Acetalated Dextran Nanoparticles Loaded into an Injectable Alginate Cryogel for Combined Chemotherapy and Cancer Vaccination

Vaccination represents a promising strategy for cancer therapy due to its ability to efficiently eliminate tumors from the host body and prevent their recurrence. Nevertheless, the current vaccines are still lacking efficacy. Combination therapies, such as those integrating chemotherapy with immunotherapy, represent a powerful tool to potentially circumvent this drawback. Herein, injectable alginate cryogels loaded with granulocyte‐macrophage colony‐stimulating factor and cytosine‐phosphodiester‐guanine‐rich oligonucleotides, are combined with spermine‐modified acetalated dextran nanoparticles (Sp‐AcDEX NPs), loaded with p53 activator Nutlin‐3a (Nut‐3a) for combined chemoimmunotherapy. The Sp‐AcDEX NPs are successfully loaded into the alginate cryogels and released over time. Furthermore, the delivery of the NPs from the cryogel enhances their accumulation in tumor tissue following peritumoral injection. Nut‐3a exerts toxicity towards the tumor cells and induces immunogenic cell death through the upregulation of surface calreticulin expression. Overall, this combination is a promising strategy to reduce cancer cell proliferation, induce immunogenic cell death, and accumulate drug payloads into the tumor. This approach may avoid cancer recurrence through the induction of in situ cancer vaccination mediated by antigens and danger signals released from the apoptotic cancer cells.     

Local Immune‐Triggered Surface‐Modified Stem Cells for Solid Tumor Immunotherapy

Here, described are additional treatment strategies that make use of human mesenchymal stem cell (hMSC)‐based local immunotherapeutic agents for the treatment of solid tumors. Dibenzocyclooctyne‐poly(ethylene glycol)‐pheophorbide A conjugates are engineered for cell surface conjugation by copper‐free click chemistry and are subsequently conjugated to hMSC (hMSC‐DPP). hMSC‐DPP can recognize and migrate toward cancer lesions, where they secrete pro‐inflammatory cytokines such as interleukin (IL)‐6, IL‐8, and heat shock protein 70 in pursuance of photodynamic therapy‐mediated cell death. The secreted immune factors trigger interferon gamma, IL‐2, IL‐4, IL‐12, and granulocyte‐macrophage colony‐stimulating factor, resulting in the local accumulation of T cells, B cells, natural killer cells, and antigen presenting cells at the tumor site. Treatment with hMSC‐DPP induces the accumulation of cytokines at the cancer site and minimizes systemic immune‐based side effects. This strategy is expected to increase the vulnerability of cancer cells to immune cells and cytokines, thus aiding in the development of a robust treatment platform for cancer immunotherapy.     

Dual Targeted Immunotherapy via In Vivo Delivery of Biohybrid RNAi‐Peptide Nanoparticles to Tumor‐Associated Macrophages and Cancer Cells

Lung cancer is associated with very poor prognosis and considered one of the leading causes of death worldwide. Here, highly potent and selective biohybrid RNA interference (RNAi)‐peptide nanoparticles (NPs) are presented that can induce specific and long‐lasting gene therapy in inflammatory tumor associated macrophages (TAMs), via an immune modulation of the tumor milieu combined with tumor suppressor effects. The data here prove that passive gene silencing can be achieved in cancer cells using regular RNAi NPs. When combined with M2 peptide–based targeted immunotherapy that immuno‐modulates TAMs cell population, a synergistic effect and long‐lived tumor eradication can be observed along with increased mice survival. Treatment with low doses of siRNA (ED₅₀ 0.0025–0.01 mg kg^?1) in a multi and long‐term dosing system substantially reduces the recruitment of inflammatory TAMs in lung tumor tissue, reduces tumor size (≈95%), and increases animal survival (≈75%) in mice. The results here suggest that it is likely that the combination of silencing important genes in tumor cells and in their supporting immune cells in the tumor microenvironment, such as TAMs, will greatly improve cancer clinical outcomes.     

