Tumor Drug Release Research Articles

Dual role of triglyceride structures facilitates anti-tumor drug delivery: Both as a self-assembling module and a responsive module

Small molecule prodrugs self-assembled nano-delivery systems with tumor responsive linkages are emerging as an effective platform. However, the heterogeneity of tumor microenvironment may limit the anti-tumor effect of prodrug nanomedicines with a single response module. Here, we chose disulfide bond as the response module and branched chain alcohol as the self-assembly modification module to construct a single-responsive prodrug. We also constructed a double-responsive paclitaxel prodrug combining triglyceride and disulfide bond, taking into account of the highly expressed lipase and glutathione levels in tumor cells. The results showed that the anti-tumor effect of single-responsive branched chain alcohol modified prodrug nanoparticles was inferior to triglyceride prodrug nanoparticles with dual response modules. The triglyceride structure can not only serve as a self-assembly modification module, but also serve as a response module for intelligent drug release in tumor. Such dual roles will facilitate the efficient delivery of small molecule self-assembled prodrugs to tumor sites.

Thermoresponsive and Substrate Self-Cycling Nanoenzyme System for Efficient Tumor Therapy.

Cerium oxide (CeO2-x) performs well in photothermal and catalytic properties due to its abundance of oxygen vacancies. Based on this, we designed a thermosensitive therapeutic nanoplatform to achieve continuous circular drug release in tumor. It can solve the limitation caused by insufficient substrate in the process of tumor treatment. Briefly, CeO2-x and camptothecin (CPT) were wrapped in an agarose hydrogel, which could be melted by the photothermal effect of CeO2-x. At the same time, the local temperature increase provided photothermal treatment, which could induce the apoptosis of tumor cell. After that, CPT was released to damage the DNA in tumor cells to realize chemical treatment. In addition, CPT could active nicotinamide adenine dinucleotide oxidase to react with O2 to increase the intracellular H2O2. After that, the exposed CeO2-x could catalyze H2O2 to generate cytotoxic reactive oxygen species for chemodynamic therapy. More importantly, CeO2-x could catalyze H2O2 to produce O2, which could combine with the catalytic action of CPT to construct a substrate self-cycling nanoenzyme system. Overall, this self-cycling nanoplatform released hypoxia in the tumor microenvironment and built a multimode tumor treatment, which achieved an ideal antitumor affect.

Developing Hypoxia-Sensitive System via Designing Tumor-Targeted Fullerene-Based Photosensitizer for Multimodal Therapy of Deep Tumor.

Photodynamic therapy (PDT) has been approved for clinic. However, powerless efficiency for deep hypoxic tumor therapy remains an enormous challenge for PDT. Herein, a hypoxia-sensitive nanotherapeutic system (FTCD-SRGD) based on fullerene (C70 ) and anoxic activating chemical prodrug tirapazamine (TPZ) is rationally designed for multimodal therapy of deep hypoxic tumors. To enhance the accumulation and achieve specific drug release in tumor, the FTCD-SRGD is modified with cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGDfK) peptide and disulfide bonds. With the exacerbated hypoxic microenvironment created by C70 consuming O2 for generating reactive oxygen species (ROS), TPZ is activated to produce toxic radical species to ablate deep tumors, which achieves a synergistic treatment of C70 -mediated PDT and hypoxia-enhanced chemotherapy. Additionally, given this hypoxia-sensitive system-induced immunogenic cell death (ICD) activating anticancer cytotoxic T lymphocyte to result in more susceptible tumor to immunotherapy, FTCD-SRGD plus immune checkpoint inhibitor (anti-PD-L1) fully inhibit deep hypoxic tumors by promoting infiltration of effector T cells in tumors. Collectively, it is the first time to develop a multimodal therapy system with fullerene-based hypoxia-sensitive PS for deep tumors. The powerful multimodal nanotherapeutic system for combining hypoxia-enhanced PDT and immunotherapy to massacre deep hypoxic tumors can provide a paradigm to combat the present bottleneck of tumor therapy.

