Polymer--cisplatin conjugate nanoparticles for acid-responsive drug delivery.
ABSTRACT: We report the synthesis of novel acid-responsive therapeutic nanoparticles (NPs) with sub-100 nm size consisting of polymer--cisplatin conjugates. The uniqueness of these drug delivery polymeric NPs lies in the covalent conjugation of each cisplatin drug to the hydrophobic segment of two biocompatible diblock copolymer chains through a hydrazone bond, resulting in highly differential drug release profile at different environmental acidity. We demonstrate that the synthesized polymer--cisplatin conjugates can readily precipitate to form sub-100 nm NPs in aqueous solution due to their very low critical micelle concentration (CMC). The resulting NPs show well-controlled cisplatin loading yield, excellent acid-responsive drug release kinetics, and enhanced in vitro cytotoxicity against ovarian cancer cells as compared to free cisplatin. As an environmentally sensitive drug delivery vehicle, these NPs can potentially minimize the drug loss during NP circulation in the blood, where the pH value is neutral, and trigger rapid intracellular drug release after the NPs are endocytosed by the target cells. This characteristic drug release profile holds the promise to suppress cancer cell chemoresistance by rapidly releasing a high dose of chemotherapy drugs inside the tumor cells, thereby improving the therapeutic efficacy of the drug payload.
Project description:Stimuli-responsive nanoparticles (NPs) are especially interesting to enhance the drug delivery specificity for biomedical applications. With the aim to achieve a highly stable and inflammation-specific drug release, we designed a reactive oxygen species (ROS)-responsive dextran-drug conjugate (Nap-Dex). By blending Nap-Dex with the acid-sensitive acetalated dextran polymer, we achieved a dual-responsive NP with high specificity toward the inflammatory environment. The inflammatory environment not only has elevated ROS levels but also has a lower pH than healthy tissues, making pH and ROS highly suitable triggers to target inflammatory diseases. The anti-inflammatory cyclooxygenase inhibitor naproxen was modified with an ROS-responsive phenylboronic acid (PBA) and conjugated onto dextran. The dextran units were functionalized with up to 87% modified naproxen. This resulted in a complete drug release from the polymer within 20 min at 10 mM H2O2. The dual-responsive NPs reduced the levels of the proinflammatory cytokine IL-6 120 times more efficiently and TNF? 6 times more efficiently than free naproxen from lipopolysaccharide (LPS)-activated macrophages. These additional anti-inflammatory effects were found to be mainly attributed to ROS-scavenging effects. In addition, the model cargo fluorescein diacetate was released in an LPS-induced inflammatory response in vitro. We believe that drug conjugation using PBA can be applied to various drugs and dextran-based materials for enhanced drug efficacy, where this work demonstrates the significance of functionalized carbohydrates polymer-drug conjugates.
Project description:The use of a nanoparticle (NP)-based antitumor drug carrier has been an emerging strategy for selectively delivering the drugs to the tumor area and, thus, reducing the side effects that are associated with a high systemic dose of antitumor drugs. Precise control of drug loading and release is critical so as to maximize the therapeutic index of the NPs. Here, we propose a simple method of synthesizing NPs with tunable drug release while maintaining their loading ability, by varying the polymer matrix density of amine- or carboxyl-functionalized hydrogel NPs. We find that the NPs with a loose matrix released more cisplatin, with up to a 33 times faster rate. Also, carboxyl-functionalized NPs loaded more cisplatin and released it at a faster rate than amine-functionalized NPs. We performed detailed Monte Carlo computer simulations that elucidate the relation between the matrix density and drug release kinetics. We found good agreement between the simulation model and the experimental results for drug release as a function of time. Also, we compared the cellular uptake between amine-functionalized NPs and carboxyl-functionalized NPs, as a higher cellular uptake of NPs leads to improved cisplatin delivery. The amine-functionalized NPs can deliver 3.5 times more cisplatin into cells than the carboxyl-functionalized NPs. The cytotoxic efficacy of both the amine-functionalized NPs and the carboxyl-functionalized NPs showed a strong correlation with the cisplatin release profile, and the latter showed a strong correlation with the NP matrix density.
Project description:The synthesis of polymer therapeutics capable of controlled loading and synchronized release of multiple therapeutic agents remains a formidable challenge in drug delivery and synthetic polymer chemistry. Herein, we report the synthesis of polymer nanoparticles (NPs) that carry precise molar ratios of doxorubicin, camptothecin, and cisplatin. To our knowledge, this work provides the first example of orthogonally triggered release of three drugs from single NPs. The highly convergent synthetic approach opens the door to new NP-based combination therapies for cancer.
