good physiological stability and enhanced cellular uptake by cancer cells. It successfully induces immunogenic cell death and PD-L1 blockade in CT26 cancer cells. The in vivo antitumor study further suggests that co-loaded nanomedicine efficiently suppresses CT26 tumor growth and elicits antitumor immune response. This study manifests that lipid polymer nanocomplexes are promising drug carriers for the efficient chemo-immunotherapy of cancer.

Smart Multistage "Trojan Horse"-Inspired Bovine Serum Albumin-Coated Liposomes for Enhancing Tumor Penetration and Antitumor Efficacy.

Poor antitumor drug penetration into tumor tissues is a global challenge in clinical cancer treatment. Here, we reported a smart multistage "Trojan Horse"-inspired bovine serum albumin (BSA)-coated liposome (HBM), including the mimics of capsid and secondary BSA-coated polymeric nanoparticles (NPs) for enhancing tumor penetration and antitumor efficacy. These drug-loaded polymeric NPs possess a capsid-like component, a well-distributed nanostructure (size: 190.1 ± 4.98 nm, PDI: 0.259), and an excellent drug loading content (15.85 ± 1.36%). Meaningfully, after the smart multistage BSA-coated liposome targeted the tumor tissue, the mimics of capsid were "taken off" under the condition of tumor-specific enzymes, releasing "Heart" BSA-modified secondary NPs to increase the ability to penetrate tumor cells for enhancing antitumor efficacy. As expected, the HBM efficiently achieves high drug penetration into PAN02 tumor cells. Moreover, compared to free DOX and HM (HBM without BSA) NPs, DOX/HBM NPs exhibited the strongest tumor penetration and the highest cytotoxicity against PAN02 tumor cells both in vitro (IC50 = 0.141 µg/mL) and in vivo. This smart multistage "Trojan Horse"-inspired BSA-coated liposome should provide a new hathpace for further development of polymeric NPs in clinical treatment.

A pH-sensitive imidazole grafted polymeric micelles nanoplatform based on ROS amplification for ferroptosis-enhanced chemodynamic therapy.

Highly toxic reactive oxygen species (ROS), crucial in inducing apoptosis and ferroptosis, are pivotal for cell death pathways in cancer therapy. However, the effectiveness of ROS-related tumor therapy is impeded by the limited intracellular ROS and substrates, coupled with the presence of abundant ROS scavengers like glutathione (GSH). In this research, we developed acid-responsive, iron-coordinated polymer nanoparticles (PPA/TF) encapsulating a mitochondrial-targeting drug alpha-tocopheryl succinate (α-TOS) for enhanced synergistic tumor treatment. The imidazole grafted micelles exhibit prolonged blood circulation and improve the delivery efficiency of the hydrophobic drug α-TOS. Additionally, PPA's design aids in delivering Fe3+, supplying ample iron ions for chemodynamic therapy (CDT) and ferroptosis through the attachment of imidazole groups to Fe3+. In the tumor's weakly acidic intracellular environment, PPA/TF facilitates pH-responsive drug release. α-TOS specifically targets mitochondria, generating ROS and replenishing those depleted by the Fenton reaction. Moreover, the presence of Fe3+ in PPA/TF amplifies ROS upregulation, promotes GSH depletion, and induces oxidative damage and ferroptosis, effectively inhibiting tumor growth. This research presents an innovative ROS-triggered amplification platform that optimizes CDT and ferroptosis for effective cancer treatment.

Facile preparation of highly adhesive yet ultra-strong poly (vinyl alcohol)/cellulose nanocrystals composite hydrogel enabled by multiple networks structure.