Abstract B004: EUS guided local administration of large surface area microparticle paclitaxel with neoadjuvant chemotherapy in locally advanced pancreatic cancer: A single center experience

Abstract Background: Locally advanced pancreatic cancer (LAPC) is defined as an unresectable tumor due to extensive vascular involvement without evidence of metastatic spread. Neoadjuvant chemotherapy with leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine-nab-paclitaxel (gem-nab) are the preferred treatments in LAPC. These treatments downstage LAPC to resectable disease in about 10%–35% of patients resulting in an increase in median survival. However, intravenous paclitaxel's hydrophobic, protein-bound nature, short half-life, and intermittent dosing hamper tumor tissue exposure time, resulting in suboptimal intratumoral bioavailability that may facilitate tumor resistance. Limited downstaging to R0 resection is likely due, in part, to the desmoplastic, fibrotic tumor microenvironment in LAPC and poorly vascularized stroma reducing availability of IV drug to tumor cells. To address this, large surface area microparticle paclitaxel (LSAM-PTX) was developed (NanOlogy LLC) for intratumoral (IT) delivery with a mean particle size (DV50) of about 2.5 µm and 3-fold increase in specific surface area over unprocessed drug. The relatively large particle size facilitates tumor retention, and increased surface area allows continuous drug release in tumor over an extended time, along with negligible systemic exposure. Methods: Data were collected prospectively on 6 of 13 (46%) subjects with LAPC who received EUS-guided fine needle injection (EUS-FNI) of LSAM-PTX in addition to neoadjuvant chemotherapy and subsequently underwent surgery at our institution from 2018 to 2019 (NCT03077685). Each subject underwent two EUS-FNI procedures four weeks apart to deliver IT LSAM-PTX suspension (15 mg/mL) in a volume equivalent to 20% of the tumor volume up to 5 mL of drug. Histopathological and immunophenotypic profiling using multiplex immunofluorescence (mIF) was performed on tumor site tissue from pre-LSAM-PTX biopsies and the resected tumor. Results: The mean duration from EUS-FNI to surgery was 6.91 months (range: 3.68-12.22 months). Histopathology was evaluated from the resected specimens to assess treatment response. Five of six subjects (83%) had R0 resections. Of the five R0 resections, one subject had a pathologic complete response, one had 10% and two had 10-20% viable tumor, and one had a partial response with tumor regression. Focal necrosis was also reported in the lone subject with an R1 resection. Immunophenotypic profiling of tissue showed an increase in adaptive and innate immune cell density, an increase in NK cells in the tumor microenvironment, and a decrease in the myeloid/MDSC populations. Conclusions: EUS-FNI of LSAM-PTX, added to neoadjuvant chemotherapy, was safe and resulted in a significant reduction in tumor volume, along with significant tumor necrosis, and favorable changes in tumor immunophenotypic configuration. These preliminary results suggest that adding LSAM-PTX to neoadjuvant chemotherapy could increase the rate of downstaging of LAPC to resectable disease and improve clinical outcomes. Citation Format: Harishankar Gopakumar, Aqsa Khan, Christina M. Zelt, Ashley Rumple, Mariajose Rojas de Leon, Neil R. Sharma. EUS guided local administration of large surface area microparticle paclitaxel with neoadjuvant chemotherapy in locally advanced pancreatic cancer: A single center experience [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B004.

Hypoxia-triggered tumor specific glutamine inhibition for reversing cisplatin resistance of chemotherapy

Cisplatin resistance of tumors significantly impedes the therapeutic effect of cisplatin chemotherapy. Excessive glutathione (GSH) that is produced by tumor cells with abnormal metabolism is the main reason for cisplatin resistance, which would inactivate intracellular cisplatin and cause tumor resistance. Intracellular GSH can be massively synthesized by glutamine (Gln) through enzymatic biochemical reactions. Therefore, inhibiting the metabolism of Gln would reduce intracellular GSH and restore the anti-tumor activity of cisplatin. Another vital feature of cisplatin-resistant tumors is the heavy hypoxia microenvironment, which is beneficial for developing hypoxia-activated drug delivery systems to realize specific drug release in tumors. Herein, we constructed a hypoxia-triggered tumor-metabolism inhibiting nanomedicine (denoted as PD@HN NPs) for high-effective cisplatin therapy. PD@HN NPs were formulated with the chemotherapy drug cisplatin, Gln inhibitor (DON), and a hypoxia-responsive carrier 2-nitroimidazole modified hyaluronic acid (HA-NI). Consequently, the PD@HN NPs demonstrate excellent anti-tumor effect on cisplatin-resistant tumors in both cisplatin-resistant cell lines and patient-derived xenograft tumor models. In general, this work presents a novel nanomedicine that reverses the cisplatin resistance of tumors and significantly enhances the therapeutic effect of cisplatin by precisely mediating the intracellular GSH metabolism under a hypoxia environment, inspiring more insights into the development of high-effective cisplatin therapy.

