Tumor-targeted Drug Delivery Systems Research Articles

Pluronic-Based Nanoparticles for Delivery of Doxorubicin to the Tumor Microenvironment by Binding to Macrophages.

The active targeting drug delivery system based on special types of endogenous cells such as macrophages has emerged as a promising strategy for tumor therapy, owing to its tumor homing property and biocompatibility. In this work, the active tumor-targeting drug delivery system carrying doxorubicin-loaded nanoparticles (DOX@MPF127-MCP-1, DMPM) on macrophage (RAW264.7) surfaces via the mediation of interaction with the CCR2/MCP-1 axis was exploited. Initially, the amphiphilic block copolymer Pluronic F127 (PF127) was carboxylated to MPF127 at the hydroxyl terminus. Subsequently, MPF127 was modified with MCP-1 peptide to prepare MPF127-MCP-1 (MPM). The DOX was wrapped in MPM to form DMPM nanomicelles (approximately 100 nm) during the self-assembly process of MPM. The DMPM spontaneously bound to macrophages (RAW264.7), which resulted in the construction of an actively targeting delivery system (macrophage-DMPM, MA-DMPM) in vitro and in vivo. The DOX in MA-DMPM was released in the acidic tumor microenvironment (TME) in a pH-responsive manner to increase DOX accumulation and enhance the tumor treatment effect. The ratio of MA-DMPM homing reached 220% in vitro compared with the control group, indicating that the MA-DMPM was excellently capable of tumor-targeting delivery. In in vivo experiments, nonsmall cell lung cancer cell (NCI-H1299) tumor models were established. The results of the fluorescence imaging system (IVIS) showed that MA-DMPM demonstrated tremendous tumor-targeting ability in vivo. The antitumor effects of MA-DMPM in vivo indicated that the proportion of tumor cell apoptosis in the DMPM-treated group was 63.33%. The findings of the tumor-bearing mouse experiment proved that MA-DMPM significantly suppressed tumor cell growth, which confirmed its immense potential and promising applications in tumor therapy.

An FOF1-ATPase motor-embedded chromatophore as a nanorobot for overcoming biological barriers and targeting acidic tumor sites

Despite the booming progress of anticancer nanomedicines in the past two decades, precise tumor-targetability and sufficient tumor-accumulation are less successful and still require further research. To tackle this challenge, herein we present a biomolecular motor (FOF1-ATPase)-embedded chromatophore as nanorobot to efficiently overcome biological barriers, and thoroughly investigate its chemotactic motility, tumor-accumulation ability and endocytosis. Chromatophores embedded with FOF1-ATPase motors were firstly extracted from Thermus thermophilus, then their properties were fully characterized. Specifically, two microfluidic platforms (laminar flow microchip and tumor microenvironment (TME) microchip) were designed and developed to fully investigate the motility, tumor-accumulation ability and endocytosis of the chromatophore nanorobot (CN). The results from the laminar flow microchip indicated that the obtained CN possessed the strongly positive chemotaxis towards protons. And the TME microchip experiments verified that the CN had a desirable tumor-accumulation ability. Cellular uptake experiments demonstrated that the CN efficiently promoted the endocytosis of the fluorescence DiO into the HT-29 cells. And the in vivo studies revealed that the intravenously administered CN exhibited vigorous tumor-targetability and accumulation ability as well as highly efficient antitumor efficacy. All the results suggested that FOF1-ATPase motors-embedded CN could be promising nanomachines with powerful self-propulsion for overcoming physiological barriers and tumor-targeted drug delivery. Statement of significanceIn this study, we demonstrated that FOF1-ATPase-embedded chromatophore nanorobots exhibit a strong proton chemotaxis, which not only plays a key role in tumor-targetability and accumulation, but also promotes tumor tissue penetration and internalization. The results of in vitro and in vivo studies indicated that drug-loaded chromatophore nanorobots are capable to simultaneously accomplish tumor-targeting, accumulation, penetration and internalization for enhanced tumor therapy. Our study provides a fundamental basis for further study on FOF1-ATPase-embedded chromatophore as tumor-targeting drug delivery systems that have promising clinical applications. It offers a new and more efficient delivery vehicle for cancer related therapeutics.

