Drug Accumulation In Tumor Tissue Research Articles

Sialic acid-modified docetaxel cationic liposomes: double targeting of tumor-associated macrophages and tumor endothelial cells

Taxane drugs are clinically used for the treatment of many types of cancers due to their excellent antitumor effects. However, the surfactants contained in the injections currently used in the clinic may have serious toxic side effects on the organism, making it necessary to develop new dosage forms. Cationic liposomes have been widely used in antitumor research because of their advantage of preferentially targeting tumor neovascularization, but antitumor by targeting tumor vasculature alone does not necessarily provide good results. Malignant tumors represent complex ecosystems, tumor-associated macrophages (TAMs) and tumor endothelial cells (TECs) in the tumor microenvironment play crucial roles in tumor growth. Therefore, given the ability to achieve active targeting of TAMs and TECs by using sialic acid (SA) as a targeting material, the potential of cationic nanoformulations to preferentially target neovascularization at the tumor site, and the excellent antitumor effects of the taxane drugs docetaxel (DOC), in the present study, sialic acid-cholesterol coupling (SA-CH) was selected as a targeting material to prepare a DOC cationic liposome (DOC-SAL) for tumor therapy. The results of the study showed that DOC-SAL had the strongest drug accumulation in tumor tissues compared with the common DOC formulations, and was able to effectively reduce the colonization of TAMs, inhibit the proliferation of tumor cells, and have the best tumor-suppressing effect. In addition, DOC-SAL was able to improve the internal microenvironment of tumors by modulating cytokines. In summary, this drug delivery system has good anti-tumor effects and provides a new option for tumor therapy.

Nucleolin-Targeting AS1411 Aptamer-Conjugated Nanospheres for Targeted Treatment of Glioblastoma.

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), for which nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres (100-300 nm in size) loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than non-specific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study reveals the potential for anti-cancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labeling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier allowing for the precise targeting of tumors. This combination has the potential to produce anti-tumor effects in the active targeted therapy of GBM.

Anti-lymphangiogenesis for boosting drug accumulation in tumors

The inadequate tumor accumulation of anti-cancer agents is a major shortcoming of current therapeutic drugs and remains an even more significant concern in the clinical prospects for nanomedicines. Various strategies aiming at regulating the intratumoral permeability of therapeutic drugs have been explored in preclinical studies, with a primary focus on vascular regulation and stromal reduction. However, these methods may trigger or facilitate tumor metastasis as a tradeoff. Therefore, there is an urgent need for innovative strategies that boost intratumoral drug accumulation without compromising treatment outcomes. As another important factor affecting drug tumor accumulation besides vasculature and stroma, the impact of tumor-associated lymphatic vessels (LVs) has not been widely considered. In the current research, we verified that anlotinib, a tyrosine kinase inhibitor with anti-lymphangiogenesis activity, and SAR131675, a selective VEGFR-3 inhibitor, effectively decreased the density of tumor lymphatic vessels in mouse cancer models, further enhancing drug accumulation in tumor tissue. By combining anlotinib with therapeutic drugs, including doxorubicin (Dox), liposomal doxorubicin (Lip-Dox), and anti-PD-L1 antibody, we observed improved anti-tumor efficacy in comparison with monotherapy regimens. Meanwhile, this strategy significantly reduced tumor metastasis and elicited stronger anti-tumor immune responses. Our work describes a new, clinically transferrable approach to augmenting intratumoral drug accumulation, which shows great potential to address the current, unsatisfactory efficacies of therapeutic drugs without introducing metastatic risk.

Statistically developed stable Camptothecin-loaded Soluplus/TPGS mixed micelles for improved ovarian cancer treatment