X‐Ray‐Induced Drug Release for Cancer Therapy

AbstractDrug delivery systems (DDSs) are designed to deliver therapeutic agents to specific target sites while minimizing systemic toxicity. Recent developments in drug‐loaded DDSs have demonstrated promising characteristics and paved new pathways for cancer treatment. Light, a prevalent external stimulus, is widely utilized to trigger drug release. However, conventional light sources primarily concentrate on the ultraviolet (UV) and visible light regions, which suffer from limited biological tissue penetration. This limitation hinders applications for deep‐tissue tumor drug release. Given their deep tissue penetration and well‐established application technology, X‐rays have recently received attention for the pursuit of controlled drug release. With precise spatiotemporal and dosage controllability, X‐rays stand as an ideal stimulus for achieving controlled drug release in deep‐tissue cancer therapy. This article explores the recent advancements in using X‐rays for stimulus‐triggered drug release in DDSs and delves into their action mechanisms.

A novel carbon-nanodots-based theranostic nano-drug delivery system for mitochondria-targeted imaging and glutathione-activated delivering camptothecin

Chemotherapy is severely limited by continuously decreased therapeutic efficacy and uncontrolled side effects on normal tissue, which can be improved by constructing a nanoparticle-based drug delivery system (DDS). Nevertheless, no studies have reported on DDS-based on carbon-nanodots (CNDs), combining subcellular organelle-targeted imaging/drug delivery, high drug loading content, and glutathione (GSH)-sensitive drug release into one system. Herein, the as-fabricated CNDs can be covalently conjugated with a mitochondria-targeting ligand (triphenylphosphine, TPP), a smart GSH-responsive disulfide linker (S-S), and the anticancer drug (camptothecin, CPT) to initially prepare a theranostic nano-DDS (TPP-CNDs-S-CPT) with the drug loading efficiency of 64.6 wt%. Owing to excellent water dispersibility, superior fluorescence properties, satisfactory cell permeability, and favorable biocompatibility, TPP-CNDs-S-CPT was successfully used for intracellular mitochondrial-targeted imaging in vitro. High intracellular GSH concentrations in tumor cells caused the cleavage of S-S, resulting in concomitant activation and release of CPT, as well as significant fluorescence enhancement. In vivo, TPP-CNDs-S-CPT exhibited lower biological toxicity and even higher tumor-activatable performance than free CPT, as well as specific cancer therapy with few side effects. The mitochondria-targeted ability and the precise drug-release in tumor make TPP-CNDs-S-CPT a hopeful chemotherapy prodrug, providing significant theoretical basis and data support for in-depth understanding and exploration of chemotherapeutic DDS-based on CNDs.

Radiotherapy‐Induced Cleavage of Quaternary Ammonium Groups Activates Prodrugs in Tumors

AbstractCleavage chemistry offers a new chance to activate chemotherapeutic prodrugs in a tumor‐selective manner, yet developing spatiotemporally controllable cleavage chemistry with deep tissue penetration is still a great challenge. Herein, we present a novel radiotherapy‐triggered cleavage chemistry that enables controlled drug release in tumors. Quaternary ammonium groups are identified as masking groups that can be efficiently removed by hydrated electrons (e−aq) from water radiolysis. The subsequently released tertiary amines can be anti‐cancer toxins or readily release functional molecules via 1,6‐elimination. This radiotherapy‐induced cleavage works successfully in living cells and tumor‐bearing mice, showing remarkable treatment efficacy when the mice are given carfilzomib prodrug and radiotherapy. This strategy provides a new perspective for combinational radiochemotherapy, which is the first‐line treatment for over 50 % of cancer patients.

