Orally available dextran-aspirin nanomedicine modulates gut inflammation and microbiota homeostasis for primary colorectal cancer therapy.

Reversing the aggravated immunosuppression hence overgrowth of colorectal cancer (CRC) caused by the gut inflammation and microbiota dysbiosis is pivotal for effective CRC therapy and metastasis inhibition. However, the low delivery efficiency and severe dose-limiting off-target toxicities caused by unsatisfied drug delivery systems remain the major obstacles in precisely modulating gut inflammation and microbiota in CRC therapy. Herein, a multifunctional oral dextran-aspirin nanomedicine (P3C-Asp) was utilized for oral treatment of primary CRC, as it could release salicylic acid (SA) while scavenging reactive oxygen species (ROS) and held great potential in modulating gut microbiota with prebiotic (dextran). Oral P3C-Asp retained in CRC tissues for over 12 h and significantly increased SA accumulation in CRC tissues over free aspirin (10.8-fold at 24 h). The enhanced SA accumulation and ROS scavenging of P3C-Asp cooperatively induced more potent inflammation relief over free aspirin, characterized as lower level of cyclooxygenase-2 and immunosuppressive cytokines. Remarkably, P3C-Asp promoted the microbiota homeostasis and notably increased the relative abundance of strengthening systemic anti-cancer immune response associated microbiota, especially lactobacillus and Akkermansia to 6.66- and 103- fold over the control group. Additionally, a demonstrable reduction in pathogens associated microbiota (among 96% to 79%) including Bacteroides could be detected. In line with our findings, inflammation relief along with enhanced abundance of lactobacillus was positively correlated with CRC inhibition. In primary CRC model, P3C-Asp achieved 2.1-fold tumor suppression rate over free aspirin, with an overall tumor suppression rate of 85%. Moreover, P3C-Asp cooperated with αPD-L1 further reduced the tumor weight of each mouse and extended the median survival of mice by 29 days over αPD-L1 alone. This study unravels the synergistic effect of gut inflammation and microbiota modulation in primary CRC treatment, and unlocks an unconventional route for immune regulation in TME with oral nanomedicine.

A polyamino acid-based phosphatidyl polymer library for in vivo mRNA delivery with spleen targeting ability.

A qualified delivery system is crucial for the successful application of messenger RNA (mRNA) technology. While lipid nanoparticles (LNPs) are currently the predominant platform for mRNA delivery, they encounter challenges such as high inflammation and difficulties in targeting non-liver tissues. Polymers offer a promising delivery solution, albeit with limitations including low transfection efficiency and potential high toxicity. Herein, we present a poly(L-glutamic acid)-based phosphatidyl polymeric carrier (PLG-PPs) for mRNA delivery that combines the dual advantages of phospholipids and polymers. The PLGs grafted with epoxy groups were firstly modified with different amines and then with alkylated dioxaphospholane oxides, which provided a library of PLG polymers grafted with various phosphatidyl groups. In vitro studies proved that PLG-PPs/mRNA polyplexes exhibited a significant increase in mRNA expression, peaking 14 716 times compared to their non-phosphatidyl parent polymer. Impressively, the subset PA8-PL3 not only facilitated efficient mRNA transfection but also selectively delivered mRNA to the spleen instead of the liver (resulting in 69.73% protein expression in the spleen) once intravenously administered. This type of phosphatidyl PLG polymer library provides a novel approach to the construction of mRNA delivery systems especially for spleen-targeted mRNA therapeutic delivery.

Hit-and-run vaccine system that overcomes limited neoantigen epitopes for efficient broad antitumor response.