In this research, Camptothecin-loaded mixed micelles (CPT-MMs) were formulated by combining Soluplus®, a novel amphiphilic excipient, with D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). The use of appropriate excipients is crucial in stabilizing micellar structures and improving drug entrapment efficiency. TPGS, with its ability to self-assemble into micelles, was an ideal candidate, and incorporating Soluplus further enhanced micelle stability and drug-loading capacity. A 32 full factorial design was employed to investigate the influence of key factors on particle size and %entrapment efficiency (%EE). The statistical analysis using Design Expert® VR software provided meaningful conclusions on the significance of each factor and their interactions, facilitating the successful optimization of CPT-MMs dispersion with improved drug delivery capabilities. The mean particle size, zeta potential, %drug loading capacity (%DLC), and (%EE) of CPT-MMs were 77.8 ± 2.67 nm, −23.4 ± 0.36 mV, 45.6 ± 1.78%, and 68.61 ± 1.8% respectively. CPT-MMs demonstrated sustained-release characteristics, preventing premature drug release and enhancing drug accumulation in tumor tissues, potentially optimizing CPT delivery for cancer treatment. Importantly, CPT-MMs dispersion exhibited lower hemolysis compared to plain CPT, indicating excellent biocompatibility and safety for intravenous administration. The sustained release of CPT from CPT-MMs dispersion may lead to reduced cytotoxicity and improved therapeutic efficacy. Additionally, the lyophilized formulation showed superior stability compared to the liquid micelles. In conclusion, the development of CPT-MMs presents a promising strategy for enhancing drug delivery and optimizing therapeutic outcomes in cancer treatment. The sustained-release feature, along with enhanced biocompatibility and stability, holds great potential for the clinical translation of these MMs as efficient drug delivery systems for ovarian cancer treatment.

Nano-Drug Delivery Systems in Oral Cancer Therapy: Recent Developments and Prospective.

Oral cancer (OC), characterized by malignant tumors in the mouth, is one of the most prevalent malignancies worldwide. Chemotherapy is a commonly used treatment for OC; however, it often leads to severe side effects on human bodies. In recent years, nanotechnology has emerged as a promising solution for managing OC using nanomaterials and nanoparticles (NPs). Nano-drug delivery systems (nano-DDSs) that employ various NPs as nanocarriers have been extensively developed to enhance current OC therapies by achieving controlled drug release and targeted drug delivery. Through searching and analyzing relevant research literature, it was found that certain nano-DDSs can improve the therapeutic effect of drugs by enhancing drug accumulation in tumor tissues. Furthermore, they can achieve targeted delivery and controlled release of drugs through adjustments in particle size, surface functionalization, and drug encapsulation technology of nano-DDSs. The application of nano-DDSs provides a new tool and strategy for OC therapy, offering personalized treatment options for OC patients by enhancing drug delivery, reducing toxic side effects, and improving therapeutic outcomes. However, the use of nano-DDSs in OC therapy still faces challenges such as toxicity, precise targeting, biodegradability, and satisfying drug-release kinetics. Overall, this review evaluates the potential and limitations of different nano-DDSs in OC therapy, focusing on their components, mechanisms of action, and laboratory therapeutic effects, aiming to provide insights into understanding, designing, and developing more effective and safer nano-DDSs. Future studies should focus on addressing these issues to further advance the application and development of nano-DDSs in OC therapy.

Cancer‐cell‐biomimetic nanoparticles for enhanced prostate cancer therapy

AbstractBACKGROUNDThe targeted delivery of traditional chemotherapeutic drugs by nanocarriers has become an effective way to reduce drug toxicity and improve antitumor effects. However, nanocarriers are easily recognized and cleared by the immune system after entering the body, thereby reducing their therapeutic effect.RESULTSIn this work, based on the biomimetic design concept, a tumor cell membrane‐coated nanoplatform (TCM/SCM/DTX) was fabricated for evading the clearance of the immune system and efficiently targeting tumor tissues to achieve efficient drug accumulation in tumor tissues. In vitro cell experiments, TCM/SCM/DTX could effectively enter prostate tumor cells and showed a good in vitro anti‐tumor effect. After administration, TCM/SCM/DTX could efficiently accumulate into tumor tissue while achieving long‐term blood circulation. The in vivo anti‐tumor results proved its effective tumor growth inhibitory effect, and the immunohistochemical results also proved that TCM/SCM/DTX significantly reduced the tissue and organ toxicity of DTX.CONCLUSIONSThis study shows that the prostate tumor cell membrane‐coated biomimetic nanocarriers can effectively deliver traditional chemotherapeutic drugs to prostate cancer tissue, which provides a new strategy for precise and efficient chemotherapy of prostate cancer, especially advanced prostate cancer. © 2023 Society of Chemical Industry (SCI).