Enhancing Triple Negative Breast Cancer Immunotherapy by ICG‐Templated Self‐Assembly of Paclitaxel Nanoparticles

Combination cancer immunotherapy has shown promising potential for simultaneously eliciting antitumor immunity and modulating the immunosuppressive tumor microenvironment (ITM). However, combination immunotherapy with multiple regimens suffers from the varied chemo‐physical properties and inconsistent pharmacokinetic profiles of the different therapeutics. To achieve tumor‐specific codelivery of the immune modulators, an indocyanine green (ICG)‐templated self‐assembly strategy for preparing dual drug‐loaded two‐in‐one nanomedicine is reported. ICG‐templated self‐assembly of paclitaxel (PTX) nanoparticles (ISPN), and the application of ISPN for combination immunotherapy of the triple negative breast cancer (TNBC) are demonstrated. The ISPN show satisfied colloidal stability and high efficacy for tumor‐specific codelivery of ICG and PTX through the enhanced tumor permeability and retention effect. Upon laser irradiation, the ICG component of ISPN highly efficiently induces immunogenic cell death of the tumor cells via activating antitumor immune response through photodynamic therapy. Meanwhile, PTX delivered by ISPN suppresses the regulatory T lymphocytes (T_regs) to combat ITM. The combination treatment of TNBC with ISPN and αPD‐L1‐medaited immune checkpoint blockade therapy displays a synergistic effect on tumor regression, metastasis inhibition, and recurrence prevention. Overall, the ICG‐templated nanomedicine may represent a robust nanoplatform for combination immunotherapy.     

iRGD Modified Chemo‐immunotherapeutic Nanoparticles for Enhanced Immunotherapy against Glioblastoma

Glioblastoma is the most common primary brain tumor in adults and still remains incurable, due to the limited accumulation of drugs in the tumor area. Herein, iRGD‐modified nanoparticles, DOX@MSN‐SS‐iRGD&1MT, are developed for simultaneous delivery of chemotherapeutic agents (doxorubicin, DOX) and immune checkpoint inhibitor (1‐methyltryptophan, 1MT) into orthotopic glioma. The nanoparticles are comprised of mesoporous silica nanoparticles loaded with DOX, combined with Asp‐Glu‐Val‐Asp (DEVD) connected 1MT, and finally modified by iRGD. These nanoparticles show the capability of penetrating through blood brain barrier into the tumor area, and significantly improve accumulation of drugs in orthotopic brain tumors with minimal side effects. The nanoparticles also activate cytotoxic CD8⁺ T lymphocytes and inhibit CD4⁺ T cells in both GL261 cells cocultured with splenocytes in vitro and GL261‐luc orthotopic tumors in vivo. Moreover, the expression of antitumor cytokines IFNα/β, IFN‐γ, TNF, IL‐17, STING, and GrzB is upregulated while protumor proteins p‐STAT3 and IL‐10 are downregulated in the brain tumor area. This study demonstrates the advantages of chemo‐immunotherapeutic nanoparticles accumulated in the brain tumor area and their effectively inhibiting tumor proliferation, which establishes a delivery platform to promote antitumor immunity against glioblastoma.     

MAPK‐Targeted Drug Delivered by a pH‐Sensitive MSNP Nanocarrier Synergizes with PD‐1 Blockade in Melanoma without T‐Cell Suppression

The combination of BRAF/MEK‐targeted therapy with immune checkpoint blockade is regarded as a promising regimen for patients with metastatic melanoma due to their complementary advantages. However, MEK‐inhibitor‐induced T‐cell toxicity impedes effective cooperation. In this experiment, a pH‐responsive on‐demand controlled release mesoporous silica nanoparticles (MSNPs) system is designed. Fluorescein‐isothiocyanate‐loaded MSNP can be specifically delivered into tumor cells rather than T‐cells. MEK‐inhibitor‐loaded MSNP avoids proliferative and functional inhibitions of T‐cells, while preserving growth suppression of tumor cells in vitro. In an in vivo model, MSNP encapsulation reverses the MEK‐inhibitor‐induced suppression of activated CD8⁺ T‐cells, and enhances the secretion of INF‐γ and IL‐2. The combination of BRAF inhibitor plus MSNP‐loaded MEK inhibitor and anti‐PD‐1 antibody synergistically inhibits tumor growth via promoting robust immune‐related antitumor response. This work provides a novel and generalized framework for combining T‐cell‐impaired targeted therapy and immune checkpoint blockade by using a nanoparticle‐based delivery system.     