Precise nano-system-based drug delivery and synergistic therapy against androgen receptor-positive triple-negative breast cancer

Targeting androgen receptor (AR) has shown great therapeutic potential in triple-negative breast cancer (TNBC), yet its efficacy remains unsatisfactory. Here, we aimed to identify promising targeted agents that synergize with enzalutamide, a second-generation AR inhibitor, in TNBC. By using a strategy for screening drug combinations based on the Sensitivity Index (SI), we found that MK-8776, a selective checkpoint kinase1 (CHK1) inhibitor, showed favorable synergism with enzalutamide in AR-positive TNBC. The combination of enzalutamide and MK-8776 was found to exert more significant anti-tumor effects in TNBC than the single application of enzalutamide or MK-8776, respectively. Furthermore, a nanoparticle-based on hyaluronic acid (HA)-modified hollow-manganese dioxide (HMnO2), named HMnE&M@H, was established to encapsulate and deliver enzalutamide and MK-8776. This HA-modified nanosystem managed targeted activation via pH/glutathione responsiveness. HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier. Collectively, our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H, providing a potential therapeutic approach for the treatment of TNBC.

Fabrication of hyaluronic acid-altered gold complex delivery for head and neck squamous cell carcinoma therapy with high antitumor efficacy and low in vivo toxicity

The use of multifunctional nanomedicines in the treatment of tumors is gaining popularity. Here, we constructed a nanodrug delivery system (HA/Au-PDA@CZT) that targets tumors and responds to pH and near-infrared (NIR) dual stimuli. By precisely interacting with an overexpressed CD44 receptor in specific cancer cells, hyaluronic acid (HA) is coated on the Au-PDA NP surface for tumor-targeting abilities. When exposed to NIR radiation, polydopamine (PDA) and gold nanoshells exhibit exceptional photothermal performance that has the potential to both accelerate and kill HLAC 78 head and neck squamous cell carcinoma cells. Antitumor investigations conducted in vivo and in vitro demonstrated that nanomedicine had remarkable synergistic benefits with chemotherapy and photothermal treatment. Only 25.2% of the cells in the HA/Au-PDA@CZT with a NIR irradiation group were viable. Any group's lowest tumor volume was shown in the tumor mice subjected to HA/Au-PDA@CZT with NIR at 0.3 ± 0.1. Consequently, for synergistic chemo-photothermal therapy, our logically designed nanoplatform would be the potential for a head and neck squamous tumor-targeting drug delivery system.

The role of polyethylenimine-functionalized gold nanoclusters carrying plasmid CMTM5 in impeding the malignant progression of prostate cancer cells by promoting EGFR endocytosis.

In this research, polyethylenimine-functionalized gold nanoclusters (PEI-AuNCs) were synthesized for the delivery of plasmid CMTM5 (pCMTM5) to prostate cancer (PCa) cells, with the objective of elucidating the mechanism underlying its anticancer efficacy. The PEI-AuNCs loaded with pCMTM5 (PEI-AuNCs@pCMTM5) tumor-targeting drug delivery system was established. Subsequently, both the obtained PEI-AuNCs and PEI-AuNCs@pCMTM5 underwent characterization through a transmission electron microscope (TEM) and dynamic light scattering (DLS). Employing RT-qPCR, western blot, flow cytometry, immunofluorescence, and co-immunoprecipitation (co-IP) assays, the consequences of CMTM5 overexpression on the expression of EGFR were investigated. Moreover, the influence of PEI-AuNCs@pCMTM5 on PC-3 cells was assessed through CCK-8, wound healing assay, and Transwell experiments. As a result, the PEI-AuNCs and PEI-AuNCs@pCMTM5 were presented as uniformly dispersed spherical with stable particle sizes and positive charges, showcasing favorable dispersion within the solution. In comparison to Lip2000, the PEI-AuNCs demonstrated superior transfection efficiency and lower cellular toxicity. Following the overexpression of CMTM5, the proliferative capacity of PC-3 cells was markedly suppressed, while both migratory and invasive abilities exhibited noteworthy reduction, with the efficacy of PEI-AuNCs@pCMTM5 consistently outperforming that of free pCMTM5. Subsequent mechanistic investigations unveiled that CMTM5 does not directly inhibit the synthesis of EGFR or facilitate its degradation, but rather influences the endocytic process of EGFR. In conclusion, the PEI-AuNCs nano-delivery system exhibits good biocompatibility and efficaciously conveys pCMTM5 to PCa cells. Crucially, pCMTM5 does not directly interact with EGFR, and CMTM5 governs the malignant progression of PC3 cells by promoting EGFR endocytosis.