Polylactic acid based polymeric nanoparticle mediated co-delivery of navitoclax and decitabine for cancer therapy

Combination chemotherapy with systemic administration of drugs in their free form can be challenging due to non-synchronized pharmacokinetics and sub-optimal tumor accumulation. The present study investigates a PLA-based block copolymeric nanocarrier for the co-delivery of navitoclax and decitabine (NAV/DCB NPs) for combination cancer therapy. NAV/DCB NPs exhibited potent in vitro synergistic cytotoxicity in both acute myeloid leukemia and breast cancer cell lines. Biodistribution studies of NAV/DCB NPs in tumor bearing mice, showed significant drug accumulation in tumor tissue and detectable quantities in plasma even after 48 h. Good hemocompatibility with reduced in vivo platelet toxicity indicated that encapsulation in PLA-based nanocarrier helped ameliorate navitoclax associated thrombocytopenia. In vivo biological activity of NAV/DCB NPs evaluated in xenograft AML and syngeneic breast cancer model, demonstrated potent tumor growth inhibition efficacy. PLA-based NAV/DCB dual NPs present a novel, safe and effective nanoformulation for combination cancer therapy in both solid tumors and hematologic malignancies.

Autophagy-inhibiting biomimetic nanodrugs enhance photothermal therapy and boost antitumor immunity.

The instinctive protective stress responses of tumor cells hamper low-temperature photothermal therapy (LTPTT), resulting in tumor recurrence and metastasis. The rapid blood clearance and low-efficiency tumor enrichment of nanomedicines also decrease the efficacy of LTPTT. In this study, we fabricated coassembled photothermal agents (indocyanine green, ICG) and autophagy inhibitors (chloroquine, CQ) and red blood cell and cancer cell hybrid membrane (RCm)-camouflaged ICGCQ@RCm nanoparticles (ICGCQ@RCm NPs) to enhance tumor LTPTT. The ICGCQ@RCm NPs exhibited prolonged blood drug circulation and markedly enhanced drug accumulation in tumor tissues. The ICGCQ@RCm NPs reduced the thermal tolerance of tumor cells to sensitize ICG-mediated LTPTT by inhibiting protective autophagy. The ICGCQ@RCm NPs exerted strong immunogenic cell death (ICD) after efficient LTPTT to activate antitumor immunity. In addition, ICGCQ@RCms optimized the therapeutic efficacy by imaging-guided LTPTT, taking advantage of the near-infrared (NIR) fluorescence of ICG. Consequently, the ICGCQ@RCm NPs effectively inhibited tumors under mild LTPTT, significantly suppressed tumor metastasis and prolonged the survival time of tumor-bearing mice. Furthermore, the ICGCQ@RCm NPs showed high biosafety in vitro and in vivo. The ICGCQ@RCm NPs demonstrated tumor-targeting and imaging-guided autophagy inhibition-sensitized LTPTT using two Food and Drug Administration (FDA)-approved drugs, which have great potential for clinical application.

A Nanogel with Effective Blood-Brain Barrier Penetration Ability through Passive and Active Dual-Targeting Function

Clinically, surgery assisted by chemotherapy is the most effective treatment of cancer. But from our clinical observation, the median survival of patients with glioblastoma is still not so good with only 15-16 months. The low therapeutic index is mainly due to the blood-brain barrier (BBB) which significantly hindered the chemotherapeutic drug accumulation in tumor tissue. One main composition of the BBB is astrocyte, which contains a lipophilic cell membrane, which prevents more than 98% of small-molecule drugs from entering the brain. Previously, we found that the nanogel with passive targeting function can increase the BBB penetration ability, which indicates that it could be used to overcome the above mentioned in vivo obstacles which promoted drug accumulation in the tumor. In this study, thermosensitive targeted nanogel delivery systems (DPPC) with cell-penetrating peptides (CPP) are introduced onto the particle surface for active astrocyte breaking. The hydrodynamic radius of DPPC is around 300 nm, the potential is about 0-5 mV, and the TEM and DLS studies further confirm its well spherical morphology and uniform distribution. The DPPC is verified as the biocompatible carriers for further application by cell viability tests. The in vitro-constructed BBB model successfully proves that DPPC can efficiently penetrate the BBB, which is attributed to both the temperature-sensitive passive targeting and the active CPP penetration. Consequently, the intracellular doxorubicin (DOX) promotes such functional DPPC at the relatively high temperature inside tumor microenvironment (TME) (~42°C), which obviously improves intratumor drug accumulation and tumor cell-killing effects. The dual-targeted nanogel delivery systems designed in this study provides a more effective strategy for the treatment of glioma.