Neoantigen cancer vaccines have been envisioned as one of the most promising means for cancer therapies. However, identifying neoantigens for tumor types with low tumor mutation burdens continues to limit the effectiveness of neoantigen vaccines. Herein, we proposed a "hit-and-run" vaccine strategy which primes T cells to attack tumor cells decorated with exogenous "neo-antigens". This vaccine strategy utilizes a peptide nanovaccine to elicit antigen-specific T cell responses after tumor-specific decoration with a nanocarrier containing the same peptide antigens. We demonstrated that a poly(2-oxazoline)s (POx) conjugated with OVA257-264 peptide through a matrix metalloprotease 2 (MMP-2) sensitive linker could efficiently and selectively decorate tumor cells with OVA peptides in vivo. Then, a POx-based nanovaccine containing OVA257-264 peptides to elicit OVA-specific T cell responses was designed. In combination with this hit-and-run vaccine system, an effective vaccine therapy was demonstrated across tumor types even without OVA antigen expression. This approach provides a promising and uniform vaccine strategy against tumors with a low tumor mutation burden.

Injectable Nano-in-Gel Vaccine for Spatial and Temporal Control of Vaccine Kinetics and Breast Cancer Postsurgical Therapy.

Breast cancer is the most commonly diagnosed cancer, and surgical resection is the first choice for its treatment. With the development of operation techniques, surgical treatment for breast cancer is evolving toward minimally invasive and breast-conserving approaches. However, breast-conserving surgery is prone to an increased risk of cancer recurrence and is becoming a key challenge that needs to be solved. In this study, we introduce a one-shot injectable nano-in-gel vaccine (NIGel-Vax) for postoperative breast cancer therapy. The NIGel-Vax was constructed by mixing protein antigens with PEI-4BImi-Man adjuvant and then encapsulated in a hydrogel made with oxidized dextran (ODEX) and 4-arm PEG-ONH2. Using 4T1 tumor-extracted proteins as antigen, the NIGel-Vax achieved a 92% tumor suppression rate and a 33% cure rate as a postoperative therapy in the 4T1 tumor model. Using the tumor-associated antigen trophoblast cell-surface antigen 2 (TROP2) protein as the antigen, NIGel-Vax achieved a 96% tumor suppression rate and a 50% cure rate in triple-negative breast cancer (TNBC) models. This design provides an encouraging approach for breast cancer postoperative management.

Killing tumor-associated bacteria with a liposomal antibiotic generates neoantigens that induce anti-tumor immune responses.

Increasing evidence implicates the tumor microbiota as a factor that can influence cancer progression. In patients with colorectal cancer (CRC), we found that pre-resection antibiotics targeting anaerobic bacteria substantially improved disease-free survival by 25.5%. For mouse studies, we designed an antibiotic silver-tinidazole complex encapsulated in liposomes (LipoAgTNZ) to eliminate tumor-associated bacteria in the primary tumor and liver metastases without causing gut microbiome dysbiosis. Mouse CRC models colonized by tumor-promoting bacteria (Fusobacterium nucleatum spp.) or probiotics (Escherichia coli Nissle spp.) responded to LipoAgTNZ therapy, which enabled more than 70% long-term survival in two F. nucleatum-infected CRC models. The antibiotic treatment generated microbial neoantigens that elicited anti-tumor CD8+ T cells. Heterologous and homologous bacterial epitopes contributed to the immunogenicity, priming T cells to recognize both infected and uninfected tumors. Our strategy targets tumor-associated bacteria to elicit anti-tumoral immunity, paving the way for microbiome-immunotherapy interventions.

Anti-phagocytosis-blocking repolarization-resistant membrane-fusogenic liposome (ARMFUL) for adoptive cell immunotherapy.

Equipping multiple functionalities on adoptive effector cells is essential to overcome the complex immunological barriers in solid tumors for superior antitumor efficacy. However, current cell engineering technologies cannot endow these functionalities to cells within a single step because of the different spatial distributions of targets in one cell. Here, we present a core-shell anti-phagocytosis-blocking repolarization-resistant membrane-fusogenic liposome (ARMFUL) to achieve one-step multiplexing cell engineering for multifunctional cell construction. Through fusing with the M1 macrophage membrane, ARMFUL inserts an anti-CD47 (aCD47)-modified lipid shell onto the surface and simultaneously delivers colony-stimulating factor 1 receptor inhibitor BLZ945-loaded core into the cytoplasm. The surface-presenting aCD47 boosts macrophage's phagocytosis against the tumor by blocking CD47. The cytoplasm-located BLZ945 prompts its polarization resistance to M2 phenotype in the immunosuppressive microenvironment via inactivating the intracellular M2 polarization signaling pathway. This ARMFUL provides a versatile cell engineering platform to customize multimodal cellular functions for enhanced adoptive cell therapy.