Project description:Podophyllotoxin (PPT) exhibited significant activity against P-glycoprotein mediated multidrug resistant (MDR) tumor cell lines; however, due to its poor solubility and high toxicity, PPT cannot be dosed systemically, preventing its clinical use for MDR cancer. We developed a nanoparticle dosage form of PPT by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose (CMC-Ac) using one-pot esterification chemistry. The polymer conjugates self-assembled into nanoparticles (NPs) of variable sizes (20-120 nm) depending on the PPT-to-PEG molar ratio (2-20). The conjugate with a low PPT/PEG molar ratio of 2 yielded NPs with a mean diameter of 20 nm and released PPT at ?5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30 nm and 120 nm respectively) that displayed slower drug release (?2.5%/day and ?1%/day respectively). The 20 nm particles exhibited 2- to 5-fold enhanced cell killing potency and 5- to 20-fold increased tumor delivery compared to the larger NPs. The biodistribution of the 20 nm PPT-NPs was highly selective to the tumor with 8-fold higher accumulation than all other examined tissues, while the larger PPT-NPs (30 and 120 nm) exhibited increased liver uptake. Within the tumor, >90% of the 20 nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20 nm PPT-NPs displayed significantly improved efficacy against MDR tumors in mice compared to the larger PPT-NPs, native PPT and the standard taxane chemotherapies, with minimal toxicity.
Project description:Novel breast carcinoma dual-targeted redox-responsive nanoparticles (NPs) based on cholesteryl-hyaluronic acid conjugates were designed for intracellular delivery of the antitumor drug doxorubicin (DOX). A series of reduction-responsive hyaluronic acid derivatives grafted with hydrophobic cholesteryl moiety (HA-ss-Chol) and GE11 peptide conjugated HA-ss-Chol (GE11-HA-ss-Chol) were synthesized. The obtained conjugates showed attractive self-assembly characteristics and high drug loading capacity. GE11-HA-ss-Chol NPs were highly stable under conditions mimicking normal physiological conditions, while showing a fast degradation of the vehicle's structure and accelerating the drug release dramatically in the presence of intracellular reductive environment. Furthermore, the cellular uptake assay confirmed GE11-HA-ss-Chol NPs were taken up by MDA-MB-231 cells through CD44- and epidermal growth factor receptor-mediated endocytosis. The internalization pathways of GE11-HA-ss-Chol NPs might involve clathrin-mediated endocytosis and macropinocytosis. The intracellular distribution of DOX in GE11-HA-ss-Chol NPs showed a faster release and more efficient nuclear delivery than the insensitive control. Enhanced in vitro cytotoxicity of GE11-HA-ss-Chol DOX-NPs further confirmed the superiority of their dual-targeting and redox-responsive capacity. Moreover, in vivo imaging investigation in MDA-MB-231 tumor-bearing mice confirmed that GE11-HA-ss-Chol NPs labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide, a near-infrared fluorescence dye, possessed a preferable tumor accumulation ability as compared to the single-targeting counterpart (HA-ss-Chol NPs). The antitumor efficacy showed an improved therapy efficacy and lower systemic side effect. These results suggest GE11-HA-ss-Chol NPs provide a good potential platform for antitumor drugs.
Project description:Conventional chemotherapy is the most common therapeutic method for treating cancer by the application of small toxic molecules thatinteract with DNA and causecell death. Unfortunately, these chemotherapeutic agents are non-selective and can damage both cancer and healthy tissues,producing diverse side effects, andthey can have a short circulation half-life and limited targeting. Many synthetic polymers have found application as nanocarriers of intelligent drug delivery systems (DDSs). Their unique physicochemical properties allow them to carry drugs with high efficiency,specificallytarget cancer tissue and control drug release. In recent years, considerable efforts have been made to design smart nanoplatforms, including amphiphilic block copolymers, polymer-drug conjugates and in particular pH- and redox-stimuli-responsive nanoparticles (NPs). This review is focused on a new generation of polymer-based DDSs with specific chemical functionalities that improve their hydrophilicity, drug loading and cellular interactions.Recentlydesigned multifunctional DDSs used in cancer therapy are highlighted in this review.