Double hit strategy using pH-sensitive liposomes containing doxorubicin and pheophorbide-a for combination tumor therapy

For successful combination therapy using nanoparticles, stable loading and targeted delivery of different drugs are important. Herein, we prepared pH-sensitive liposomes with hydrophilic doxorubicin (Dox) in the core and hydrophobic pheophobide-a (Pba) in the lipid membrane (pH-lipo-Dox-Pba). The liposomes provided high drug accumulation in tumor tissue, with an enhanced permeability and retention (EPR) effect and enhanced binding to tumor cells by cyclic Arg-Gly-Asp peptide (cRGD). After cellular uptake, Dox was released in response to the endo-lysosomal acidic pH and moved into the nucleus, while Pba remained in the cytosol. Therefore, a double hit strategy composed of a simultaneous attack on nucleus and cytosol could be achieved by chemo- and photodynamic therapy. High tumor accumulation of pH-lipo-Dox-Pba was observed after intravenous injection into 4T1 tumor-bearing mice. Effective suppression of tumor growth in the same mouse model demonstrated a synergetic effect of combination therapy enabled by the double hit strategy using pH-lipo-Dox-Pba.

Biomimetic 2D layered double hydroxide nanocomposites for hyperthermia-facilitated homologous targeting cancer photo-chemotherapy

BackgroundMulti-modal therapy has attracted increasing attention as it provides enhanced effectiveness and potential stimulation of the immune community. However, low accumulation at the tumor sites and quick immune clearance of the anti-tumor agents are still insurmountable challenges. Hypothetically, cancer cell membrane (CCM) can homologously target the tumor whereas multi-modal therapy can complement the disadvantages of singular therapies. Meanwhile, moderate hyperthermia induced by photothermal therapy can boost the cellular uptake of therapeutic agents by cancer cells.ResultsCCM-cloaked indocyanine green (ICG)-incorporated and abraxane (PTX-BSA)-loaded layered double hydroxide (LDH) nanosheets (LIPC NSs) were fabricated for target efficient photo-chemotherapy of colorectal carcinoma (CRC). The CCM-cloaked LDH delivery system showed efficient homologous targeting and cytotoxicity, which was further enhanced under laser irradiation to synergize CRC apoptosis. On the other hand, CCM-cloaking remarkably reduced the uptake of LDH NSs by HEK 293T cells and macrophages, implying mitigation of the side effects and the immune clearance, respectively. In vivo data further exhibited that LIPC NSs enhanced the drug accumulation in tumor tissues and significantly retarded tumor progression under laser irradiation at very low therapeutic doses (1.2 and 0.6 mg/kg of ICG and PTX-BSA), without observed side effects on other organs.ConclusionsThis research has demonstrated that targeting delivery efficiency and immune-escaping ability of LIPC NSs are tremendously enhanced by CCM cloaking for efficient tumor accumulation and in situ generated hyperthermia boosts the uptake of LIPC NSs by cancer cells, a potential effective way to improve the multi-modal cancer therapy.Graphical

Collagenase IV and clusterin-modified polycaprolactone-polyethylene glycol nanoparticles for penetrating dense tumor tissues.

Purpose: Novel collagenase IV (ColIV) and clusterin (CLU)-modified polycaprolactone-polyethylene glycol (PCL-PEG) nanoparticles that load doxorubicin (DOX) were designed and fully evaluated in vitro and in vivo.Methods: PCL-PEG-ColIV was synthesized by linking PCL-PEG and ColIV through a carbodiimide method. DOX-loaded nanoparticles (DOX-PCL-PEG-ColIV) were self-assembly prepared, followed by noncovalently adsorbing CLU on the DOX-PCL-PEG-ColIV surface to obtain DOX-PCL-PEG-ColIV /CLU nanoparticles, which can penetrate through the tumor extracellular matrix (ECM) and inhibit phagocytosis by macrophage. The physicochemical properties of nanoparticles were characterized. The cellular uptake and antiphagocytosis ability of nanoparticles in MCF-7 tumor cells and RAW264.7 cells were investigated. The penetration ability of nanoparticles was individually evaluated in the two-dimensional (2D) and three-dimensional (3D) ECM models. The tissue distribution and antitumor effect of nanoparticles were evaluated in MCF-7 cell-bearing nude mice.Results: Compared with DOX-PCL-PEG-COOH nanoparticles, DOX-PCL-PEG-ColIV/CLU nanoparticles could effectively overcome the phagocytosis by RAW264.7 and showed excellent cellular uptake in MCF-7 cells. In addition, they showed remarkable penetration ability through the 2D and 3D ECM models. DOX-PCL-PEG-ColIV/CLU nanoparticles significantly reduced the drug distribution in the liver and spleen and enhanced the drug accumulation in tumor tissue compared with DOX-PCL-PEG-COOH or DOX-PCL-PEG-ColIV nanoparticles. DOX-PCL-PEG-ColIV/CLU nanoparticles showed remarkable antitumor effect but did not cause severe pathological damages in the main tissues, including the heart, liver, spleen, lung, and kidney.Conclusion: Novel ColIV and CLU-modified PCL-PEG nanoparticles showed excellent cellular uptake, ECM penetration, antiphagocytosis, and antitumor effects both in vitro and in vivo.