Comprehensive evaluation of biopolymer immune implants for peritoneal metastasis carcinoma therapy.

Immunotherapy has been widely used in the treatment of advanced stage cancers with spreading metastases, while the fully activation of immune system often requires sustained and long-acting immune stimulation by immunotherapeutic agents. In previous studies, we designed a biopolymer immune implant by dynamic covalent bonds and achieved sustained release of loaded immunotherapeutic agents, thus stimulated systemic immune activation and elicited immune memory effects. Herein, we further optimized the implants and carried out a comprehensive evaluation of the implants on peritoneal metastasis carcinoma (PMC) therapy. Our results showed that the implants fabricated with 8-arm polyethylene glycol amine (8-arm PEG-NH2) and 40% oxidation degree dextran (ODEX) exhibited a satisfactory degradation time for activating the antitumor immunity. The drug combination of oxaliplatin (OxP) and resiquimod (R848) could be sustainably released from the implants for 18 days. The implants cured 75% of mice with PMC and elicited immune memory effects to resist tumor re-challenge without obvious side effects observed. Mechanism analysis revealed that the implants could serve as an in-situ vaccine to enhance the infiltration of activated dendritic cells (DCs), T cells and natural killer (NK) cells inside the tumor, as well as increase the serum tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ) and interleukin 12 (IL-12) levels. These results strongly support the clinical translation potential of this sustained released biopolymer immune implants for PMC therapy.

Membrane-Fusion-Mediated Multiplex Engineering of Tumor Cell Surface Glycans for Enhanced NK Cell Therapy.

Natural killer (NK) cell therapies show potential for tumor treatment but are immunologically resisted by the overexpressed immunosuppressing tumor cell surface glycans. To reverse this glycan-mediated immunosuppression, the surface NK-inhibitory glycan expressions need to be downregulated and NK-activating glycan levels should be elevated synchronously with optimal efficiency. Here, a core-shell membrane-fusogenic liposome (MFL) is designed to simultaneously achieve the physical modification of NK-activating glycans and biological inhibition of immunosuppressing glycans on the tumor cell surface via a membrane-fusion manner. Loaded into a tumor-microenvironment-triggered-degradable thermosensitive hydrogel, MFLs could be conveniently injected and controllably released into local tumor. Through fusion with tumor cell membrane, the released MFLs could simultaneously deliver sialyltransferase-inhibitor-loaded core into cytoplasm, and anchor NK-activating-glycan-modified shell onto tumor surface. This spatially-differential distribution of core and shell in one cell ensures the effective inhibition of intracellular sialyltransferase to downregulate immunosuppressing sialic acid, and direct presentation of NK-activating Lewis X trisaccharide (LeX) on tumor surface simultaneously. Consequentially, the sialic acid-caused immunosuppression of tumor surface is reprogrammed to be LeX-induced NK activation, resulting in sensitive susceptibility to NK-cell-mediated recognition and lysis for improved tumor elimination. This MFL provides a novel platform for multiplex cell engineering and personalized regulation of intercellular interactions for enhanced cancer immunotherapy.

In Situ Reprogramming of Tumors for Activating the OX40/OX40 Ligand Checkpoint Pathway and Boosting Antitumor Immunity.