Project description:In this work, we prepared a stimuli-responsive system for drug delivery and controlled release by engineering the bovine serum albumin (BSA). The doxorubicin (DOX)-loaded BSA nanoparticles (NPs) were conveniently prepared using desolvation method, followed by crosslinking through Schiff base bonds, leading to pH-sensitive DOX-loaded system (DOXs@BSA NPs). The resulted DOXs@BSA NPs showed high drug loading capacity (21.4%), and the particle size was about 130?nm with narrow polydispersity and high negative surface charge (-20.5?mV). The pH-sensitivity of DOXs@BSA NPs was evidenced by the size changes and charge reversal after incubation at different pH values. The DOXs@BSA NPs showed high serum stability which indicated the prolonged circulation time. The in vitro drug release experiment showed that the release of DOX was obviously accelerated by acidity because of disassembly of NPs induced by cleavage of Schiff base bonds. The drug release mechanism was thoroughly studied using a semi-empirical model, further confirming the pH played an important role in drug controlled release process. The results of cytotoxicity assay revealed that DOXs@BSA NPs exhibited much higher toxic effects for tumor cells in comparison to the free DOX control. Collectively, these results demonstrated that DOXs@BSA NPs might be potential application for drug delivery and controlled release in cancer chemotherapy. Moreover, this work also showed that preparation of stimuli-responsive drug delivery system by engineering the commercial biomaterials could be a promising method to develop multi-functional nanomedicine.
Project description:Increasing the clinical efficacy of toxic chemotherapy drugs such as cisplatin (CDDP), via targeted drug delivery, is a key area of research in cancer treatment. In this study, CDDP-loaded poly(lactic-co-glycolic acid) (PLGA) polymeric nanoparticles (NPs) were successfully prepared using electrohydrodynamic atomization (EHDA). The configuration was varied to control the distribution of CDDP within the particles, and high encapsulation efficiency (>70%) of the drug was achieved. NPs were produced with either a core-shell (CS) or a matrix (uniform) structure. It was shown that CS NPs had the most sustained release of the 2 formulations, demonstrating a slower linear release post initial "burst" and longer duration. The role of particle architecture on the rate of drug release in vitro was confirmed by fitting the experimental data with various kinetic models. This indicated that the release process was a simple diffusion mechanism. The CS NPs were effectively internalized into the endolysosomal compartments of cancer cells and demonstrated an increased cytotoxic efficacy (concentration of a drug that gives half maximal response [EC<sub>50</sub>] reaching 6.2 µM) compared to free drug (EC<sub>50</sub> =9 µM) and uniform CDDP-distributed NPs (EC<sub>50</sub> =7.6 µM) in vitro. Thus, these experiments indicate that engineering the structure of PLGA NPs can be exploited to control both the dosage and the release characteristics for improved clinical chemotherapy treatment.
Project description:We report a new approach to cisplatin storage and release using porous hollow nanoparticles (PHNPs) of Fe(3)O(4). We prepared the PHNPs by controlled oxidation of Fe NPs at 250 degrees C followed by acid etching. The opening pores ( approximately 2-4 nm) facilitated the cisplatin diffusion into the cavity of the hollow structure. The porous shell was stable in neutral or basic physiological conditions, and cisplatin escape from the cavity through the same pores was a diffusion-controlled slow process with t(1/2) = 16 h. However, in low pH (<6) conditions, the pores were subject to acidic etching, resulting in wider pore gaps and faster release of cisplatin with t(1/2) < 4 h. Once coupled with Herceptin to the surface, the cisplatin-loaded hollow NPs could target to breast cancer SK-BR-3 cells with IC(50) reaching 2.9 muM, much lower than 6.8 muM needed for free cisplatin. Our model experiments indicate that the low pH-responsive PHNPs of Fe(3)O(4) can be exploited as a cisplatin delivery vehicle for target-specific therapeutic applications.
Project description:Nanoparticles (NPs) have emerged as a potential tool to improve cancer treatment. Among the proposed uses in imaging and therapy, their use as a drug delivery scaffold has been extensively highlighted. However, there are still some controversial points which need a deeper understanding before clinical application can occur. Here the use of gold nanoparticles (AuNPs) to detoxify the antitumoral agent cisplatin, linked to a nanoparticle via a pH-sensitive coordination bond for endosomal release, is presented. The NP conjugate design has important effects on pharmacokinetics, conjugate evolution and biodistribution and results in an absence of observed toxicity. Besides, AuNPs present unique opportunities as drug delivery scaffolds due to their size and surface tunability. Here we show that cisplatin-induced toxicity is clearly reduced without affecting the therapeutic benefits in mice models. The NPs not only act as carriers, but also protect the drug from deactivation by plasma proteins until conjugates are internalized in cells and cisplatin is released. Additionally, the possibility to track the drug (Pt) and vehicle (Au) separately as a function of organ and time enables a better understanding of how nanocarriers are processed by the organism.