Abstract 6255: Augmented lung tumor infiltration of chemotherapeutics using synthetic antigen receptor- mesenchymal stem cells (SAR-MSCs)

Abstract Targeted delivery can improve drug accumulation in tumor tissue and treatment outcomes. However, currently available options suffer from a lack of selectivity for tumor cells. Mesenchymal Stem cells (MSCs) can be engineered with chemotherapeutic-loaded polymeric nanoparticles (PNPs) for tumor-targeted delivery, owing to their characteristic tumor tropic properties. Although nano-engineered MSCs demonstrated significant anticancer activity in multiple ovarian cancer models, their non-specific accumulation in clearance organs such as lungs and liver remains a concern. Parallel to the concept of chimeric antigen receptor (CAR)-T cell therapy, we advance here a strategy of modifying MSCs with synthetic antigen receptors (SARs) that target specific antigens overexpressed on cancer cells. Our approach consists of stably incorporating recombinant protein G (PG) on the surface of MSCs, followed by binding of a full-length IgG to the PG handle. Because protein G binds to the Fc region of IgG, antigen-binding affinity of the antibody is conserved. Epidermal growth factor receptor (EGFR) has been reported to be overexpressed and implicated in the pathogenesis of several malignancies especially lung cancer. Cetuximab (Cmab) is an anti-EGFR monoclonal antibody used in the treatment of metastatic lung cancer. In the current study, SAR-MSCs were developed by coating the nano-engineered MSCs with palmitated PG, followed by incorporating Cmab on the cell surface. Flow cytometry and confocal microscopy were used to confirm the incorporation of fluorescently labeled PAPG handle on MSC surface. Similarly, the installation of fluorescently labeled antibody on PAPG-functionalized MSCs was confirmed by flow cytometry. Preliminary efficacy studies in a mouse orthotopic A549-luc human lung adenocarcinoma model demonstrated significantly (P<0.05) improved survival of mice treated with Cmab-modified nano-engineered MSCs compared to isotype IgG-modified nano-engineered MSCs control group. These results suggest that the SAR technology could further improve the effectiveness of MSCs as tumor targeted drug delivery vehicles. Citation Format: Susheel Kumar Nethi, Drishti Sehgal, Jayanth Panyam, Swayam Prabha. Augmented lung tumor infiltration of chemotherapeutics using synthetic antigen receptor- mesenchymal stem cells (SAR-MSCs) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6255.

Black phosphorus nanosheets and docetaxel micelles co-incorporated thermoreversible hydrogel for combination chemo-photodynamic therapy.

The platform of the combination chemo-photodynamic therapy has received widespread attention for enhancing anticancer efficacy and inhibiting tumor growth, which supports thermosensitive and controlled drug release. Here, an injectable thermoreversible hydrogel (BPNSs/DTX-M-hydrogel) co-encapsulating black phosphorus nanosheets (BPNSs) and docetaxel (DTX) micelles was prepared to increase drug accumulation in tumor tissue and improve anticancer efficacy. BPNSs were prepared by liquid exfoliation method with a simple and rapid preparation, and DTX micelles were prepared by the thin film dispersion method. Hydrogel was prepared with F127 as hydrogel matrix for intratumoral injection. BPNSs, DTX micelles, and BPNSs/DTX-M-hydrogel were characterized by particle size, morphology, stability and degradation, phase transition feature, and photodynamic performance. And the in vivo anticancer efficacy was evaluated in 4T1 tumor-bearing Balb/c mice. The results showed that the particle size of DTX micelles and BPNSs were about 16 and 180nm, respectively. The hydrogel with the transformation temperature at near body exhibited great photodynamic efficacy and good biodegradability. Moreover, BPNSs/DTX-M-hydrogel with the combination of chemotherapy and photodynamic therapy exhibited unique anticancer efficacy with low toxicity. In conclusion, the combination platform of chemo-photodynamic therapy based on BPNSs could be a prospective strategy in antitumor research. Graphical abstract.