Poly (vinyl alcohol) (PVA) hydrogel showed potential applications in bioengineering and wearable sensors fields. It is still a huge challenge to prepare highly adhesive yet strong poly (vinyl alcohol) hydrogel with good biocompatibility. Herein, we prepared a highly self-adhesive and strong poly (vinyl alcohol)/tannic acid@cellulose nanocrystals (PVA/TA@CNCs) composite hydrogel using TA@CNCs as functional nanofiller via facile freezing-thawing method. Multiple networks consisting of hydrogen bonding and coordination interactions endowed the hydrogel with high mechanical strength, excellent flexibility and fracture toughness with adequate energy dissipation mechanism and relatively dense network structure. The tensile strength of PVA/TA@CNCs hydrogel reached the maximum of 463 kPa, increasing by 367 % in comparison with pure PVA hydrogel (99 kPa), demonstrating the synergistic reinforcing and toughening effect of TA@CNCs. The hydrogel exhibited extremely high adhesion not only for various dry and wet substrates such as plastic, metal, Teflon, rubber, glass, leaf, but also sweaty human skin, showing good adhesion durability. The highest adhesion strength to silicone rubber, steel plate and pigskin could reach 197 kPa, 100 kPa and 46.9 kPa, respectively. Meanwhile the hydrogel had negligible cytotoxicity to cells and showed good biocompatibility.

Efficiency co-delivery of ellagic acid and oxygen by a non-invasive liposome for ameliorating diabetic retinopathy.

Diabetic retinopathy (DR) is one of the serious complications of diabetes, which has become the fourth leading cause of vision loss worldwide. Current treatment of DR relies on intravitreal injections of antiangiogenic agents, which has made considerable achievements in reducing visual impairment. However, long-term invasive injections require advanced technology and can lead to poor patient compliance as well as the incidence of ocular complications including bleeding, endophthalmitis, retinal detachment and others. Hence, we developed non-invasive liposomes (EA-Hb/TAT&isoDGR-Lipo) for efficiency co-delivery of ellagic acid and oxygen, which can be administered intravenously or by eye drops. Among that, ellagic acid (EA), as an aldose reductase inhibitor, could remove excessive reactive oxygen species (ROS) induced by high glucose for preventing retinal cell apoptosis, as well as reduce retinal angiogenesis through the blockage of VEGFR2 signaling pathway; carried oxygen could ameliorate DR hypoxia, and further enhanced the anti-neovascularization efficacy. Our results showed that EA-Hb/TAT&isoDGR-Lipo not only effectively protected retinal cells from high glucose-induced damage, but also inhibited VEGF-induced vascular endothelial cells migration, invasion, and tube formation in vitro. In addition, in a hypoxic cell model, EA-Hb/TAT&isoDGR-Lipo could reverse retinal cell hypoxia, thereby reducing the expression of VEGF. Significantly, after being administered as an injection or eye drops, EA-Hb/TAT&isoDGR-Lipo obviously ameliorated the structure (central retinal thickness and retinal vascular network) of retina by eliminating ROS and down-regulating the expression of GFAP, HIF-1α, VEGF and p-VEGFR2 in a DR mouse model. In summary, EA-Hb/TAT&isoDGR-Lipo holds great potentials in improvement of DR, which provides a novel approach for the treatment of DR.

Redox-responsive polyethyleneimine/tetrahedron DNA/doxorubicin nanocomplexes for deep cell/tissue penetration to overcome multidrug resistance.

Deep penetration of nanomedicines to cancer cells and tissues is a main obstacle to conquering multidrug resistant (MDR) cancer. Here, we presented redox-responsive polyethyleneimine (disulfide cross-linked PEI, PSP)/tetrahedral DNA (TDNs)/doxorubicin (DOX) nanocomplexes (NCs), PSP/TDNs@DOX NCs, to accomplish tumor cell/tissue penetration for overcoming MDR. The NCs can respond to glutathione and DNase I to disassociate and release DOX. In vitro study revealed that the NCs (N/P = 30) with positive charge could be associated to cell membranes and "dig holes" on them, evoking the membrane-breaking for enhanced cellular internalization and bypassing endocytosis regardless of drug-resistant mechanism. Transwell and 3D tumor models study established that NCs can efficiently depart from cells through "holes leakage" and "infected" surrounding cells to penetrate into deep tumor tissues. In vivo study showed that the PSP/TDNs@DOX NCs exhibited superior tumor penetration and therapeutic efficiency in xenografted drug-resistant tumor mouse models including human breast (MCF-7/R) and ovarian (SKOV3/R) cancer, which represent MDR with characteristics of DOX efflux and impermeability, respectively.

pH-sensitive polymeric micelles assembled by stereocomplexation between PLLA-b-PLys and PDLA-b-mPEG for drug delivery.

