Sustained Release Of Anticancer Drugs Research Articles

The Effect of Co-Delivery of Oxygen and Anticancer Drugs on the Viability of Healthy and Cancer Cells under Normoxic and Hypoxic Conditions.

Hypoxia, cancer, tissue damage, and acidic pH conditions are interrelated, as chronic hypoxic conditions enhance the malignant phenotype of cancer cells, causing more aggressive tissue destruction, and hypoxic cells rely on anaerobic glycolysis, leading to the accumulation of lactic acid. Therefore, the administration of oxygen is necessary to support the functions of healthy cells until the formation of new blood vessels and to increase the oxygen supply to cancerous tissues to improve the efficacy of antitumor drugs on tumor cells. In addition to O2 supply, pH-dependent delivery of anticancer drugs is desired to target cancer cells and reduce drug side effects on healthy cells. However, the simultaneous delivery of O2 and pH-dependent anticancer drugs via nanomaterials and their effects on the viability of normal and cancer cells under hypoxic conditions have not been studied in sufficient numbers. This study describes the synthesis of a pH-responsive nanomaterial containing oxygen and anticancer drugs that exhibits sustained O2 release over a 14 d period under hypoxic conditions and pH-dependent sustained release of anticancer drugs over 30 d. The simultaneous administration of O2 and anticancer drugs results in higher cell survival of normal cells than that of cancer cells under hypoxic and normoxic conditions.

Injectable hyaluronic acid–cyclodextrin-based hydrogels for localized and sustained release of anticancer drugs

Injectable hyaluronic acid–cyclodextrin-based hydrogels for localized and sustained release of anticancer drugs

Metal organic framework-based polymeric hydrogel: A promising drug delivery vehicle for the treatment of breast cancer

The constraints associated with current cancer therapies have inspired scientists to develop advanced, precise, and safe drug delivery methods. These delivery systems boost treatment effectiveness, minimize harm to healthy cells, and combat cancer recurrence. To design advanced drug delivery vehicle with these character, in the present manuscript, we have designed a self-healing and injectable hybrid hydrogel through synergistically interacting metal organic framework, CuBTC with the poly(vinyl alcohol) (PVA). This hybrid hydrogel acts as a localized drug delivery system and was used to encapsulate and release the anticancer drug 5-Fluorouracil selectively at the targeted site in response to the physiological pH. The hydrogel was formed through transforming the gaussian coil like matrix of PVA-CuBTC into a three-dimensional network of hydrogel upon the addition of crosslinker; borax. The biocompatible character of the hydrogel was confirmed through cell viability test. The biocompatible hybrid hydrogel then was used to encapsulate and studied for the pH responsive release behavior of the anti-cancer drug, 5-FU. The in vitro cytotoxicity of the drug-loaded hydrogel was evaluated against MCF-7 and HeLa cells. The study confirms that the hybrid hydrogel is effective for targeted and sustained release of anticancer drugs at cancer sites.

Osteosarcoma cell death induced by innovative scaffolds doped with chemotherapeutics.

Osteosarcoma (OS) cancer treatments include systemic chemotherapy and surgical resection. In the last years, novel treatment approaches have been proposed, which employ a drug-delivery system to prevent offside effects and improves treatment efficacy. Locally delivering anticancer compounds improves on high local concentrations with more efficient tumour-killing effect, reduced drugs resistance and confined systemic effects. Here, the synthesis of injectable strontium-doped calcium phosphate (SrCPC) scaffold was proposed as drug delivery system to combine bone tissue regeneration and anticancer treatment by controlled release of methotrexate (MTX) and doxorubicin (DOX), coded as SrCPC-MTX and SrCPC-DOX, respectively. The drug-loaded cements were tested in an in vitro model of human OS cell line SAOS-2, engineered OS cell line (SAOS-2-eGFP) and U2-OS. The ability of doped scaffolds to induce OS cell death and apoptosis was assessed analysing cell proliferation and Caspase-3/7 activities, respectively. To determine if OS cells grown on doped-scaffolds change their migratory ability and invasiveness, a wound-healing assay was performed. In addition, the osteogenic potential of SrCPC material was evaluated using human adipose derived-mesenchymal stem cells. Osteogenic markers such as (i) the mineral matrix deposition was analysed by alizarin red staining; (ii) the osteocalcin (OCN) protein expression was investigated by enzyme-linked immunosorbent assay test, and (iii) the osteogenic process was studied by real-time polymerase chain reaction array. The delivery system induced cell-killing cytotoxic effects and apoptosis in OS cell lines up to Day 7. SrCPC demonstrates a good cytocompatibility and it induced upregulation of osteogenic genes involved in the skeletal development pathway, together with OCN protein expression and mineral matrix deposition. The proposed approach, based on the local, sustained release of anticancer drugs from nanostructured biomimetic drug-loaded cements is promising for future therapies aiming to combine bone regeneration and anticancer local therapy.