Multistage tumor microenvironment-responsive theranostic nanopeanuts: Toward multimode imaging guided chemo-photodynamic therapy

It is of great importance to develop tumor microenvironment (TME) responsive and adjustable theranostic nano-systems for specific and efficient cancer treatment. However, carrier-based nanomedicines are often inefficacious in vivo due to low drug-loading efficiency, lack of synergistic effects, poor targeting specificity and limited drug accumulation in tumor tissues. Herein, we report a new multimodal theranostic nanoplatform which is assembled from Fe3O4 nanoclusters, MnO2 nanosheets with multifunctional and cross-linked polyphosphazene. This peanut-like nanoplatform exhibited enhanced chemo/photodynamic therapy (CT/PDT) effect as well as significant tumor-targeting capacity. In addition, Fe3O4 cores and MnO2 nanoshells enables T1/T2 magnetic resonance imaging (MRI) of tumor tissues, while photosensitizer methylene blue (MB) allows for fluorescence imaging and PDT simultaneously. Importantly, nanopeanut agents could dual-regulate intracellular oxygen and glutathione (GSH) levels in TME by MnO2 shells, to relieve hypoxic condition and produce enough ROS to induce cell apoptosis. Our research demonstrated that the multistage TME-responsive nanoplatform is ideally suitable for tumor specific drug delivery and real-time disease tracking with enhanced theranostic properties.

Drug-Polymer Hybrid Macromolecular Engineering: Degradable PEG Integrated by Platinum(IV) for Cancer Therapy

Summary Drug delivery systems (DDSs) based on macromolecular engineering have attracted much attention in biotechnology and medicine due to their versatile and tunable chemistry. However, concern about the biosafety issue of polymeric carriers is increasing. For example, non-biodegradability of high-molecular-weight poly(ethylene glycol) (PEG) causes serious side effects. To solve this, here we propose a safer, simpler, and more efficient polymeric DDS with a drug-polymer hybrid macromolecular engineering concept. The DDS consists of a degradable PEG integrated with a hydrophobic platinum(IV) prodrug with responsive bonds in the polymeric backbone. This polymer maintains the advantages of both high-molecular-weight PEG in improving the pharmacokinetics of drugs with high drug accumulation in tumor tissues and low-molecular-weight PEG, which is easily excreted, reducing its side effects. It is also associated with tunable amphiphilicity and drug loading efficiency, contributed by the drug-polymer hybrid. This work provides a novel strategy for the design of polymeric biodegradable DDSs.

A lanthanide-peptide-derived bacterium-like nanotheranostic with high tumor-targeting, -imaging and -killing properties

Nanostructures formed with bioactive peptides offer an exciting prospect in clinical oncology as a novel class of therapeutic agents for human cancers. Despite their therapeutic potential, however, peptide-based nanomedicines are often inefficacious in vivo due to low cargo-loading efficiency, poor tumor cell-targeting specificity and limited drug accumulation in tumor tissues. Here, we describe the design, via assembly of a p53-activating peptide termed PMI, functionalized PEG and fluorescent lanthanide oxyfluoride nanocrystals, of a novel nanotheranostic shaped in flexible rods. This lanthanide-peptide nanorod or LProd of bionic nature exhibited significantly enhanced tumor-targeting and -imaging properties compared to its spherical counterpart. Importantly, LProd potently inhibited tumor growth in a mouse model of human colon cancer through activating tumor suppressor protein p53 via MDM2/MDMX antagonism, while maintaining a highly favorable biosafety profile. Our data demonstrate that LProd as a multifunctional theranostic platform is ideally suited for tumor-specific peptide drug delivery with real-time disease tracking, thereby broadly impacting clinical development of antitumor peptides.