Antibody-decorated chitosan-iodoacetamide-coated nanocarriers for the potential delivery of doxorubicin to breast cancer cells

Using an active targeting approach of chemotherapeutics-loaded nanocarriers (NCs) with monoclonal antibodies is a potential strategy to improve the specificity of the delivery systems and reduce adverse reactions of chemotherapeutic drugs. Specific targeting of the human epidermal growth factor receptor-2 (HER-2), expressed excessively in HER-2-positive breast cancer cells, can be achieved by conjugating NCs with an anti–HER-2 monoclonal antibody. We constructed trastuzumab-conjugated chitosan iodoacetamide-coated NCs containing doxorubicin (Tras-Dox-CHI-IA-NCs) as a tumor-targeted drug delivery system, during the study. Chitosan-iodoacetamide (CHI-IA) was synthesized and utilized to prepare trastuzumab-conjugated NCs (Tras-NCs). The morphology, physicochemical properties, drug loading, drug release, and biological activities of the NCs were elucidated. The Tras-NCs were spherical, with a particle size of approximately 76 nm, and had a positive zeta potential; after incorporating the drug, the size of the Tras-NC increased. A prolonged, 24-h drug release from the NCs was achieved. The Tras-NCs exhibited high cellular accumulation and significantly higher antitumor activity against HER-2-positive breast cancer cells than the unconjugated NCs and the drug solution. Therefore, Tras-Dox-CHI-IA-NCs could be a promising nanocarrier for HER-2-positive breast cancer.

Abstract A032: Cell membrane coated- Biomimetic biodegradable nanoparticles for tumor targeted delivery of THP-doxorubicin using polylactic acid based redox responsive polymer

Abstract Chemotherapy is a widely used systemic treatment modality for cancer treatment as it kills the rapidly dividing cells. However, the administered chemo-drugs cause systemic toxicity, have fast degradation rate at physiological conditions hence low bioavailability and poor tumor accumulation. These shortcomings can be mitigated by the use of tumor targeting drug delivery systems. The nanoparticles can further be tailor made according to physiological conditions of the tumor microenvironment. Herein, the redox responsive polymer has been synthesized by introducing the disulphide linkage in the polymer. The drug release profile indicated the release of the drug is more efficient in presence of 10mM Dithiothreitol(reducing agent for disulphide linkage) when compared to 0mM dithiothreitol. In this context, this study investigates the therapeutic efficacy of THP-doxorubicin encapsulated in polylactic acid based redox responsive nanoparticle(NP) whose surface have been modified with tumor (4T1) and macrophage (J774) cell membranes. The coated cell membrane provides advantages such as immune escape, long blood circulation time, specific molecular recognition and cell targeting. The prepared nanoparticles have a hydrodynamic size of 210±10 nm with zeta potential of -30±3 mV. The cellular internalization studies of free drug vs the cell membrane coated NPs (CMNPs) were done and it was confirmed that CMNPs were internalized more efficiently in one hour drug incubation study. The same was confirmed when cancer cell proliferation inhibition assay was done, and half maximal inhibitory concentration of free drug, uncoated NPs and CMNPs were 0.31µM , 0.463µM and 0.137µM respectively. This study provides the synthesis and characterization of redox responsive polymer, preparation of cell membrane coated nanoparticles and in-vitro studies for the same. This study has a future scope in the field of personalized medicine at much cheaper price when compared to active targeting methods by antibodies, CART, proteins etc. Citation Format: Harshdeep Kaur, Harpal Singh, Neetu Singh. Cell membrane coated- Biomimetic biodegradable nanoparticles for tumor targeted delivery of THP-doxorubicin using polylactic acid based redox responsive polymer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A032.