OX40 (CD134, TNFRSF4) is a member of the tumor necrosis factor receptor superfamily that can be activated by its cognate ligand OX40L (CD252, TNFSF4) and functions as a pair of T cell costimulatory molecules. The interaction between OX40 and OX40L (OX40/OX40L) plays a critical role in regulating antitumor immunity, including promoting effector T cells expansion and survival, blocking natural regulatory T cells (Treg) activity, and antagonizing inducible Treg generation. However, current OX40 agonists including anti-OX40 monoclonal antibodies (aOX40) have serious side effects after systemic administration, which limits their clinical success and application. Herein, we propose a strategy to reprogram tumor cells into OX40L-expressing "artificial" antigen-presenting cells (APCs) by OX40L plasmid-loaded nanoparticles for boosting antitumor immunity in situ. A novel gene transfection carrier was prepared by a modular hierarchical assembly method, which could efficiently transfect various tumor cells and express OX40L proteins on their surface. These surface-decorated OX40L proteins were proved to stimulate T cell proliferation in vitro while stimulating strong antitumor immune responses in vivo. Importantly, this in situ reprogramming strategy did not induce any toxicity as observed in aOX40 treatment, thus providing a novel method for immune checkpoint stimulator application.

Nucleobase-crosslinked poly(2-oxazoline) nanoparticles as paclitaxel carriers with enhanced stability and ultra-high drug loading capacity for breast cancer therapy.

Poly(2-oxazoline) (POx) has been regarded as a potential candidate for drug delivery carrier to meet the challenges of nanomedicine clinical translation, due to its excellent biocompatibility and self-assembly properties. The drug loading capacity and stability of amphiphilic POxs as drug nanocarriers, however, tend to be insufficient. Herein, we report a strategy to prepare nucleobase-crosslinked POx nanoparticles (NPs) with enhanced stability and ultra-high paclitaxel (PTX) loading capacity for breast cancer therapy. An amphiphilic amine-functionalized POx (PMBEOx-NH2) was firstly prepared through a click reaction between cysteamines and vinyl groups in poly(2-methyl-2-oxazoline)-block-poly (2­butyl­2-oxazoline-co-2-butenyl-2-oxazoline) (PMBEOx). Complementary nucleobase-pairs adenine (A) and uracil (U) were subsequently conjugated to PMBEOx-NH2 to give functional POxs (POxA and POxU), respectively. Due to the nucleobase interactions formed between A and U, NPs formed by POxA and POxU at a molar ratio of 1:1 displayed ultrahigh PTX loading capacity (38.2%, PTX/POxA@U), excellent stability, and reduced particle size compared to the uncross-linked PTX-loaded NPs (PTX/PMBEOx). Besides the prolonged blood circulation and enhanced tumor accumulation, the smaller PTX/POxA@U NPs also have better tumor penetration ability compared with PTX/PMBEOx, thus leading to a higher tumor suppression rate in two murine breast cancer models (E0711 and 4T1). These results proved that the therapeutic effect of chemotherapeutic drugs could be improved remarkably through a reasonable optimization of nanocarriers.

Mannan-decorated pathogen-like polymeric nanoparticles as nanovaccine carriers for eliciting superior anticancer immunity.

Using nanotechnology for cancer vaccine design holds great promise because of the intrinsic feature of nanoparticles in being captured by antigen-presenting cells (APCs). However, there are still obstacles in current nanovaccine systems in achieving efficient tumor therapeutic effects, which could partially be attributed to the unsatisfactory vaccine carrier design. Herein, we report a mannan-decorated pathogen-like polymeric nanoparticle as a protein vaccine carrier for eliciting robust anticancer immunity. This nanovaccine was constructed as a core-shell structure with mannan as the shell, polylactic acid-polyethylenimine (PLA-PEI) assembled nanoparticle as the core, and protein antigens and Toll-like receptor 9 (TLR9) agonist CpG absorbed onto the PLA-PEI core via electrostatic interactions. Compared to other hydrophilic materials, mannan decoration could greatly enhance the lymph node draining ability of the nanovaccine and promote the capturing by the CD8+ dendritic cells (DCs) in the lymph node, while PLA-PEI as the inner core could enhance antigen endosome escape thus promoting the antigen cross-presentation. In addition, mannan itself as a TLR4 agonist could synergize with CpG for maximally activating the DCs. Excitingly, we observed in several murine tumor models that using this nanovaccine alone could elicit robust immune response in vivo and result in superior anti-tumor effects with 50% of mice completely cured. This study strongly evidenced that mannan decoration and a rationally designed nanovaccine system could be quite robust in tumor vaccine therapy.