Lauric acid-based thermosensitive delivery system for the treatment of head and neck squamous cell carcinoma

Traditional treatments for head and neck squamous cell carcinoma (HNSCC) such as surgery, radiation therapy, and chemotherapy, often have severe side effects. Local delivery of chemotherapeutic agents can be a promising approach to minimise systemic toxicity and improve efficacy. Lauric acid (LA), was explored as a novel injectable thermosensitive drug reservoir as a depot for sustained release of anticancer drugs to treat HNSCC. LA was characterised in terms of melting temperature and gelation time. The efficacy of LA-based drug formulations was tested in vitro in a HNSCC cell line and in vivo in a mouse model of HNSCC. LA was modified to have a melting point of 38.5 °C and a gelation time of 40 s at 37.5 °C, rendering it suitable for injection at body temperature. LA- based doxorubicin (DOXO) formulation showed slow release with a maximum of 18% release after 3 days. The in vitro study showed that LA enhanced the cytotoxic effect of DOXO. LA combined with DOXO prevented tumour progression and LA alone significantly reduced the original tumour volume compared to the untreated control group. These findings confirmed that LA can function as practical carrier for the local delivery of chemotherapeutics and provides a safe and simple strategy for the delivery of hydrophobic anticancer drugs and warrant further testing in clinical trials.

Electrosprayed Stearic-Acid-Coated Ethylcellulose Microparticles for an Improved Sustained Release of Anticancer Drug.

Sustained release is highly desired for "efficacious, safe and convenient" drug delivery, particularly for those anticancer drug molecules with toxicity. In this study, a modified coaxial electrospraying process was developed to coat a hydrophobic lipid, i.e., stearic acid (SA), on composites composed of the anticancer drug tamoxifen citrate (TC) and insoluble polymeric matrix ethylcellulose (EC). Compared with the electrosprayed TC-EC composite microparticles M1, the electrosprayed SA-coated hybrid microparticles M2 were able to provide an improved TC sustained-release profile. The 30% and 90% loaded drug sustained-release time periods were extended to 3.21 h and 19.43 h for M2, respectively, which were significantly longer than those provided by M1 (0.88 h and 9.98 h, respectively). The morphology, inner structure, physical state, and compatibility of the components of the particles M1 and M2 were disclosed through SEM, TEM, XRD, and FTIR. Based on the analyses, the drug sustained-release mechanism of multiple factors co-acting for microparticles M2 is suggested, which include the reasonable selections and organizations of lipid and polymeric excipient, the blank SA shell drug loading, the regularly round shape, and also the high density. The reported protocols pioneered a brand-new manner for developing sustained drug delivery hybrids through a combination of insoluble cellulose gels and lipid using modified coaxial electrospraying.

Carbon quantum dots derived from cassava stems via acid/alkali-assisted hydrothermal carbonization: formation, mechanism and application in drug release