PEG-modified carbon-based nanoparticles as tumor-targeted drug delivery system reducing doxorubicin-induced cardiotoxicity

Herein, a doxorubicin-loaded carbon-based drug delivery system, denoted as PC-DOX, composed of pH-responsive imine bond was developed for the tumor-targeted treatment. PC-DOX with a uniform particle size around 180 nm was synthesized by coating of as-synthesized hollow carbon-based nanoparticles (NPs) with dialdehyde PEG, which was used as carrier to attach DOX covalently through dynamic covalent bond. The unique structure endowed the advantages of specific tumor targeting and tumor microenvironment (TME) specific drug delivery capacity with PC-DOX. For the one hand, the tumor targeting caused by the enhanced permeability and retention (EPR) effect could significantly improve the tumor cellular uptake. For the other hand, the pH-responsiveness could realize the effective DOX accumulation in tumor tissues, avoiding the unwanted side effect to the normal tissues. As a result, PC-DOX with high DOX loading capacity (70.12%) and excellent biocompatibility, concurrently, presented a significant anti-tumor effect at a low mass concentration (DOX equivalent dose: 20 μg/mL). Another attractive characteristic of PC-DOX was the remarkable protective effect towards DOX-induced cardiotoxicity, which could be clearly observed from in vitro cellular, and animal assays. Compared with free DOX, the cardiomyocyte viability increased by average 30.58%, and the heart function was also significantly improved. This novel drug delivery nanoplatform provides a new method for the future clinical application of DOX in the cancer’s therapeutics.

Targeted drug delivery approaches for the management of tumors

The treatment of tumors requires specific and selective drug delivery approaches capable of efficiently eliminating the root cause of oncogenesis. In this context, targeted drug delivery strategies are the preferred choice due to their exceptional recognition of tumor cell biology and their high transfection efficacy within the tumor microenvironment. The emergence of nanoscale techniques has marked significant milestones in the successful management of various types of tumors. The development of targeted delivery approaches for tumor therapeutics has gained momentum over the past few decades. However, in contrast to the plethora of successful pre-clinical studies, only a limited number of passively targeted nanocarriers have been approved for clinical use, and none of the actively targeted nanocarriers have advanced beyond clinical trials. This review delves into the major molecular principles associated with tumorigenesis, including active targeting, passive targeting, and cell-mediated targeting. It also explores the biological barriers (systemic, biological, and cellular) encountered in tumor drug delivery. Moreover, the review examines various tumor-targeted drug delivery systems that have been developed over the past decade. These systems encompass polymeric nanoparticles (micelles, nanoparticles, dendrimers, and polyplexes), lipid-based carriers (solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsion), vesicular systems (liposomes, niosomes, aquasomes, and phytosomes), and inorganic nanocarriers (iron oxide nanoparticles, quantum dots, carbon-based nanoparticles, and mesoporous silica nanoparticles), all designed for the alleviation of tumors.

Evaluation of the efficiency of intersystem crossing to a triplet state of fullerene in complexes with amino acids

The important photophysical process that determines the efficiency of photosensitizers is saturation of a triplet state by intersystem crossing during light absorption. In the present work, C60 fullerene complexes with amino acids glycine, lysine, methionine and threonine were studied as promising photosensitizers. All these complexes, for which the calculations were done, demonstrate high values of rate constants of transition to triplet states and a high probability of the ability to generate reactive oxygen species through excitation in the visible spectrum. The carboxyl groups of amino acids that are not involved in electronic excitation can be used as the component of specific DNA aptamers for conjugation to photoactive complexes for a tumor-targeting drug delivery system.

Cell-nanocarrier drug delivery system: a promising strategy for cancer therapy.