Actively Targeted Deep Tissue Imaging and Photothermal‐Chemo Therapy of Breast Cancer by Antibody‐Functionalized Drug‐Loaded X‐Ray‐Responsive Bismuth Sulfide@Mesoporous Silica Core–Shell Nanoparticles

A theranostic platform combining synergistic therapy and real‐time imaging attracts enormous attention but still faces great challenges, such as tedious modifications and lack of efficient accumulation in tumor. Here, a novel type of theranostic agent, bismuth sulfide@mesoporous silica (Bi₂S₃@mPS) core‐shell nanoparticles (NPs), for targeted image‐guided therapy of human epidermal growth factor receptor‐2 (HER‐2) positive breast cancer is developed. To generate such NPs, polyvinylpyrrolidone decorated rod‐like Bi₂S₃ NPs are chemically encapsulated with a mesoporous silica (mPS) layer and loaded with an anticancer drug, doxorubicin. The resultant NPs are then chemically conjugated with trastuzumab (Tam, a monoclonal antibody targeting HER‐2 overexpressed breast cancer cells) to form Tam‐Bi₂S₃@mPS NPs. By in vitro and in vivo studies, it is demonstrated that the Tam‐Bi₂S₃@mPS bear multiple desired features for cancer theranostics, including good biocompatibility and drug loading ability as well as precise and active tumor targeting and accumulation (with a bismuth content in tumor being ≈16 times that of nontargeted group). They can simultaneously serve both as an excellent contrast enhancement probe (due to the presence of strong X‐ray‐attenuating bismuth element) for computed tomography deep tissue tumor imaging and as a therapeutic agent to destruct tumors and prevent metastasis by synergistic photothermal‐chemo therapy.     

Immune Complexes Mimicking Synthetic Vaccine Nanoparticles for Enhanced Migration and Cross‐Presentation of Dendritic Cells

The well‐designed activation of dendritic cells (DCs) by enhancing the delivery of antigens and immunostimulatory adjuvants into DCs is a key strategy for efficient cancer immunotherapy. Antigen‐antibody immune complexes (ICs) are known to directly bind to and cross‐link Fc‐gamma receptors (FcγRs) on DCs, which induce enhanced migration of DCs to draining lymph nodes through the up‐regulation of the chemokine receptor CCR7 and cross‐presentation inducing cytotoxic T lymphocyte (CTL) response against tumor antigen. In this study, ICs mimicking synthetic vaccine nanoparticles (NPs) are designed and synthesized by the coating of poly (lactic‐co‐glycolic acid) (PLGA) NPs containing adjuvant (CpG oligodeoxynuleotides (ODNs) as toll‐like receptor 9 ligands) with ovalbumin (OVA) proteins (as model antigens) and by the formation of OVA–OVA antibody ICs. Through the combination of FcγRs‐mediated efficient antigen uptake and CpG ODNs‐based immunostimulation, the secretion of TNF‐α (12.3‐fold), IL‐6 (7.29‐fold), and IL‐12 (11‐fold), homing ability to lymph nodes (7.5‐fold), and cross‐presentation (83.8‐fold IL‐2 secretion) are dramatically increased in DCs treated with PLGA(IC/CpG) NPs. Furthermore, mice vaccinated with DCs treated with PLGA(IC/CpG) NPs induced significant tumor (EG7‐OVA) growth inhibition as well as prolonged survival through CTL‐mediated enhanced cytotoxicity, antigen‐specific responses, and IFN‐γ secretion.     

pH/Cathepsin B Hierarchical‐Responsive Nanoconjugates for Enhanced Tumor Penetration and Chemo‐Immunotherapy

An ideal cancer nanomedicine should precisely deliver therapeutics to its intracellular target within tumor cells. However, the multiple biological barriers seriously hinder their delivery efficiency, leading to unsatisfactory therapeutic outcome. Herein, pH/cathepsin B hierarchical‐responsive nanoconjugates (HRNs) are reported to overcome these barriers by sequentially responding to extra‐ and intracellular stimuli in solid tumors for programmed delivery of docetaxel (DTX). The HRNs have stable nanostructures (≈40 nm) in blood circulation for efficient tumor accumulation, while the tumor extracellular acidity induces the rapid dissociation of HRNs into polymer conjugates (≈5 nm), facilitating the deep tumor penetration and cellular internalization. After being trapped into the lysosomes, the conjugates are cleaved by cathepsin B to release bioactive DTX into cytoplasm and inhibit cell proliferation. In addition to the direct inhibition effect, HRNs can trigger the in vivo antitumor immune responses via the immunogenic modulation of tumor cells, activation of dendritic cells (DCs), and generation of cytotoxic T‐cell responses. By employing a combination with α‐PD‐1 (programmed cell death 1) therapy, synergistic antitumor efficacy is achieved in B16 expressing ovalbumin (B16OVA) tumor model. Hence, this strategy demonstrates high efficiency for precise intracellular delivery of chemotherapeutics and provides a potential clinical candidate for cancer chemo‐immunotherapy.     