Nano-trapping CXCL13 reduces regulatory B cells in tumor microenvironment and inhibits tumor growth.

Interactions between different cell types in the tumor microenvironment (TME) affect tumor growth. Tumor-associated fibroblasts produce C-X-C motif chemokine ligand 13 (CXCL13) which recruits B cells to the TME. B-cells in the TME differentiate into regulatory B cells (Bregs) (IL-10+CD1d+CD5+CD138+CD19+). We highlight these Breg cells as a new important factor in the modulation of the immunosuppressive TME in different desmoplastic murine tumor models. In addition, CXCL13 also stimulates epithelial-mesenchymal transition (EMT) of the tumor cells. The tumorigenic roles of CXCL13 led us to explore an innovative anti-cancer strategy based on delivering plasmid DNA encoding a CXCL13 trap to reduce Bregs differentiation and normalize EMT, thereby suppressing tumor growth. CXCL13 trap suppressed tumor growth in pancreatic cancer, BRAF-mutant melanoma, and triple-negative breast cancer. In this study, following treatment, the affected tumor remained dormant resulting in prolonged progression-free survival of the host.

A Minimalist Binary Vaccine Carrier for Personalized Postoperative Cancer Vaccine Therapy.

In recent years, significant evolutions have been made in applying nanotechnologies for prophylactic and therapeutic cancer vaccine design. However, the clinical translation of nanovaccines is still limited owing to their complicated compositions and difficulties in the spatiotemporal coordination of antigen-presenting cell activation and antigen cross-presentation. Herein, a minimalist binary nanovaccine (BiVax) is designed that integrates innate stimulating activity into the carrier to elicit robust antitumor immunity. The authors started by making a series of azole molecules end-capped polyethylenimine (PEI-M), and were surprised to find that over 60% of the PEI-M polymers have innate stimulating activity via activation of the stimulator of interferon genes pathway. PEI-4BImi, a PEI-M obtained from a series of polymers, elicits robust antitumor immune responses when used as a subcutaneously injected nanovaccine by simply mixing with ovalbumin antigens, and this BiVax system performs much better than the traditional ternary vaccine system, as well as, commercialized aluminum-containing adjuvants. This system also enables the fast preparation of personalized BiVax by compositing PEI-4BImi with autologous tumor cell membrane protein antigens, and a 60% postoperative cure rate is observed when combined with immune checkpoint inhibitors.

Combatting Helicobacter pylori with oral nanomedicines.

Helicobacter pylori (H. pylori) infection is considered to be the main cause of most digestive diseases,such as chronic active gastritis, gastroduodenal ulcers, or even gastric cancer. Oral medication is a transformative approach to treat H. pylori-induced infections. However, unlike intravenous administration, orally administrated drugs have to overcome various barriers before reaching the infected sites, which significantly limits the therapeutic efficacy. These challenges may be addressed by emerging nanomedicine that is equipped with nanotechnology approaches to enable efficient and effective targeted delivery of drugs. Herein, in this review, we first discuss the conventional therapy for the eradication of H. pylori. Through the introduction of the critical barriers of oral administration, the benefits of nanomedicine are highlighted. Recently-published examples of nanocarriers for combating H. pylori in terms of design, preparation, and antimicrobial mechanisms are then presented, followed by our perspective on potential future research directions of oral nanomedicines.

A simple and general strategy for postsurgical personalized cancer vaccine therapy based on an injectable dynamic covalent hydrogel.

Cancer vaccines artificially stimulate the immune system against cancer and are considered the most promising treatment of cancer. However, the current progress in vaccine research against cancer is still limited and slow, partially due to the difficulties in identifying and obtaining tumor-specific antigens. Considering surgery as the first choice for tumor treatment in most cases, the authors evaluated whether the resected tumor can be directly used as a source of tumor antigens for designing personalized cancer vaccines. Based on this idea, herein, the authors report a dynamic covalent hydrogel-based vaccine (DCHVax) for personalized postsurgical management of tumors. The study uses proteins extracted from the resected tumor as antigens, CpG as the adjuvant, and a multi-armed poly(ethylene glycol) (8-arm PEG)/oxidized dextran (ODEX) dynamically cross-linked hydrogel as the matrix. Subcutaneous injection of DCHVax recruits dendritic cells to the matrix in situ and elicits robust tumor-specific immune responses. Thus, it effectively inhibits the postoperative growth of the residual tumor in several murine tumor models. This simple and personalized method to develop cancer vaccines may be promising in developing clinically relevant strategies for postoperative cancer treatment.