Tumor targeting has been a great challenge for drug delivery systems. A number of nanotechnology-derived drug carriers have been developed for cancer treatment to improve efficacy and biocompatibility. Among them, the emergence of cell-nanocarriers has attracted great attention, which simulates cell function and has good biocompatibility. They can also escape the clearance of reticuloendothelial system, showing a long-cycle effect. The inherent tumor migration and tumor homing ability of cells increase their significance as tumor-targeting vectors. In this review, we focus on the combination of stem cells, immune cells, red blood cells, and cell membranes to nanocarriers, which enable chemotherapy agents to efficiently target lesion sites and improve drug distribution while being low toxic and safe. In addition, we discuss the pros and cons of these nanoparticles as well as the challenges and opportunities that lie ahead. Although research to address these limitations is still ongoing, this promising tumor-targeted drug delivery system will provide a safe and effective platform against cancer.

Co-Delivery of Hesperetin and Cisplatin via Hyaluronic Acid-Modified Liposome for Targeted Inhibition of Aggression and Metastasis of Triple-Negative Breast Cancer.

Having no specific therapy for triple-negative breast cancer (TNBC), this subtype has the lowest survival rate and highest metastatic risk of breast cancer since the tumor inflammatory microenvironment mainly accounts for heterogeneity-induced insensitivity to chemotherapy and epithelial-mesenchymal transition (EMT). This study reports hyaluronic acid (HA)-modified liposomes loaded with cisplatin (CDDP) and hesperetin (Hes) (CDDP-HA-Lip/Hes) for active targeting to relieve systematic toxicity and effective anti-tumor/anti-metastasis ability of TNBC. Our results revealed that HA modification promoted the cellular uptake of the synthesized CDDP-HA-Lip/Hes nanoparticles in MDA-MB-231 cells and accumulation in tumor sites in vivo, indicating deeper tumor penetration. Importantly, CDDP-HA-Lip/Hes inhibited the PI3K/Akt/mTOR pathway to alleviate the inflammation in the tumor and with a crosstalk to suppress the process of the EMT, increasing the chemosensitivity and inhibiting tumor metastasis. Meanwhile, CDDP-HA-Lip/Hes could significantly inhibit the aggression and metastasis of TNBC with less side effects on normal tissues. Overall, this study provides a tumor-targeting drug delivery system with great potential for treating TNBC and its lung metastasis robustly.

Combination losartan with hyaluronic acid modified diethyldithiocarbamate loaded hollow copper sulfide nanoparticles for the treatment of breast cancer and metastasis

The application of photothermal therapy (PTT) is greatly limited by the low accumulation of photothermal agents, uneven photothermal distribution, and heat endurance of cancer cells. Worse still, despite PTT enhances immunogenicity, the anti-tumor immune efficacy is still unsatisfactory due to the inefficient immunogenic cell death (ICD) induction and poor infiltration of immune cells. To solve the above problems of PTT, we developed hyaluronic acid (HA) modified hollow copper sulfide nanoparticles encapsulating diethyldithiocarbamate (DDTC) to construct a breast tumor targeting and near infrared (NIR) photo-responsive drug delivery system (D-HCuS@HA), which further combined with losartan to improve the accumulation and penetration in the tumor site. Upon irradiation, D-HCuS@HA realized enhanced PTT and released cytotoxic Cu(DDTC)2 to eliminate heat endurance tumor cells, thereby enhancing anti-tumor effect and inducing effective ICD. Moreover, the combination with losartan could remodel the tumor microenvironment, allowing more T cells to infiltrate into the tumor, and significantly inhibiting the occurrence and development of metastatic tumors. In vitro/vivo results revealed the great potential of D-HCuS@HA combined with losartan, which provides a new paradigm for anti-tumor and anti-metastases.

Hyaluronic Acid-Based Nanocarriers for Anticancer Drug Delivery.