Combination of Bacterial‐Photothermal Therapy with an Anti‐PD‐1 Peptide Depot for Enhanced Immunity against Advanced Cancer

Photothermal therapy (PTT) is a promising cancer treatment, but it has so far proven successful only with relatively small subcutaneous tumors in animal models. Treating larger tumors (≈200 mm³) is challenging because most PTT materials do not efficiently reach the hypoxic, avascular center of tumors, and the immunosuppressive tumor microenvironment prevents T cells from fighting against residual tumor cells, thereby allowing recurrence and metastasis. Here, the widely used PTT material polydopamine is coated on the surface of the facultative anaerobe Salmonella VNP20009, which can penetrate deep into larger tumors. The coated bacteria are intravenously injected followed by near‐infrared laser irradiation at the tumor site, combined with a local inoculation of phospholipid‐based phase separation gel containing the anti‐programmed cell death‐1 peptide AUNP‐12. The gel releases AUNP‐12 sustainably during 42 days, maintaining the tumor microenvironment as immunopermissive. Using a mouse model of melanoma, this triple combination of biotherapy, PTT, and sustainable programmed cell death‐1 (PD‐1) blockade shows high efficiency on eliciting robust antitumor immune responses and eliminating relatively large tumors in 50% of animals within 80 days. Thus, the results shed new light on a previously unrecognized immunological facet of bacteria‐mediated therapy, and this innovative triple therapy may be a powerful cancer immunotherapy tool.     

Gel–Liposome‐Mediated Co‐Delivery of Anticancer Membrane‐Associated Proteins and Small‐Molecule Drugs for Enhanced Therapeutic Efficacy

A programmed drug‐delivery system that can transport different anticancer therapeutics to their distinct targets holds vast promise for cancer treatment. Herein, a core–shell‐based “nanodepot” consisting of a liposomal core and a crosslinked‐gel shell (designated Gelipo) is developed for the sequential and site‐specific delivery (SSSD) of tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and doxorubicin (Dox). As a small‐molecule drug intercalating the nuclear DNA, Dox is loaded in the aqueous core of the liposome, while TRAIL, acting on the death receptor (DR) on the plasma membrane, is encapsulated in the outer shell made of crosslinked hyaluronic acid (HA). The degradation of the HA shell by HAase that is concentrated in the tumor environment results in the rapid extracellular release of TRAIL and subsequent internalization of the liposomes. The parallel activity of TRAIL and Dox show synergistic anticancer efficacy. The half‐maximal inhibitory concentration (IC₅₀) of TRAIL and Dox co‐loaded Gelipo (TRAIL/Dox‐Gelipo) toward human breast cancer (MDA‐MB‐231) cells is 83 ng mL^–1 (Dox concentration), which presents a 5.9‐fold increase in the cytotoxicity compared to 569 ng mL^–1 of Dox‐loaded Gelipo (Dox‐Gelipo). Moreover, with the programmed choreography, Gelipo significantly improves the inhibition of the tumor growth in the MDA‐MB‐231 xenograft tumor animal model.     

Generic Strategy of Preparing Fluorescent Conjugated‐Polymer‐Loaded Poly(DL‐lactide‐co‐Glycolide) Nanoparticles for Targeted Cell Imaging

A general strategy for the preparation of highly fluorescent poly(DL‐lactide‐co‐glycolide) (PLGA) nanoparticles (NPs) loaded with conjugated polymers (CPs) is reported. The process involves encapsulation of organic‐soluble CPs with PLGA using a modified solvent extraction/evaporation technique. The obtained NPs are stable in aqueous media with biocompatible and functionalizable surfaces. In addition, fluorescent properties of the CP‐loaded PLGA NPs (CPL NPs) could be fine‐tuned by loading different types of CPs into the PLGA matrix. Four types of CPL NPs are prepared with a volume‐average hydrodynamic diameter ranging from 243 to 272 nm. The application of CPL NPs for bio‐imaging is demonstrated through incubation with MCF‐7 breast cancer cells. Confocal laser scanning microscopy studies reveal that the CPL NPs are internalized in cytoplasm around the nuclei with intense fluorescence. After conjugation with folic acid, cellular uptake of the surface‐functionalized CPL NPs is greatly enhanced via receptor‐mediated endocytosis by MCF‐7 breast cancer cells, as compared to that for NIH/3T3 fibroblast cells, which indicates a selective targeting effect of the folate‐functionalized CPL NPs in cellular imaging. The merits of CPL NPs, such as low cytotoxicity, high fluorescence, good photostability, and feasible surface functionalization, will inspire extensive study of CPL NPs as a new generation of probes for specific biological imaging and detection.     