Manipulating Liver Bile Acid Signaling by Nanodelivery of Bile Acid Receptor Modulators for Liver Cancer Immunotherapy.

Gut bacteria and their metabolites influence the immune microenvironment of liver through the gut-liver axis, thus representing emerging therapeutic targets for liver cancer therapy. However, directly manipulating gut microbiota or their metabolites is not practical in clinic since the safety concerns and the complicated mechanism of action. Considering the dysregulated bile acid profiles associated with liver cancer, here we propose a strategy that directly manipulates the primary and secondary bile acid receptors through nanoapproach as an alternative and more precise way for liver cancer therapy. We show that nanodelivery of bile acid receptor modulators elicited robust antitumor immune responses and significantly changed the immune microenvironment in the murine hepatic tumor. In addition, ex vivo stimulation on both murine and patient hepatic tumor tissues suggests the observation here may be meaningful for clinical practice. This study elucidates a novel and precise strategy for liver cancer immunotherapy.

In-Situ-Sprayed Dual-Functional Immunotherapeutic Gel for Colorectal Cancer Postsurgical Treatment.

Surgery remains the most preferred treatment options for colorectal cancer (CRC). Paradoxically, local recurrence and distant metastasis are usually accelerated postsurgery as a consequence of local and systemic immunosuppression caused by surgery. Therefore, modulating tumor postoperative immune microenvironment and activating systemic antitumor immunity are necessary supplementaries for CRC therapy. Here, an in-situ-sprayed immunotherapeutic gel loaded with anti-OX40 antibody (iSGels@aOX40) is reported for CRC postsurgical treatment. The iSGel is formed instantly after spraying with strong adhesion ability via crosslinking between tannic acid (TA) and poly(l-glutamic acid)-g-methoxy poly(ethylene glycol)/phenyl boronic acid (PLG-g-mPEG/PBA). TA not only serves as one component of the iSGel but also relieves the postsurgical immunosuppressive microenvironment by inhibiting the activity of cyclo-oxygenase-2 (COX-2). The aOX40 serves as an immune agonistic antibody and is released from the iSGel in a constant manner lasting for over 20 days. In a subcutaneous murine CRC model, the iSGels@aOX40 results in complete inhibition on tumor recurrence. In addition, the cured mice show resistance to tumor re-challenge, suggesting that immune memory effects are established after the iSGels@aOX40 treatment. In an orthotopic CRC peritoneal metastatic model, the iSGels@aOX40 also remarkably inhibits the growth of the abdominal metastatic tumors, suggesting great potential for clinical CRC therapy.

Functional bionanomaterials for cell surface engineering in cancer immunotherapy.

The cell surface is the forward position in cancer immunotherapy, with surface ligand and receptor interactions between various cells for determining immune privilege or recognition. Therefore, cell surface engineering (CSE) that manipulates the surface interactions between the immune effector cells (IECs) and tumor cells represents a promising means for eliciting effective anticancer immunity. Specifically, taking advantage of the development in biomaterials and nanotechnology, the use of functional bionanomaterials for CSE is attracting more and more attention in recent years. Rationally designed functional biomaterials have been applied to construct artificial functional modules on the surface of cells through genetic engineering, metabolic labeling, chemical conjugation, hydrophobic insertion, and many other means, and the CSE process can be performed both ex vivo and in vivo, on either IECs or tumor cells, and results in enhanced anticancer immunity and various new cancer immunity paradigms. In this review, we will summarize the recent exciting progresses made in the application of functional bionanomaterials for CSE especially in establishing effective recognition and interaction between IECs and tumor cells.

Supramolecular Assembled Programmable Nanomedicine As In Situ Cancer Vaccine for Cancer Immunotherapy.