Hyaluronic acid (HA), a main component of the extracellular matrix, is widely utilized to deliver anticancer drugs due to its biocompatibility, biodegradability, non-toxicity, non-immunogenicity and numerous modification sites, such as carboxyl and hydroxyl groups. Moreover, HA serves as a natural ligand for tumor-targeted drug delivery systems, as it contains the endocytic HA receptor, CD44, which is overexpressed in many cancer cells. Therefore, HA-based nanocarriers have been developed to improve drug delivery efficiency and distinguish between healthy and cancerous tissues, resulting in reduced residual toxicity and off-target accumulation. This article comprehensively reviews the fabrication of anticancer drug nanocarriers based on HA in the context of prodrugs, organic carrier materials (micelles, liposomes, nanoparticles, microbubbles and hydrogels) and inorganic composite nanocarriers (gold nanoparticles, quantum dots, carbon nanotubes and silicon dioxide). Additionally, the progress achieved in the design and optimization of these nanocarriers and their effects on cancer therapy are discussed. Finally, the review provides a summary of the perspectives, the lessons learned so far and the outlook towards further developments in this field.

Targeted glioblastoma therapy by integrating brain-targeting peptides and corn-derived cancer cell-penetrating proteins into nanoparticles to cross blood-brain tumor barriers

Targeted brain tumor therapy by nanoparticles (NPs) remains a daunting challenge due to the difficulty for NPs to go through the blood-brain barriers (BBB) and blood-brain tumor barriers (BBTB). In addition, Dactolisib (Dac) is an effective dual PI3K/mTOR inhibitor for cancer treatment. It was the first PI3K inhibitor to enter clinical trials but exhibited toxicity to normal tissues if not delivered to tumor sites by a tumor-targeting carrier. To explore Dac for glioblastoma (GBM) therapy while avoiding its toxicity, we developed a new brain tumor-targeting drug delivery system self-assembled from zein, a cell membrane-penetrating amphiphilic protein originally present in corn. Specifically, the amphiphilicity of zein drove it to self-assemble into NPs that encapsulated Dac with high efficiency. RVG29, a 29-mer brain-targeting peptide, was chemically conjugated to zein constituting the NPs, forming Dac-encapsulated NPs (zein-RVG-Dac_NPs). In vitro assays were conducted to verify the capability of the NPs in penetrating BBB/BBTB, targeting GBM cancer cells and killing them. ELISA was employed to assess the expression of nicotinic acetylcholine receptors (nAChR) on the cancer cells to understand the mechanism of cancer cell membrane penetration by the NPs. The NPs were intravenously injected into orthotopic GBM mice models to demonstrate the brain tumor targeting as well as the effective GBM therapy due to the targeted delivery of Dac to brain tumors. The treated tumors were immunohistochemically analyzed to verify the tumor destruction. To confirm the biosafety of the NPs in treating GBM, we also histopathologically evaluated the major normal organs and chemically analyzed the blood biomarkers. We found that a combination of zein and RVG29 facilitated the zein-RVG-Dac_NPs to cross the BBB/BBTB and became uptaken by the GBM cells through the nAChR-mediated pathways, enabling the NPs to cross BBB/BBTB and deliver Dac selectively to GBM cells. Hence, administration of the NPs through tail veins significantly increased the accumulation of Dac in the orthotopic brain tumor of mice and effectively inhibited tumor growth. Neither toxicity nor adverse effects in the major organs were found due to the excellent biocompatibility of zein and the targeted delivery of Dac into brain tumor cells. Hence, integrating a cell-penetrating natural protein (zein) and a brain-targeting peptide (RVG29) can form NPs that can effectively penetrate BBB/BBTB and then enter brain tumor cells to release Dac, leading to highly effective targeted brain cancer therapy. Such NPs can be extended to the development of therapeutics for treating different brain diseases due to their unique combination of biocompatibility and brain-targeting capability.

Systemic Tumor Suppression via Macrophage-Driven Automated Homing of Metal-Phenolic-Gated Nanosponges for Metastatic Melanoma.