Near‐Infrared Fluorescent Theranostic Cisplatin Prodrug with Transcatheter Intra‐Arterial Therapy: Application to Rabbit Hepatocellular Carcinoma

AbstractTranscatheter intra‐arterial therapy (TIT) has become valuable in the battle against primary and secondary hepatic malignancies. However, the lack of a mechanism to visualize real‐time drug release and avoid fast metabolic clearance of chemotherapeutic agents is the primary barrier to TIT for hepatocellular carcinoma. Here, a specific near‐infrared (NIR) fluorescent prodrug platform, that is, DSPE‐mPEG/DCM‐S‐Pt micelles (DCM‐S‐Pt@PEG), to assist TIT in direct administration to large mammals like rabbits, is presented. DCM‐S‐Pt@PEG consists of a NIR fluorophore for tracing drug release, a nonspecific antitumor drug cisplatin for hepatocellular carcinoma treatment, a glutathione‐activatable disulfide linker, and a DSPE‐mPEG nano‐micelle carrier for controllable drug release. DCM‐S‐Pt@PEG can make the drug accumulation in tumor tissues enhance the therapeutic effect by: i) specific delivery of prodrug to hepatic tumor tissues through the femoral artery by TIT, ii) sustained drug‐release from the biodegradable lipid DSPE‐mPEG micelle to minimize metabolic clearance, and iii) cancer biomarker–activated drug release. It provides a promising strategy to assist TIT in treating unresectable devastating hepatocellular carcinoma administration in the rabbit model, rather than common mouse model.

A facile approach for fabricating CD44-targeted delivery of hyaluronic acid-functionalized PCL nanoparticles in urethane-induced lung cancer: Bcl-2, MMP-9, caspase-9, and BAX as potential markers.

Lung carcinoma ranks highest in cancer-related death (about 20% of total cancer deaths) due to poor prognosis and lack of efficient management therapy. Owing to the lack of effective therapeutic approaches, survival rate of less than 5years persists over the years among non-small cell lung cancer (NSCLC) patients. Capsaicin (CAP) is well reported for its antiproliferative and antioxidant properties in various literature but lacks an appropriate delivery carrier. The present study was aimed to develop CAP-loaded hyaluronic acid (HA) nanoparticles (NPs) utilizing layer by layer technique to achieve enhanced and precise delivery as well as target specificity. The NPs were evaluated for in vitro release, particle size, zeta potential, and cytotoxicity on A549 cells. The optimized NPs exhibited a particle size of 194 ± 2.90nm, - 27.87 ± 3.21mV zeta potential, and 80.70 ± 4.29% release, respectively, over a period of 48h. Flow cytometric analysis revealed superior performance of HA-PCL-CAP in terms of suppressed cell viability in A549 cell lines when compared with CAP and PCL-CAP. Further, HA-anchored NPs were evaluated in vivo for their therapeutic efficacy in urethane-induced lung carcinoma in rat model. The superlative therapeutic potential of HA-PCL-CAP was advocated from the results of reactive oxygen species and mitochondrial membrane-mediated apoptosis. HA-PCL-CAP-administered groups presented greater therapeutic efficacy as revealed through reduced tumor volume and improved animal survival rate. A greater drug accumulation in tumor tissue as revealed from biodistribution studies evidences targeting potential of HA-PCL-CAP in urethane-induced lung carcinoma. Graphical abstract ᅟ.

Synthetic Glycopolypeptide Micelle for Targeted Drug Delivery to Hepatic Carcinoma.

The targeted delivery of chemotherapy drugs to tumor lesions is a major challenge for the treatment of tumors. Up until now, various polymeric nanoparticles have been explored to improve the targetability of these therapeutic drugs through passive or active targeting processes. In the design and construction of polymer nanoparticles, glycopolypeptide has shown great potential owing to its excellent targeting ability and biocompatibility. In order to enhance the antitumor effect of doxorubicin (DOX), a glycopolypeptide-based micelle (GPM) modified by α-lactose (Lac) was synthesized for targeted treatment of hepatoma. The DOX-loaded GPM (i.e., GPM/DOX) could significantly target human hepatoma (HepG2) cells and further inhibit their proliferation in vitro. Additionally, GPM/DOX exhibited a much higher drug accumulation in tumor tissue and a stronger antitumor effect in vivo than free DOX. The above results revealed that this drug delivery system provides a promising platform for the targeting therapy of hepatic cancer.