Using nanotechnology for improving the immunotherapy efficiency represents a major research interest in recent years. However, there are paradoxes and obstacles in using a single nanoparticle to fulfill all the requirements in the complicated immune activation processes. Herein, a supramolecular assembled programmable immune activation nanomedicine (PIAN) for sequentially finishing multiple steps after intravenous injection and eliciting robust antitumor immunity in situ is reported. The programmable nanomedicine is constructed by supramolecular assembly via host-guest interactions between poly-[(N-2-hydroxyethyl)-aspartamide]-Pt(IV)/ß-cyclodextrin (PPCD), CpG/polyamidoamine-thioketal-adamantane (CpG/PAMAM-TK-Ad), and methoxy poly(ethylene glycol)-thioketal-adamantane (mPEG-TK-Ad). After intravenous injection and accumulation at the tumor site, the high level of reactive oxygen species in the tumor microenvironment promotes PIAN dissociation and the release of PPCD (mediating tumor cell killing and antigen release) and CpG/PAMAM (mediating antigen capturing and transferring to the tumor-draining lymph nodes). This results in antigen-presenting cell activation, antigen presentation, and robust antitumor immune responses. In combination with anti-PD-L1 antibody, the PIAN cures 40% of mice in a colorectal cancer model. This PIAN provides a new framework for designing programmable nanomedicine as in situ cancer vaccine for cancer immunotherapy.

Cisplatin Loaded Poly(L-glutamic acid)-g-Methoxy Polyethylene Glycol Complex Nanoparticles Combined with Gemcitabine Presents Improved Safety and Lasting Anti-Tumor Efficacy in a Murine Xenograft Model of Human Aggressive B Cell Lymphoma.

Cisplatin (CDDP) is a highly effective anti-tumor drug with a broad spectrum of activity. However, the clinical efficacy of CDDP-containing regimens is yet unsatisfactory due to the severe dose-related toxicity of CDDP. In a previous study, CDDP nanoparticles (L-CDDP) forms a complex as CDDP with poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) with improved safety compared to CDDP. Herein, a murine xenograft model of human aggressive B cell lymphoma (BCL) was established to explore anti-lymphoma efficiency of L-CDDP combined with GEM. BJAB cells represent an aggressive BCL, which were utilized to explore the anti-proliferative effect, cell apoptosis via CCK-8 test and flow cytometry technology, respectively. Toxicity experiment and the maximum tolerated dose (MTD) test were conducted in Kunming mice. Tumor inhibition experiment was conducted at the dose of MTD in SCID beige mice-bearing lymphoma. In this study, the loading capacity and encapsulating efficiency of CDDP in the L-CDDP was 18.3% and 89.7%, respectively, and the hydrodynamic diameter of the prepared L-CDDP was 20.6 nm. The CCK-8 data indicated that the anti-proliferative activity of monodrug groups (GEM, CDDP, L-CDDP) was dose- and time-dependent in BJAB cells. The synergistic effects in anti-lymphoma were detected in these two groups (GEM+CDDP, GEM + L-CDDP). Compared to control group, the proportion of apoptotic cells in experimental groups in BJAB cells was significantly higher at 48 h. Toxicity assays revealed that GEM + L-CDDP regimen had low hematological toxicity, hepatotoxicity, and nephrotoxicity. Tumor inhibition experiment demonstrated that GEM + L-CDDP group exhibited significant tumor-suppressing effects. Moreover, tumors continued to shrink in GEM + L-CDDP group, while these appeared to grow in the GEM + CDDP group. Finally, tumor necrosis was most prominent in the GEM + CDDP and GEM + L-CDDP groups, as assessed by hematoxylin-eosin staining. In conclusion, compared to CDDP, L-CDDP combined with GEM seriously induces BJAB cell apoptosis. Also, GEM + L-CDDP exhibits low hematotoxicity, hepatotoxicity, and nephrotoxicity. Importantly, GEM + L-CDDP presents lasting anti-lymphoma efficacy in a SCID beige mice-bearing lymphoma.