Cell-based therapies comprising the administration of living cells to patients for direct therapeutic activities have experienced remarkable success in the clinic, of which macrophages hold great potential for targeted drug delivery due to their inherent chemotactic mobility and homing ability to tumors with high efficiency. However, such targeted delivery of drugs through cellular systems remains a significant challenge due to the complexity of balancing high drug-loading with high accumulations in solid tumors. Herein, a tumor-targeting cellular drug delivery system (MAGN) by surface engineering of tumor-homing macrophages (Mφs) with biologically responsive nanosponges is reported. The pores of the nanosponges are blocked with iron-tannic acid complexes that serve as gatekeepers by holding encapsulated drugs until reaching the acidic tumor microenvironment. Molecular dynamics simulations and interfacial force studies are performed to provide mechanistic insights into the "ON-OFF" gating effect of the polyphenol-based supramolecular gatekeepers on the nanosponge channels. The cellular chemotaxis of the Mφ carriers enabled efficient tumor-targeted delivery of drugs and systemic suppression of tumor burden and lung metastases in vivo. The findings suggest that the MAGN platform offers a versatile strategy to efficiently load therapeutic drugs to treat advanced metastatic cancers with a high loading capacity of various therapeutic drugs.

Synthesis and Biopharmaceutical Evaluation of Nanoparticles Containing Resveratrol, an Anti-cancer Drug

The chemotherapy of cancer disease become increasingly important in recent years because ease of operation. The traditional cancer chemotherapy is based on the promise that tumor cells are more likely to be killed by anticancer drugs because of the faster proliferation of those cancer cells. However, in reality most of the drugs cannot differentiate cancer cells from the normal cells. This result the undesirable effect of the drug because of the lack of selectivity i.e the patients always at risk of cytotoxicity. So the development of tumor targeted drug delivery systems in which they recognize the intrinsic difference between normal cells and tumor cells is an important requirement for effective tumor therapy. These carriers include nanoparticles, nanotubes, Nano rods, centromeres, micelles, solid lipid nanoparticles, microspheres. In this experiment, all the materials used in the experiments were of analytical grade. Synthesis of CDI-activated poloxamer-407, NH2 terminated poloxamer-407,Folate conjugated poloxamer-407 and prototype formulation of Liquid crystalline nanoparticle were prepared. Drug loading was done with the optimized formula. In vitro drug release from the nanoparticles was determined in phosphate buffer pH 7.4 and Zero-order model, first order model, Higuchi’s model, kosmeyer-Peppas model also tried for compatibility. The cytotoxicity studies in the final formula by Brine shrimp experiments were done and found that it is significant. There are only 0.01% differences in each case. It was found that in-vitro drug release of resveratrol from optimized LCN at pH 7.4 and pH5 was best explained by Higuchi’s equation, as the plot showed the highest linearity with a regression coefficient of 0.9528 and 0.9404 respectively. The entrapment efficiency of optimized LCN was found to be 87.43 ± 0.52 % which was in close agreement with the value predicted by design expert software. It was found that the invitro drug release of resveratrol from optimized LCN at pH 7.4 and pH 5 was best explained by Higuchi’s equation, as the plot showed the highest linearity with a regression coefficient of 0.9528 and 0.9404 respectively.

Sustained and Targeted Delivery of Self-Assembled Doxorubicin Nonapeptides Using pH-Responsive Hydrogels for Osteosarcoma Chemotherapy

While chemotherapeutic agents have particularly potent effects in many types of cancer, their clinical applications are still far from satisfactory due to off-target drug exposure, chemotherapy resistance, and adverse effects, especially in osteosarcoma. Therefore, it is clinically promising to construct a novel tumor-targeted drug delivery system to control drug release and alleviate side effects. In this study, a pH-responsive nonapeptide hydrogel was designed and fabricated for the tumor-targeted drug delivery of doxorubicin (DOX). Using a solid-phase synthesis method, a nonapeptide named P1 peptide that is structurally akin to surfactant-like peptides (SLPs) due to its hydrophobic tail and hydrophilic head was synthesized. The physicochemical properties of the P1 hydrogel were characterized via encapsulation capacity, transmission electron microscopy (TEM), circular dichroism (CD), zeta potential, rheological analysis, and drug release studies. We also used in vitro and in vivo experiments to investigate the cytocompatibility and tumor inhibitory efficacy of the drug-loaded peptide hydrogel. The P1 peptide could self-assemble into biodegradable hydrogels under neutral conditions, and the prepared drug-loaded hydrogels exhibited good injectability and biocompatibility. The in vitro drug release studies showed that DOX-P1 hydrogels had high sensitivity to acidic conditions (pH 5.8 versus 7.4, up to 3.6-fold). Furthermore, the in vivo experiments demonstrated that the DOX-P1 hydrogel could not only amplify the therapeutic effect but also increase DOX accumulation at the tumor site. Our study proposes a promising approach to designing a pH-responsive hydrogel with controlled doxorubicin-release action based on self-assembled nonapeptides for targeted chemotherapy.