Green and sustainable carbon quantum dots from lignocellulosic biomass (LB-CQDs) have been widely used in various fields. However, the recalcitrant nature of lignocellulose leads to the low yield of LB-CQDs. In this work, we proposed an effective strategy for obtaining high yield LB-CQDs from cassava stems through acid/alkali-assist hydrothermal carbonization. The results indicated that LB-CQDs processed by HNO3 +urea (N-U-CQDs) exhibited the best fluorescence characteristics due to their smaller size and higher N content. Compared with unmodified LB-CQDs, the yield and fluorescence efficiency of N-U-CQDs increased by 36% and 80%, respectively. Meanwhile, a speculation was made on the formation route and luminescence mechanism of LB-CQDs from acid/alkali-assist hydrothermal carbonization. In addition, biomass mineral materials CaCO3 was induced by LB-CQDs to prepare carrier materials CQDs/CaCO3 for the loading and sustained-release of anticancer drug (doxorubicin, DOX). The results suggested the retained specific recognition of DOX@CQDs/CaCO3 for diseased cells. Compared to the environment simulating normal tissue with pH= 7.4, DOX@CQDs/CaCO3 exhibited faster release efficiency (52.6%, 4 h) and higher release amount (93.1%, 48 h) of loaded DOX in the environment simulating cancer cells with pH= 5.0. Therefore, it offered a novel strategy for the efficient conversion of lignocellulose into CQDs and the application of LB-CQDs in drug release.

Injectable hydrogel imbibed with camptothecin-loaded mesoporous silica nanoparticles as an implantable sustained delivery depot for cancer therapy

In recent years, injectable stimuli-sensitive hydrogels are employed as suitable drug delivery carriers for the release of various anti-cancer drugs. However, large pore size of the microporous hydrogel trigger release of small molecular anticancer drug that limits hydrogel application in cancer therapy. Therefore, introducing reinforcing fillers such as mesoporous silica nanoparticles (MSNs) can not only load different type of anticancer drugs but also prevent the premature release of drugs due to the strengthening of the networks. Furthermore, high specific surface area, suitable size, large pore volume, and stable physicochemical properties of MSNs can improve the therapeutic efficacy. In this study, to sustain the release of hydrophobic anticancer drug, camptothecin (CPT) was loaded into MSNs, and then imbibed into the physiological stimuli-sensitive poly(ethylene glycol)-poly(β-aminoester urethane) (PAEU) hydrogels. MSN-imbibed PAEU hydrogels exhibited prolonged release of CPT than MSNs and PAEU hydrogel alone. Furthermore, MSN-imbibed PAEU copolymers form stable viscoelastic gel depot into the subcutaneous layers of Sprague-Dawley rats and found to be safe and not induced toxicity to healthy organs, implying biodegradability and safety of the hydrogels. Interestingly, CPT-loaded hydrogels shown dose-dependent toxicity to A549 and B16F10 cells. These results demonstrated that MSN-imbibed PAEU hydrogel with biocompatible, biodegradable, and in situ gel forming property could be a useful drug delivery depot for sustained release of anticancer drugs.

Folate Conjugated Polyethylene Glycol Probe for Tumor-Targeted Drug Delivery of 5-Fluorouracil.

A targeted delivery system is primarily intended to carry a potent anticancer drug to specific tumor sites within the bodily tissues. In the present study, a carrier system has been designed using folic acid (FA), bis-amine polyethylene glycol (PEG), and an anticancer drug, 5-fluorouracil (5-FU). FA and PEG were joined via an amide bond, and the resulting FA-PEG-NH2 was coupled to 5-FU producing folate-polyethylene glycol conjugated 5-fluorouracil (FA-PEG-5-FU). Spectroscopic techniques (UV-Vis, 1HNMR, FTIR, and HPLC) were used for the characterization of products. Prodrug (FA-PEG-5-FU) was analyzed for drug release profile (in vitro) up to 10 days and compared to a standard anticancer drug (5-FU). Folate conjugate was also analyzed to study its folate receptors (FR) mediated transport and in vitro cytotoxicity assays using HeLa cancer cells/Vero cells, respectively, and antitumor activity in tumor-bearing mice models. Folate conjugate showed steady drug release patterns and improved uptake in the HeLa cancer cells than Vero cells. Folate conjugate treated mice group showed smaller tumor volumes; specifically after the 15th day post-treatment, tumor sizes were decreased significantly compared to the standard drug group (5-FU). Molecular docking findings demonstrated importance of Trp138, Trp140, and Lys136 in the stabilization of flexible loop flanking the active site. The folic acid conjugated probe has shown the potential of targeted drug delivery and sustained release of anticancer drug to tumor lesions with intact antitumor efficacy.

One-Step In Situ Self-Assembly of Biodegradable Films for Long-Term Intravesical Bladder Cancer Therapy.