Radiotherapy-Induced Cleavage of Quaternary Ammonium Groups Activates Prodrugs in Tumors.

Cleavage chemistry offers a new chance to activate chemotherapeutic prodrugs in a tumor-selective manner, yet developing spatiotemporally controllable cleavage chemistry with deep tissue penetration is still a great challenge. Herein, we present a novel radiotherapy-triggered cleavage chemistry that enables controlled drug release in tumors. Quaternary ammonium groups are identified as masking groups that can be efficiently removed by hydrated electrons (e-aq ) from water radiolysis. The subsequently released tertiary amines can be anti-cancer toxins or readily release functional molecules via 1,6-elimination. This radiotherapy-induced cleavage works successfully in living cells and tumor-bearing mice, showing remarkable treatment efficacy when the mice are given carfilzomib prodrug and radiotherapy. This strategy provides a new perspective for combinational radiochemotherapy, which is the first-line treatment for over 50 % of cancer patients.

Construction of Intelligent Responsive Drug Delivery System and Multi-Mode Imaging Based on Gold Nanodots.

Cancer remains a formidable global problem with a high mortality rate. There are many effective anti-cancer drugs in clinical use, among which paclitaxel (PTX) has good effects on non-small cell lung cancer, ovarian cancer, and breast cancer. However, when applied to the clinic, PTX still has many limitations, such as poor water solubility, drug resistance, and side effects on healthy tissues. A gold nanodots-paclitaxel-polylysine (AuNDs-PTX-PLL) core-shell nano-system of integrated diagnosis and treatment is constructed to achieve intelligent responsive drug delivery. On the one hand, the problem of poor water-solubility and drug resistance of PTX are solved. On the other hand,the nano-system has an excellent intelligent response effect. Drugs can only be released in the weakly acidic environment of the tumor, which reduces the damage and side effects to normal tissues. Moreover, the nano-system can be used for real-time tracking and auxiliary diagnosis for the tumor through the multi-mode imaging mode, such as fluorescence, photoacoustic, and computed tomography to achieve accurate visualization. The photothermal effect of AuNDs is beneficial to promote the release of drugs. The nano-system integrates multi-mode imaging, chemotherapy, intelligent drug release in tumor weakly acidic environment, and has excellentpractical application prospects in tumor diagnosis and treatment.

Microenvironment-Responsive Prodrug-Induced Pyroptosis Boosts Cancer Immunotherapy.

The absence of tumor antigens leads to a low response rate, which represents a major challenge in immune checkpoint blockade (ICB) therapy. Pyroptosis, which releases tumor antigens and damage‐associated molecular patterns (DAMPs) that induce antitumor immunity and boost ICB efficiency, potentially leads to injury when occurring in normal tissues. Therefore, a strategy and highly efficient agent to induce tumor‐specific pyroptosis but reduce pyroptosis in normal tissues is urgently required. Here, a smart tumor microenvironmental reactive oxygen species (ROS)/glutathione (GSH) dual‐responsive nano‐prodrug (denoted as MCPP) with high paclitaxel (PTX) and photosensitizer purpurin 18 (P18) loading is rationally designed. The ROS/GSH dual‐responsive system facilitates the nano‐prodrug response to high ROS/GSH in the tumor microenvironment and achieves optimal drug release in tumors. ROS generated by P18 after laser irradiation achieves controlled release and induces tumor cell pyroptosis with PTX by chemo‐photodynamic therapy. Pyroptotic tumor cells release DAMPs, thus initiating adaptive immunity, boosting ICB efficiency, achieving tumor regression, generating immunological memory, and preventing tumor recurrence. Mechanistically, chemo‐photodynamic therapy and control‐release PTX synergistically induce gasdermin E (GSDME)‐related pyroptosis. It is speculated that inspired chemo‐photodynamic therapy using the presented nano‐prodrug strategy can be a smart strategy to trigger pyroptosis and augment ICB efficiency.

Quantification of Drug Release Degree In Vivo Using Antibody-Guided, Dual-NIR-Dye Ratiometric System.

