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.

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.

A double-layer dura mater based on poly(caprolactone-co-lactide) film and polyurethane sponge: preparation, characterization, and biodegradation study.

Synthetic, biodegradable polymers hold great potential in dura mater substitution. In this study, a dura mater-mimetic double-layer film@sponge composite was developed. The composite contains a poly(caprolactone-co-lactide) (PCLA) film and polyurethane (PU) sponge, which simulates the hard and soft layers of dura mater, respectively. PCLA films were prepared by a solution-casting method and showed excellent mechanical properties and tolerance to water. PU sponge was hydrophilic and had a high water-absorption rate (about 500%). The double-layer composite (film@sponge) integrated the good mechanical properties of the films and the good water absorption of the sponge. The excellent biocompatibility and biodegradability of the PCLA film@PU sponge composites were verified by in vitro degradation and cytotoxicity study and the in vivo implantation in the back of rats. Importantly, the film@sponge composite had a suitable degradation rate and good biocompatibility, holding potential in the field of dural repair.

A tumor extracellular pH-sensitive PD-L1 binding peptide nanoparticle for chemo-immunotherapy of cancer.

Chemo-immunotherapy is a promising model for the combination treatment of cancer. Many solid tumors overexpress programmed cell death ligand (PD-L1) for immune suppression. In this study, a PD-L1 binding peptide conjugate (DCS) nanoparticle with tumor extracellular pH-responsiveness was developed for efficient chemo-immunotherapy of colon cancer. A hydrophilic D-type polypeptide (D-PPA) and two hydrophobic stearyl chains were linked with a pH-sensitive linker to obtain amphiphilic DCS, which could self-assemble into nanoparticles (NPs). Anticancer agent doxorubicin (DOX) was loaded to obtain DOX@DCS NPs, which could accumulate at the tumor site by enhanced permeability and retention effect and release D-PPA at tumor extracellular pH. The release of D-PPA could not only lead to instability and aggregation of NPs for enhanced tumor retention but also block PD-1/PD-L1 to avoid immune escape and elicit enhanced immune response. In addition, DOX could induce immunogenic cell death (ICD) of cancer cells and promote anti-tumor immune response with the combination of PD-1/PD-L1 blocking. DOX@DCS showed efficient inhibition of CT26 tumors and induced immune response both in vitro and in vivo. Overall, our study reported a facile yet robust nanosystem based on an immune blocking peptide and a chemotherapeutic ICD inducer for efficient chemo-immunotherapy of cancer.

Mitochondria-targeted tetrahedral DNA nanostructures for doxorubicin delivery and enhancement of apoptosis.

Mitochondria-targeted nanoparticles, such as liposomes, polymers and inorganic particles, suffer from heterogeneity, low biocompatibility and low drug loading efficiency. Here, we present a novel delivery platform based on tetrahedral DNA nanostructures (TDNs) that enable the mitochondrial transportation of the anticancer drug doxorubicin (DOX) for cancer therapy. In our design, DOX was intercalated into TDNs, which executed the cell-killing function inside the tumor cells. Various numbers of d-(KLAKLAK)2 (KLA) were conjugated to TDNs to achieve the mitochondria targeting effect. The mean size of the KLA-modified TDNs was about 15 nm, and the TDNs were stable in FBS. The DOX loading efficiency of the TDNs was up to around 77%. The 3KLA-modified TDNs exhibited the most efficient DOX accumulation in mitochondria, leading to an effective release of cytochrome c, and the upregulated expression levels of caspase-9, caspase-3, p21 and p53. Meanwhile, 3KLA-TDNs/DOX elevated the pro-apoptotic Bax, reduced the anti-apoptotic Bcl-2 protein expression and increased the Bax/Bcl-2 ratio, which finally activated the mitochondria-mediated, programmed apoptosis pathway to enhance the anticancer efficacy in vitro. This 3KLA-TDN and DOX co-assembling strategy can be further developed to transport other anthracyclines and chemotherapeutic agents for enhanced apoptosis effects.