Multifunctional Graphene Oxide Nanodelivery Platform for Breast Cancer Treatment.

Breastcancer(BC) has the highest global prevalence among all malignancies in women and the second highest prevalence in the overall population. Paclitaxel(PTX),atricyclicditerpenoid, is effective against BC. However, its poor solubility in water and the allergenicity of its dissolution medium limited itsclinicalapplication. In this work, we established a multifunctional graphene oxide (GO) tumor-targeting drug delivery system using nanosized grapheneoxide(nGO) modified with D-tocopherol polyethylene glycol succinate (TPGS) and arginine-glycine-asparticacid(RGD) for PTX loading. The obtained RGD-TPGS-nGO-PTX was 310.20±19.86 nm in size; the polydispersity index (PDI) and zeta potential were 0.21±0.020 and -23.42 mV, respectively. Themeandrugloading capacityof RGD-TPGS-nGO-PTX was 48.78%. RGD-TPGS-nGO-PTX showed satisfactory biocompatibility and biosafety and had no significant toxic effects on zebrafish embryos. Importantly, it exerted excellent cytotoxicity against MDA-MB-231 cells, reversed multi-drug resistance (MDR) in MCF-7/ADR cells, and showed significant anti-tumor efficacy in tumor-bearing nude mice. These findings strongly suggested that the multifunctional GO tumor-targeting drug delivery system RGD-TPGS-nGO-PTX could be used in clinical settings to improve PTX delivery, reverse MDR and increase the therapeutic efficacy of BC treatment.

A Novel Dextran-Based Dual Drug Conjugate Targeted Tumors with High Biodistribution Ratio of Tumors to Normal Tissues.

PurposeMost chemotherapeutic agents possess poor water solubility and show more significant accumulations in normal tissues than in tumor tissues, resulting in serious side effects. To this end, a novel dextran-based dual drug delivery system with high biodistribution ratio of tumors to normal tissues was developed.MethodsA bi-functionalized dextran was developed, and several negatively charged dextran-based dual conjugates containing two different types of drugs, docetaxel and docosahexaenoic acid (DTX and DHA, respectively) were synthesized. The structures of these conjugates were characterized using nuclear magnetic resonance and liquid chromatography/mass spectrometry (1H-NMR and LC/MS, respectively) analysis. Cell growth inhibition, apoptosis, cell cycle distribution, and cellular uptake were measured in vitro. Drug biodistribution and pharmacokinetics were investigated in mice bearing 4T1 tumors using LC/MS analysis. Drug biodistribution was also explored by in vivo imaging. The effects of these conjugates on tumor growth were evaluated in three mice models.ResultsThe dextran–docosahexaenoic acid (DHA)– docetaxel (DTX) conjugates caused a significant enhancement of DTX water solubility and improvement in pharmacokinetic characteristics. The optimized dextran–DHA–DTX conjugate A treatment produced a 2.1- to 15.5-fold increase in intra-tumoral DTX amounts for up to 96 h compared to parent DTX treatment. Meanwhile, the concentrations of DTX released from conjugate A in normal tissues were much lower than those of the parent DTX. This study demonstrated that DHA could lead to an improvement in the efficacy of the conjugates and that the conjugate with the shortest linker displayed more activity than conjugates with longer linkers. Moreover, conjugate A completely eradicated all MCF-7 xenograft tumors without causing any obvious side effects and totally outperformed both the conventional DTX formulation and Abraxane in mice.ConclusionThese dextran-based dual drug conjugates may represent an innovative tumor targeting drug delivery system that can selectively deliver anticancer agents to tumors.