Fluorescent dyes linked to drug delivery systems provide important real-time information on the efficacy of drug delivery. However, the quantitative monitoring of drug distribution is challenging because of interferences from the biological sample and instrumental setup. To improve quantification of anticancer drug delivery followed by drug release in tumor, we equipped an antibody-drug conjugate (ADC) with a turn-on near-infrared (NIR) dye, sensitive to drug release, and a reference NIR dye. In this study, chlorambucil (CLB) was chosen as a model anticancer drug and Trastuzumab monoclonal antibody specific to Her2 receptors overexpressed in many tumors was taken as the carrier. The advantage of the obtained dual-dye ratiometric system for drug release monitoring was demonstrated in mice model.

Dual Receptor-Targeted and Redox-Sensitive Polymeric Micelles Self-Assembled from a Folic Acid-Hyaluronic Acid-SS-Vitamin E Succinate Polymer for Precise Cancer Therapy.

PurposePoor site-specific delivery and insufficient intracellular drug release in tumors are inherent disadvantages to successful chemotherapy. In this study, an extraordinary polymeric micelle nanoplatform was designed for the efficient delivery of paclitaxel (PTX) by combining dual receptor-mediated active targeting and stimuli response to intracellular reduction potential.MethodsThe dual-targeted redox-sensitive polymer, folic acid-hyaluronic acid-SS-vitamin E succinate (FHSV), was synthesized via an amidation reaction and characterized by 1H-NMR. Then, PTX-loaded FHSV micelles (PTX/FHSV) were prepared by a dialysis method. The physiochemical properties of the micelles were explored. Moreover, in vitro cytological experiments and in vivo animal studies were carried out to evaluate the antitumor efficacy of polymeric micelles.ResultsThe PTX/FHSV micelles exhibited a uniform, near-spherical morphology (148.8 ± 1.4 nm) and a high drug loading capacity (11.28% ± 0.25). Triggered by the high concentration of glutathione, PTX/FHSV micelles could quickly release their loaded drug into the release medium. The in vitro cytological evaluations showed that, compared with Taxol or single receptor-targeted micelles, FHSV micelles yielded higher cellular uptake by the dual receptor-mediated endocytosis pathway, thus leading to significantly superior cytotoxicity and apoptosis in tumor cells but less cytotoxicity in normal cells. More importantly, in the in vivo antitumor experiments, PTX/FHSV micelles exhibited enhanced tumor accumulation and produced remarkable tumor growth inhibition with minimal systemic toxicity.ConclusionOur results suggest that this well-designed FHSV polymer has promising potential for use as a vehicle of chemotherapeutic drugs for precise cancer therapy.

Synergistic triple-combination therapy with hyaluronic acid-shelled PPy/CPT nanoparticles results in tumor regression and prevents tumor recurrence and metastasis in 4T1 breast cancer

Breast cancer is characterized by high aggression, poor prognosis, and high recurrence rate. Early detection and specific targeted treatment with less toxicity are the ultimate goals for breast cancer therapy. To improve antitumor therapeutic effects, we developed a novel polypyrrole nanoparticle using the near infrared dye IRDye800CW with camptothecin (CPT)-conjugated hyaluronic acid (HA) shell (PPy@CPT-HA-IRDye800CW) and performed a photothermal therapy (PTT), along with chemotherapy, guided by fluorescence and photoacoustic dual-modality imaging, in combination with immunotherapy. Irradiation with near infrared (NIR) light offered a strong PTT effect and promoted CPT drug release in tumors. Moreover, we found that chemo-photothermal therapy with PPy@CPT-HA-IRDye800CW NPs, in combination with immune checkpoint inhibitor anti-PD-L1 immunotherapy, synergistically enhanced the anti-tumor immune response, thereby eliminating primary breast cancer and preventing tumor metastases and recurrences in 4T1 tumor-bearing mice. This approach may provide important clues for the clinical management of breast cancer and other malignant tumors.