Intravesical instillation therapy is increasingly recognized as one of the most common clinical treatment strategies for bladder cancer. However, the antitumor efficacy of chemotherapy drugs is still limited due to their rapid clearance by periodic urination. To circumvent this issue, a drug-loaded thin film comprising the self-assembly of tannic acid (TA) and ferric ions (Fe3+) was in situ fabricated on the bladder wall in vivo. As expected, the TA@Fe film with adjustable thickness could effectively prolong the residence time of anticancer drugs in the bladder and realize sustained release of anticancer drugs. Together with the antibacterial properties, the TA@Fe film enabled improved chemotherapeutic efficacy. Moreover, the TA@Fe film caused no adverse effects on bladder function, demonstrating the in vivo biocompatibility. In addition, the T2 contrast effect of Fe3+ was employed to real-time monitor the disassembly of the TA@Fe film and the ensuing drug release process by magnetic resonance imaging. We believe that the TA@Fe-based drug delivery platform with enhanced retention in the bladder would be of great potential for treating various bladder diseases.

Development of “on-demand” thermo-responsive hydrogels for anti-cancer drugs sustained release: Rational design, in silico prediction and in vitro validation in colon cancer models

A rational design accurate based on the use of Statistical Design of the Experiments (DoE) and Molecular Dynamics Simulations Studies allows the prediction and the understanding of thermo-responsive hydrogels prepared regarding their gelation temperature and anti-cancer drug release rate. N-isopropylacrilamide (NIPAM) modified with specific co-monomers and crosslinkers, can be used to prepare “on-demand” thermo-responsive hydrogels with the ideal properties for clinical applications in which local sustained release of drugs is crucial. Two preferential formulations resulting from the predictive studies of DoE and In Silico methods were synthesized by radical polymerization, fully characterized, and loaded with the anticancer drug Doxorubicin (Dox). The hydrogel formulations were characterized by swelling rate, turbidity, FTIR, 1H NMR, SEM, gelation time, rheology, and biocompatibility assays. Both formulations demonstrated adequate morphologic, rheological, and biocompatibility properties; however, important differences in terms of drug retention were detected. As demonstrated by a Dox cumulative release study and posteriorly confirmed by an efficacy assay in an in vitro colorectal cancer model, the formulation composed by NIPAM and 4-penten-1-ol crosslinked with poly(ethylene glycol) diacrylate (PEGDA) (PNiPenPH) present a slow release over the time, presenting ideal properties to become and ideal depot system for the local sustained release of anticancer drugs as adjuvant therapy or in the case of non-resectable tumors.

Tissue-adhesive and highly mechanical double-network hydrogel for cryopreservation and sustained release of anti-cancer drugs

Applications of hydrogels served as drug carriers are severely limited by several main drawbacks of instable network structure, weak mechanical strength, shortage of tissue-adhesive ability, as well as poor anti-frozen performance, especially for some anti-cancer drugs (e.g., lomustine) those should be stored at subzero temperature to maintain their bioactivity. In the present work, a kind of hybrid polyacrylamide/alginate-CaCl2 (PAAm/Alg-Ca) based double-network (DN) hydrogel presented high tensile strength of 61.81 ​± ​5.14 ​kPa, a low water contact angle of 22.5° ​± ​0.8°, and sufficient adhesion on various wet substrates (234.56 ​± ​8.55 ​Pa). More interestingly, pH-responsive swelling behavior, excellent cold-resistance, as well as efficient recoverability at a low temperature of −20 ​°C was shown in such hydrogel. On the basis of biocompatibility result and a sustained drug release behavior using lomustine as a testing model, our proposed PAAm/Alg-Ca based DN hydrogel paves the way for development of anti-cancer drugs cryopreservation and delivery vehicle.