Inhibition of Immunosuppressive Tumors by Polymer‐Assisted Inductions of Immunogenic Cell Death and Multivalent PD‐L1 Crosslinking

Checkpoint blockade immunotherapies harness the host's own immune system to fight cancer, but only work against tumors infiltrated by swarms of preexisting T cells. Unfortunately, most cancers to date are immune‐deserted. Here, a polymer‐assisted combination of immunogenic chemotherapy and PD‐L1 degradation is reported for efficacious treatment in originally nonimmunogenic cancer. “Priming” tumors with backbone‐degradable polymer‐epirubicin conjugates elicits immunogenic cell death and fosters tumor‐specific CD8+ T cell response. Sequential treatment with a multivalent polymer‐peptide antagonist to PD‐L1 overcomes adaptive PD‐L1 enrichment following chemotherapy, biases the recycling of PD‐L1 to lysosome degradation via surface receptor crosslinking, and produces prolonged elimination of PD‐L1 rather than the transient blocking afforded by standard anti‐PD‐L1 antibodies. Together, these findings establish the polymer‐facilitated tumor targeting of immunogenic drugs and surface crosslinking of PD‐L1 as a potential new therapeutic strategy to propagate long‐term antitumor immunity, which might broaden the application of immunotherapy to immunosuppressive cancers.     

Phenylboronic Acid‐Decorated Chondroitin Sulfate A‐Based Theranostic Nanoparticles for Enhanced Tumor Targeting and Penetration

Phenylboronic acid‐functionalized chondroitin sulfate A (CSA)–deoxycholic‐acid (DOCA)‐based nanoparticles (NPs) are prepared for tumor targeting and penetration. (3‐Aminomethylphenyl)boronic acid (AMPB) is conjugated to CSA–DOCA conjugate via amide bond formation, and its successful synthesis is confirmed using proton nuclear magnetic resonance spectroscopy (¹H‐NMR). Doxorubicin (DOX)‐loaded CSA–DOCA–AMPB NPs with a mean diameter of ≈200 nm, a narrow size distribution, negative zeta potential, and spherical morphology are prepared. DOX release from NPs is enhanced at acidic pH compared to physiological pH. CSA–DOCA–AMPB NPs exhibit improved cellular uptake in A549 (human lung adenocarcinoma) cells and penetration into A549 multicellular spheroids compared to CSA–DOCA NPs as evidenced by confocal laser scanning microscopy and flow cytometry. In vivo tumor targeting and penetrating by CSA–DOCA–AMPB NPs, based on both CSA–CD44 receptor and boronic acid–sialic acid interactions, is revealed using near‐infrared fluorescence (NIRF) imaging. Penetration of NPs to the core of the tumor mass is observed in an A549 tumor xenografted mouse model and verified by three‐dimensional NIRF imaging. Multiple intravenous injections of DOX‐loaded CSA–DOCA–AMPB NPs efficiently inhibit the growth of A549 tumor in the xenografted mouse model and increase apoptosis. These boronic acid‐rich NPs are promising candidates for cancer therapy and imaging.     

Gated Mesoporous SiO2 Nanoparticles Using K+‐Stabilized G‐Quadruplexes

The K⁺‐induced formation of G‐quadruplexes provides a versatile motif to lock or unlock substrates trapped in the pores of mesoporous SiO₂ nanoparticles, MP‐SiO₂ NPs. In one system, the substrate is locked in the MP‐SiO₂ NPs by K⁺‐ion‐stabilized G‐quadruplex units, and the pores are unlocked by the elimination of K⁺ ions using Kryptofix [2.2.2] (KP) or 18‐crown‐6‐ether (CE) from the G‐quadruplexes. In the second system, the substrate is locked in the pores by means of K⁺‐stabilized aptameric G‐quadruplex/thrombin units. Unlocking of the pores is triggered by the dissociation of the aptamer/thrombin complexes through the KP‐ or CE‐mediated elimination of the stabilizing K⁺ ions. In the third system, duplex DNA units lock the pores of MP‐SiO₂ NPs, and the release of the entrapped substrate is stimulated by the K⁺‐ion‐induced dissociation of the duplex caps through the formation of the K⁺‐stabilized G‐quadruplexes. The latter system is further implemented to release the anti‐cancer drug, doxorubicin, in the presence of K⁺ ions, from the MP‐SiO₂ NPs. Preliminary intracellular experiments reveal that doxorubicin‐loaded MP‐SiO₂ NPs lead to effective death of breast cancer cells.     