Olive Oil‐Based Ultrafine Theranostic Photo Nanoemulsions: A Versatile Tumor Maneuvering Nanoplatform for Precise Controlled Drug Release in Tumor and Complete Tumor Eradication Mediated by Photo‐Chemotherapy

AbstractPhotothermal therapy (PTT) is an efficient approach to treat tumors. However, heterogeneous distribution of heat by PTT in the tumor region often results in tumor regrowth and metastasis. Integrating PTT with chemotherapy in a precisely controlled tumor maneuvering and drug‐releasing nanoconstruct will be an ideal strategy for higher therapeutic index. Herein, nanoemulsions (NEMSn) based on a highly biocompatible extra virgin olive oil are developed to encapsulate IR‐780 for PTT and near infrared fluorescence imaging as well as doxorubicin (DOX) for chemotherapy. NEMSn are further stabilized with Tween‐20 and hyaluronic acid to form an ultrafine theranostic photo nanoemulsions (UTPNEMSn) for combinatorial photo‐chemotherapy. Once injected into the system, UTPNEMS homes to the tumor region owing to passive targeting. Tumor accumulated UTPNEMSn readily destabilizes upon laser irradiation to release the DOX, thereby synergizing the therapeutic effects of DOX and PTT. In vivo studies demonstrate a complete tumor eradication without tumor recurrence or systemic toxicity, owing to their biocompatible formulation. By virtue of the olive oil based NEMSNs and precise controlled drug releasing properties collaborating with the synergistic therapeutic modalities, UTPNEMSn are able to provide a promising method for controlled drug delivery systems.

Enhancing Antitumor Efficacy by Simultaneous ATP-Responsive Chemodrug Release and Cancer Cell Sensitization Based on a Smart Nanoagent.

The exploitation of smart nanoagents based drug delivery systems (DDSs) has proven to be a promising strategy for fighting cancers. Hitherto, such nanoagents still face challenges associated with their complicated synthesis, insufficient drug release in tumors, and low cancer cell chemosensitivity. Here, the engineering of an adenosine triphosphate (ATP)‐activatable nanoagent is demonstrated based on self‐assembled quantum dots‐phenolic nanoclusters to circumvent such challenges. The smart nanoagent constructed through a one‐step assembly not only has high drug loading and low cytotoxicity to normal cells, but also enables ATP‐activated disassembly and controlled drug delivery in cancer cells. Particularly, the nanoagent can induce cell ATP depletion and increase cell chemosensitivity for significantly enhanced cancer chemotherapy. Systematic in vitro and in vivo studies further reveal the capabilities of the nanoagent for intracellular ATP imaging, high tumor accumulation, and eventual body clearance. As a result, the presented multifunctional smart nanoagent shows enhanced antitumor efficacy by simultaneous ATP‐responsive chemodrug release and cancer cell sensitization. These findings offer new insights toward the design of smart nanoagents for improved cancer therapeutics.

PH-activatable polymeric nanodrugs enhanced tumor chemo/antiangiogenic combination therapy through improving targeting drug release

It was widely accepted that polymeric nanodrugs held superiority in enhancing antitumor efficacy, reducing side effect and achieving better long-term prognosis. However, there still existed disputes that whether their therapeutic efficiency was closely related to insure effective release of hydrophobic drug located in their hydrophobic core in tumor site. In order to investigate this controversy, we constructed two polymeric nanodrugs (pH-activatable sLMWH-UOA and non-sensitive LMWH-UOA) with low molecular weight heparin (LMWH) and ursolic acid (UOA) for chemo-and anti-angiogenic combination therapy in hepatocellular carcinoma. The degradation ratio of pH-activatable sLMWH-UOA increased by 33% compared with non-sensitive LMWH-UOA in in vitro degradation study. Besides, confocal microscopy captured that sLMWH-UOA could effectively release drug in acidic microenvironment of lysosome while LMWH-UOA nearly could not. More importantly, in contrast with LMWH-UOA, sLMWH-UOA presented pH-dependent cytotoxicity, indicating that promoting drug release played a key role in enhancing the cytotoxicity of polymeric nanodrugs. Additionally, in vivo pharmacodynamic evaluation showed that although non-sensitive LMWH-UOA had benefited from enhanced tumor targeting drug delivery ability to achieve absolute advantage over free drug combination therapy in antitumor combination therapy, sLMWH-UOA could acquire further optimized combined therapeutic effect with better drug release in tumor. All above, application of tumor-triggered chemical bonds to construct polymeric nanodrugs held vast prospect for improving the therapeutic efficiency for tumor cells.