Neem gum based pH responsive hydrogel matrix: A new pharmaceutical excipient for the sustained release of anticancer drug

The present research work was aimed to synthesize neem gum-based site-specific drug delivery device for anticancer drug methotrexate at different pH condition. The hydrogel-based drug delivery device was synthesized by optimizing reaction parameters using a factorial design approach response surface method. This model comprised of various sets of reactions with varying concentrations of solvent, crosslinker, initiator and monomer under microwave radiation. Characterization of the candidate hydrogel was done using UV–visible spectrophotometer, FTIR, SEM, Raman, and XRD techniques. The release profile of the hydrogels network was studied through a methotrexate under different pH conditions. The drug encapsulation capacity was found to be around 93% and 90% in pH 7.4 and 6.8. Drug release through the synthesized hydrogel matrix was found to show non-Fickian behaviour at each medium. The hydrogel network showed less release in pH 6.8 than pH 7.4, suggesting that hydrogels may be suitable drug carriers for release of anticancer drug delivery system. Hemolysis testing was also done to check the compatibility of the synthesized drug delivery device with the four different blood samples. Hemolysis was found to be less than 1% in the case of all blood groups, which indicates that the synthesized candidate polymers are biocompatible with all blood groups.

Fabrication of Curcumin-Modified TiO2 Nanoarrays via Cyclodextrin Based Polymer Functional Coatings for Osteosarcoma Therapy.

The incomplete removal of bone tumors leads to increased local recurrence and poor prognosis. To prevent ostoperative tumor recurrence and simultaneously repair surgery-caused bone defects, there is a need of great significance to develop implantable biomaterials possessing both cancer cell-killing ability and excellent bioactivity. In this work, a functionalized titanium-based implant is successfully fabricated by loading curcumin (CUR) onto cyclodextrin based polymer (pCD) modified titanium dioxide (TiO2 ) nanorod arrays. Herein, a polydopamine (pDA) assisted film is implemented as a first coating layer onto the surface of the TiO2 nanoarrays to guarantee the robust anchorage of the pCD. The pCD coating acts as a reservoir for CUR, allowing for efficient drug loading and sustained release of anticancer drugs. Studies show that the CUR-modified surfaces (TiO2 /pDA/pCD/CUR) can significantly promote apoptosis of osteosarcoma cells in vitro by inducing mitochondrial dysfunction caused by the ROS overproduction, and meanwhile, effectively inhibit the tumor growth in vivo. Moreover, such functionalized implants with surface density of loaded CUR at 22.48 µg cm-2 or lower support the attachment and proliferation of osteoblasts in vitro. These results successfully demonstrate that as-prepared TiO2 /pDA/pCD/CUR constructs have combined anticancer performance and good biocompatibility, which has great promise for the surgical therapy of bone tumors.

Multifunctional Chitosan/Porous Silicon@Au Nanocomposite Hydrogels for Long-Term and Repeatedly Localized Combinatorial Therapy of Cancer via a Single Injection.

Considering the future clinical applications of localized cancer therapy, it is of great importance to construct injectable biodegradable nanocomposite hydrogels with combinatorial therapeutic efficacy. Here, porous silicon nanoparticles (PSiNPs) as host matrix were chosen to fabricate PSiNPs@Au nanocomposites via in situ reductive synthesis of gold nanoparticles. Then PSiNPs@Au nanocomposites were further incorporated into thermosensitive chitosan (CS) hydrogels to construct CS/PSiNPs@Au nanocomposite hydrogels, which showed in situ gelation at physiological temperature, excellent biodegradability, and biocompatibility. Especially with the encapsulation of CS hydrogels, PSiNPs@Au nanocomposites had a long-term stable photothermal effect with higher local temperature under near-infrared (NIR) laser irradiation, whether in vitro or in vivo. Besides, assisted by NIR laser irradiation, CS/PSiNPs@Au nanocomposite hydrogels exhibited a long-term sustained release of anticancer drugs (doxorubicin hydrochloride, DOX) in acidic tumor environments. Finally, DOX/CS/PSiNPs@Au precursors were administrated into tumor-bearing mice via a single intratumoral injection, which presented a significant synergistic chemo-photothermal therapeutic efficacy under repeated NIR laser irradiation during long-term cancer treatments. Accordingly, we developed a novel strategy to prepare multifunctional CS/PSiNPs@Au nanocomposite hydrogels and also demonstrated their potential applications in localized cancer therapy in future clinics.

In search of bioinspired hydrogels from amphiphilic peptides: a template for nanoparticle stabilization for the sustained release of anticancer drugs

This report presents the efficiency of palmitic acid-based proteolytically stable, biocompatible hydrogelators for the sustained release of anticancer drugs.