pH-responsive stereocomplexed micelles based on poly(l-lactic acid)-b-polylysine/poly(d-lactic acid)-b-methoxy poly(ethylene glycol) (PLLA-b-PLys/PDLA-b-mPEG) were fabricated by stereocomplexation between enantiomeric PLA segments. The morphology, critical micelle concentration, formation of stereocomplexation and pH sensitivity of the stereocomplexed micelles were investigated by TEM, DLS, fluorescence spectra, DSC, XRD, and the acid-base titration method. Interestingly, it was observed that compared to PLLA-b-PLys micelles, the stereocomplexed micelles showed lower critical micelle concentration. Anticancer drug doxorubicin (DOX) was encapsulated in the stereocomplexed micelles and then they were incubated with Hela cells to study the in vitro anti-tumor effect. The results showed that the DOX-loaded stereocomplexed micelles exhibited a slower drug release behavior and a weaker efficacy of intracellular proliferation inhibition than PLLA-b-PLys micelles. Stereocomplexation would provide a favorable platform to construct stable micelles for cancer therapy.

Highly stable RGD/disulfide bridge-bearing star-shaped biodegradable nanocarriers for enhancing drug-loading efficiency, rapid cellular uptake, and on-demand cargo release.

BACKGROUND: Stability, enhanced drug-loading efficiency (DLE), and specific accumulation of therapeutics at tumor sites remain major challenges for successful cancer therapy. PURPOSE: This study describes a newly developed intelligent nanosystem that integrates stealthy, active targeting, stimulus-responsiveness, and π-π interaction properties in a single carrier, based on the multifunctional star-shaped biodegradable polyester. PATIENTS AND METHODS: This highly stable, smart nanocarrier with spherical structures and a low critical micelle concentration (CMC) can provide spacious harbor and strong π-π interaction and hydrophobic interactions for hydrophobic doxorubicin (DOX). Its structure and morphology were characterized by proton nuclear magnetic resonance (1H-NMR) spectra, Fourier transform infrared (FTIR) spectra, Gel permeation chromatography (GPC), dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Antitumor effciency of polymeric micelles using CCK-8 assay, and the intracellular-activated delivery system was tracked by confocal laser scanning microscopy (CLSM) and flow cytometry. RESULTS: The synthesized copolymer can be self-assembled into nanoparticles with size of 50 nm and critical micellar concentration of 2.10 µg/mL. The drug-loading content of nanoparticles can be enhanced to 17.35%. Additionally, the stimulus-responsive evaluation and drug release study showed that the nanocarrier can rapidly respond to the intracellular reductive environment and dissociate for drug release. An in vitro study demonstrated that the nanocarrier can ferry doxorubicin selectively into tumor tissue, rapidly enter cancer cells, and controllably release its payload in response to an intracellular reductive environment, resulting in excellent antitumor activity in vitro. CONCLUSION: This study provides a facile and versatile approach for the design of multifunctional star-shaped biodegradable polyester nanovehicles for effective cancer treatment.

Multifunctional nanoparticles self-assembled from polyethylenimine-based graft polymers as efficient anticancer drug delivery.

Multiple functionalization of nanoparticles has attracted great interest in drug delivery. In this paper, polymeric amphiphiles of polyethylenimine (PEI) conjugated with methoxy poly(ethylene glycol) aldehyde (mPEG-CHO), poly(ε caprolactone) aldehyde (PCL-CHO) and pyrene-1-carboxaldehyde (Py-CHO) were synthesized via Schiff's reaction. The conjugates self-assembled into nanoparticles with pH-sensitivity to load anticancer drug doxorubicin (DOX), further coated with hyaluronic acid (HA) for tumor targeting. The mean size of nanoparticles was about 100nm and the stability of the nanoparticles was well in aqueous solution. The nanoparticles coated with HA showed faster disassembly in acidic solution, resulting in faster drug release in the medium with pH 5.0 compared to uncoated nanoparticles. Moreover, the nanoparticles exhibited an endosomal escape function to accelerate the release of DOX in cancer cells, which led to low IC50s to kill breast cancer cells (4T1) and liver cancer cells (HepG2) in vitro.