Biodegradable Drug-Loaded Hydroxyapatite Nanotherapeutic Agent for Targeted Drug Release in Tumors.

Tumor-targeted drug delivery systems have been increasingly used to improve the therapeutic efficiency of anticancer drugs and reduce their toxic side effects in vivo. Focused on this point, doxorubicin (DOX)-loaded hydroxyapatite (HAP) nanorods consisting of folic acid (FA) modification (DOX@HAP-FA) were developed for efficient antitumor treatment. The DOX-loaded nanorods were synthesized through in situ coprecipitation and hydrothermal method with a DOX template, demonstrating a new procedure for drug loading in HAP materials. DOX could be efficiently released from DOX@HAP-FA within 24 h in weakly acidic buffer solution (pH = 6.0) because of the degradation of HAP nanorods. With endocytosis under the mediation of folate receptors, the nanorods exhibited enhanced cellular uptake and further degraded, and consequently, the proliferation of targeted cells was inhibited. More importantly, in a tumor-bearing mouse model, DOX@HAP-FA treatment demonstrated excellent tumor growth inhibition. In addition, no apparent side effects were observed during the treatment. These results suggested that DOX@HAP-FA may be a promising nanotherapeutic agent for effective cancer treatment in vivo.

Suppress orthotopic colon cancer and its metastasis through exact targeting and highly selective drug release by a smart nanomicelle

The treatment of metastatic cancer is a huge challenge at the moment. Highly precise targeting delivery and drug release in tumor have always been our pursuit in cancer therapy, especially to advance cancer with metastasis, for increasing the efficacy and biosafety. We established a smart nanosized micelle, formed by tocopherol succinate (TOS) conjugated hyaluronic acid (HA) using a disulfide bond linker. The micelle (HA-SS-TOS, HSST) can highly specifically bind with CD44 receptor over-expressed tumor, and response selectively to high GSH level in the cells, inducing disulfide bond breakage and the release of the payload (paclitaxel, PTX). To predict the antitumor efficacy of the micelles more clinically, we established an orthotopic colon cancer model with high metastasis rate, which could be visualized by the luciferase bioluminescence. Our data confirmed CD44 high expression in the colon cancer cells. Highly matching between the micellar fluorescence and bioluminescence of cancer cells in intestines demonstrated an exact recognition of our micelles to orthotopic colon tumor and its metastatic cells, attributing to the mediation of CD44 receptors. Furthermore, the fluorescence of the released Nile Red from the micelles was found only in the tumor and its metastatic cells, and almost completely overlapped with the bioluminescence of the cancer cells, indicating a highly selective drug release. Our micelles presented an excellent therapeutic effect against metastatic colon cancer, and induced significantly prolonged survival time for the mice, which might become a promising nanomedicine platform for the future clinical application against advanced cancers with high CD44 receptor expression.

GSH-Activated NIR Fluorescent Prodrug for Podophyllotoxin Delivery.

Theranostic prodrug therapy enables the targeted delivery of anticancer drugs with minimized adverse effects and real-time in situ monitoring of activation of the prodrugs. In this work, we report the synthesis and biological assessment of the near-infrared (NIR) prodrug DCM-S-PPT and its amphiphilic copolymer (mPEG-DSPE)-encapsulated nanoparticles. DCM-S-PPT is composed of podophyllotoxin (PPT) as the anticancer moiety and a dicyanomethylene-4H-pyran (DCM) derivative as the NIR fluorescent reporter, which are linked by a thiol-specific cleavable disulfide bond. In vitro experiments indicated that DCM-S-PPT has low cytotoxicity and that glutathione (GSH) can activate DCM-S-PPT resulting in PPT release and a concomitant significant enhancement in NIR fluorescence at 665 nm. After being intravenously injected into tumor-bearing nude mice, DCM-S-PPT exhibited excellent tumor-activated performance. Furthermore, we have demonstrated that mPEG-DSPE as a nanocarrier loaded with DCM-S-PPT (mPEG-DSPE/DCM-S-PPT) showed even greater tumor-targeting performance than DCM-S-PPT on account of the enhanced permeability and retention effect. Its tumor-targeting ability and specific drug release in tumors make DCM-S-PPT a promising prodrug that could provide a significant strategy for theranostic drug delivery systems.