Myeloid‐Derived Suppressor Cell Membrane‐Coated Magnetic Nanoparticles for Cancer Theranostics by Inducing Macrophage Polarization and Synergizing Immunogenic Cell Death

A major challenge for traditional cancer therapy, including surgical resection, chemoradiotherapy, and immunotherapy, is how to induce tumor cell death and leverage the host immune system at the same time. Here, a myeloid‐derived suppressor cell (MDSC) membrane‐coated iron oxide magnetic nanoparticle (MNP@MDSC) to overcome this conundrum for cancer therapy is developed. In this study, MNP@MDSC demonstrates its superior performance in immune evasion, active tumor‐targeting, magnetic resonance imaging, and photothermal therapy (PTT)‐induced tumor killing. Compared with red blood cell membrane‐coated nanoparticles (MNPs@RBC) or naked MNPs, MNP@MDSCs are much more effective in active tumor‐targeting, a beneficial property afforded by coating MNP with membranes from naturally occurring MDSC, thus converting the MNP into “smart” agents that like to accumulate in tumors as the source MDSCs. Once targeted to the tumor microenvironment, MNPs@MDSC can act as a PTT agents for enhanced antitumor response by inducing immunogenic cell death, reprogramming the tumor infiltrating macrophages, and reducing the tumor's metabolic activity. These benefits, in combination with the excellent biocompatibility and pharmacological kinetics characteristics, make MNP@MDSC a promising, multimodal agent for cancer theranostics.     

Biocompatible Nanoparticles with Aggregation‐Induced Emission Characteristics as Far‐Red/Near‐Infrared Fluorescent Bioprobes for In Vitro and In Vivo Imaging Applications

Light emission of 2‐(2,6‐bis((E)‐4‐(diphenylamino)styryl)‐4H‐pyran‐4‐ylidene)malononitrile (TPA‐DCM) is weakened by aggregate formation. Attaching tetraphenylethene (TPE) units as terminals to TPA‐DCM dramatically changes its emission behavior: the resulting fluorogen, 2‐(2,6‐bis((E)‐4‐(phenyl(4′‐(1,2,2‐triphenylvinyl)‐[1,1′‐biphenyl]‐4‐yl)amino)styryl)‐4H‐pyran‐4‐ylidene)malononitrile (TPE‐TPA‐DCM), is more emissive in the aggregate state, showing the novel phenomenon of aggregation‐induced emission (AIE). Formulation of TPE‐TPA‐DCM using bovine serum albumin (BSA) as the polymer matrix yields uniformly sized protein nanoparticles (NPs) with high brightness and low cytotoxicity. Applications of the fluorogen‐loaded BSA NPs for in vitro and in vivo far‐red/near‐infrared (FR/NIR) bioimaging are successfully demonstrated using MCF‐7 breast‐cancer cells and a murine hepatoma‐22 (H₂₂)‐tumor‐bearing mouse model, respectively. The AIE‐active fluorogen‐loaded BSA NPs show an excellent cancer cell uptake and a prominent tumor‐targeting ability in vivo due to the enhanced permeability and retention effect.     

Triphenylphosphonium‐Conjugated Poly(ε‐caprolactone)‐Based Self‐Assembled Nanostructures as Nanosized Drugs and Drug Delivery Carriers for Mitochondria‐Targeting Synergistic Anticancer Drug Delivery