Correction: In search of bioinspired hydrogels from amphiphilic peptides: a template for nanoparticle stabilization for the sustained release of anticancer drugs

Correction for ‘In search of bioinspired hydrogels from amphiphilic peptides: a template for nanoparticle stabilization for the sustained release of anticancer drugs’ by Radha Rani Mehra et al., New J. Chem., 2019, 43, 11666–11678.

Preparation and characterization of folic acid functionalized bioactive glass for targeted delivery and sustained release of methotrexate.

We have successfully prepared a novel targeted drug delivery system, composed of folic acid (FA) as targeting molecule, methotrexate (MTX) as anticancer drug, and bioactive glass (BG) as carrier. The BG nanoparticles were synthesized by sol-gel method with the dodecylamine as template. The surface of BG nanoparticles was grafted with amino groups by (3-aminopropyl) triethoxysilane, then, FA and MTX were covalently conjugated to the surface of modified BG through amidation reaction, so FA functionalized BG (BG-FA) and targeted drug delivery system (MTX-BG-FA) were prepared. The physicochemical properties of BG, BG-NH2 , and BG-FA were characterized by various methods, such as X-ray diffraction, scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, ultraviolet-visible, and so on. Moreover, the drug release results showed that the MTX-BG-FA had sustained release property because of the peptide bond between MTX and BG-FA. And the cytocompatibility evaluation demonstrated that the BG and BG-FA were biocompatible and BG-FA even could promote cell proliferation, while the MTX-BG-FA had high cytotoxicity owning to the sustained release of anticancer drug. From the above, it could be concluded that MTX-BG-FA could kill tumor cells targetedly and sustainedly, which made it a good cancer targeted therapy material. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 319-329, 2019.

Synthesis of stimuli-responsive chitosan nanocomposites via RAFT copolymerization for doxorubicin delivery

In this study, a unique stimuli-responsive hydrogel nanocomposite was prepared via surface reversible addition fragmentation chain transfer (RAFT) copolymerization of acrylic acid and N‑isopropyl acrylamide onto chitosan and subsequent in situ synthesis of magnetic Fe3O4 nanoparticles. In the next age, the structure and morphology of synthetic magnetic nanocomposite were characterized by FTIR, XRD, VSM, SEM, and TEM techniques. The modified hydrogel nanocomposite was employed as an excellent carrier for controlled releasing of anticancer drug doxorubicin (DOX). The results indicated that the maximum of DOX loading efficiency of nanocomposite was 89%. Notably, in vitro drug release studies showed that DOX was released in a sustained-release manner for the nanocomposites. From the results of in vitro release studies, dual temperature and pH responsiveness of the nanocomposite was demonstrated, and 82% of total DOX was released from the hydrogel within 2 days. Due to the unique structures and properties, the chitosan-based nanocomposite may be utilized as a promising drug carrier for controlled and sustained release of anticancer drugs.

Glycol chitin/PAA hydrogel composite incorporated bio-functionalized PLGA microspheres intended for sustained release of anticancer drug through intratumoral injection

A novel anti-hepatoma drug release hybrid system is prepared by using poly(acrylic acid) (PAA) and glycol chitin as substrate in combination with Paclitaxel (PTX)-loaded bio-biofunctionalized poly(lactic-co-glycolic acid) (PLGA) micro-particles, which is intended for cancer therapy through intratumoral injection. The rheological behavior of glycol chitin (7 wt%)/PAA illustrates that it has low gelling temperature (i.e. 17 °C at pH 7.56) which ensures that the formulation turns to gel at physiological condition. The gelling time of glycol chitin/PAA is 16 minutes at 25 °C and 3 minutes at 37 °C, which is convenient for doctors to inject the in-situ gel formulations into the tumor location of patient. The drug release behavior reveals that the system can dramatically postpone the drug release. The cell viability test indicates that the micro-particles with drug still have 62% inhibitory effect on hepatoma cells in the fourteenth day after combing with hydrogel. This system is a promising approach for cancer therapy through intratumoral injection of in-situ gel formulations to extend retention time at tumor sites.