For mitochondria‐targeting delivery, a coupling reaction between poly(ε‐caprolactone) diol (PCL diol) and 4‐carboxybutyltriphenylphosphonium (4‐carboxybutyl TPP) results in the synthesis of amphiphilic TPP‐PCL‐TPP (TPCL) polymers with a bola‐like structure. In aqueous environments, the TPCL polymer self‐assembled via cosolvent dispersion and film hydration, resulting in the formation of cationic nanoparticles (NPs) less than 50 nm in size with zeta‐potentials of approximately 40 mV. Interestingly, different preparation methods for TPCL NPs result in various morphologies such as nanovesicles, nanofibers, and nanosheets. In vitro cytotoxicity results with TPCL NPs indicate IC₅₀ values of approximately 10–60 μg mL^?1, suggesting their potential as anticancer nanodrugs. TPCL NPs can be loaded both with hydrophobic doxorubicin (Dox) and its hydrophilic salt form (Dox·HCl), and their drug loading contents are approximately 2–10 wt% depending on the loading method and the hydrophilicity/hydrophobicity of the drugs. Although Dox·HCl exhibits more cellular and nuclear uptake, resulting in greater antitumor effects than Dox, most drug‐loaded TPCL NPs exhibit higher mitochondrial uptake and approximately 2–7‐fold higher mitochondria‐to‐nucleus preference than free drugs, resulting in superior (approximately 7.5–18‐fold) tumor‐killing activity for most drug‐loaded TPCL NPs compared with free drugs. In conclusion, TPCL‐based nanoparticles have potential both as antitumor nanodrugs themselves and as nanocarriers for chemical therapeutics.     

Polyhedral Oligomeric Silsesquioxanes‐Containing Conjugated Polymer Loaded PLGA Nanoparticles with Trastuzumab (Herceptin) Functionalization for HER2‐Positive Cancer Cell Detection

The synthesis of polyhedral oligomeric silsesquioxanes (POSS)‐containing conjugated polymer (CP) and the polymer loaded poly(lactic‐co‐glycolic‐acid) (PLGA) nanoparticles (NPs) with surface antibody functionalization for human epidermal growth factor receptor 2 (HER2)‐positive cancer cell detection are reported. Due to the steric hindrance of POSS, NPs prepared from POSS‐containing CP show improved photoluminescence quantum yield as compared to that for the corresponding linear CP encapsulated NPs. In addition, the amount of ‐NH₂ groups on NP surface is well‐controlled by changing the molar ratio of poly(lactic‐co‐glycolic‐acid)‐b‐poly(ethylene glycol) (PLGA‐b‐PEG‐NH₂) to PLGA‐OCH₃ during NP formulation. Further conjugation of the NH₂‐functionalized CP NPs with trastuzumab (Herceptin) yields NPs with fine‐tuned protein density. These NPs are able to discriminate SKBR‐3 breast cancer cells from MCF‐7 breast cancer cells and NIH/3T3 fibroblast cells both on substrate and in suspension by taking advantage of the specific binding affinity between trastuzumab and HER2 overexpressed in SKBR‐3 breast cancer cell membrane. The high quantum yield and fine‐tuned surface specific protein functionalization make the POSS‐containing CP loaded NPs a good candidate for targeted biological imaging and detection.     

Multifunctional Nanoparticle Loaded Injectable Thermoresponsive Hydrogel as NIR Controlled Release Platform for Local Photothermal Immunotherapy to Prevent Breast Cancer Postoperative Recurrence and Metastases

For breast cancer patients who have undergone breast‐conserving surgery, effective treatments to prevent local recurrences and metastases is very essential. Here, a local injectable therapeutic platform based on a thermosensitive PLEL hydrogel with near‐infrared (NIR)‐stimulated drug release is developed to achieve synergistic photothermal immunotherapy for prevention of breast cancer postoperative relapse. Self‐assembled multifunctional nanoparticles (RIC NPs) are composed of three therapeutic components including indocyanine green, a photothermal agent; resiquimod (R848), a TLR‐7/8 agonist; and CPG ODNs, a TLR‐9 agonist. RIC NPs are physically incorporated into the thermosensitive PLEL hydrogel. The RIC NPs encapsulated PLEL hydrogel (RIC NPs@PLEL) is then locally injected into the tumor resection cavity for local photothermal therapy to ablate residue tumor tissues and produce tumor‐associated antigens. At the same time, NIR also triggers the release of immune components CPG ODNs and R848 from thermoresponsive hydrogels PLEL. The released immune components, together with tumor‐associated antigens, work as an in situ cancer vaccine for postsurgical immunotherapy by inducing effective and sustained antitumor immune effect. Overall, this work suggests that photothermal immunotherapy based on local hydrogel delivery system has great potential as a promising tool for the postsurgical management of breast cancer to prevent recurrences and metastases.