Drug Delivery In Cancer Therapy Research Articles

Synthesis of Photo, Oxidative, and Reductive Triple-Stimuli-Responsive Block Copolymer Micelles as Nanocarriers for Controlled Release.

With the rapid development of nanotechnology, stimuli-responsive nanomaterials have provided an alternative for designing controllable drug delivery systems due to their spatiotemporally controllable properties. The environment of the human body is complex and cancer cells proliferate rapidly; the traditional nanocarriers could not release the loaded drugs sufficiently, and the release level of the drug is not sufficient for the requirement of treatment. Herein, a photoresponsive, glutathione, and reactive oxygen species block copolymer mPEG2k-ONB-SS-PO-mPEG2k is prepared by Cu(I)-catalyzed azide-alkyne cycloaddition click polymerization. The ο-nitrobenzyl groups, peroxalate ester bonds, disulfide bonds, and triazole units are regularly and repeatedly arranged in hydrophobic blocks. The photo, oxidative, and reductive responsive characteristics of the copolymers in different conditions were investigated by ultraviolet and visible spectrophotometry, dynamic light scattering, and transmission electron microscopy. Nile Red is encapsulated into the core of micelles as a model drug and exhibits the drug release behaviors in various environments. This research provides a way to design potential drug carriers and a promising platform for efficient intracellular drug delivery in cancer therapy.

Anastrozole Loaded Nanostructured Lipid Carriers : Preparation and Evaluation

Anastrozole (ANZ) is considered constitute of the fourth –generation of Non–steroidal aromatase blockage, ANZ has use for hormone receptor positive breast cancer in postmenopausal women. The serious side effects of ANZ including, vaginal dryness, hot flashes, irritability, breast tenderness and un–stability in circulation.
 Nanostructured lipid carriers (NLCs) have recently emerged as a multifunctional platform for drug delivery in cancer therapy.
 Five formula were composed of (200 mg of glyceryl monostearate, 40 mg of oleic acid , 1% (w/w) Tween 80, 1% (w/w) Poloxamer 407, 1% (w/w) soy lecithin and Vitamin E Polyethylene Glycol Succinate.
 The mean particle size, polydispersity index, zeta potential, entrapment efficiency, loading capacity range of optimum formula F05 (166±3.86 nm), (0.271±0.04), (–23.7±2.65 mV), (42.43±3.90%) and (1.23±0.35%) respectively that prepared by same above composition but higher amplitude value (70%). The in–vitro drug leakage study demonstrated intact formula through 5 hours, with an approximately 78.37% of the drug was encapsulated, that exhibit an anomalous release mechanism.

Dual-ligated metal organic framework as novel multifunctional nanovehicle for targeted drug delivery for hepatic cancer treatment

In the last decade, nanosized metal organic frameworks (NMOFs) have gained an increasing applicability as multifunctional nanocarriers for drug delivery in cancer therapy. However, only a limited number of platforms have been reported that can serve as an effective targeted drug delivery system (DDSs). Herein, we report rational design and construction of doxorubicin (DOX)-loaded nanoscale Zr (IV)-based NMOF (NH2-UiO-66) decorated with active tumor targeting moieties; folic acid (FA), lactobionic acid (LA), glycyrrhetinic acid (GA), and dual ligands of LA and GA, as efficient multifunctional DDSs for hepatocellular carcinoma (HCC) therapy. The success of modification was exhaustively validated by various structural, thermal and microscopic techniques. Biocompatibility studies indicated the safety of pristine NH2-UiO-66 against HSF cells whereas DOX-loaded dual-ligated NMOF was found to possess superior cytotoxicity against HepG2 cells which was further confirmed by flow cytometry. Moreover, fluorescence microscopy was used for monitoring cellular uptake in comparison to the non-ligated and mono-ligated NMOF. Additionally, the newly developed dual-ligated NMOF depicted a pH-responsiveness towards the DOX release. These findings open new avenues in designing various NMOF-based DDSs that actively target hepatic cancer to achieve precise therapy.

Engineered Cell-Penetrating Peptides for Mitochondrion-Targeted Drug Delivery in Cancer Therapy.

Mitochondrion is a promising target in cancer therapy. However, gaining access to this organelle is difficult due to the obstacles to cross the complicated mitochondrial membrane. Cell-penetrating peptides (CPPs) with mitochondrion-targeting ability, named mitochondrion-targeting peptides (MTPs), are efficient tools to deliver exogenous therapeutics into mitochondria. Herein, we report several new MTPs, which can be readily synthesized via resin-based solid-phase peptide synthesis. In particular, MTP3 (compound 5), consisting of three positively charged arginines and two D- and L- alternating naphthylalanines, demonstrated excellent mitochondrion-targeting ability with high Pearson's correlation coefficient, suggesting that MTP3 has good potential for mitochondrion-targeted drug delivery. As proof-of-concept, the feasibility of MTP3 was validated by the preparation of a mitochondrion-targeting prodrug (compound 17, doxorubicin-based prodrug). This prodrug was subsequently confirmed to be specifically transported to the mitochondria of tumor cells, where it was able to release the native doxorubicin upon intracellular GSH activation, leading to mitochondrial depolarization and eventually cell death. Importantly, compound 17 showed good cytotoxicity against human tumor cells while negligible toxicity towards normal cells, indicating its potential as a potent mitochondrial medicine for targeted cancer therapy. Our study thus opens a way for engineered CPPs to be used to deliver bioactive cargos in mitochondrion-targeted cancer therapy.

Liposomes: Structure, Biomedical Applications, and Stability Parameters With Emphasis on Cholesterol.

Liposomes are essentially a subtype of nanoparticles comprising a hydrophobic tail and a hydrophilic head constituting a phospholipid membrane. The spherical or multilayered spherical structures of liposomes are highly rich in lipid contents with numerous criteria for their classification, including structural features, structural parameters, and size, synthesis methods, preparation, and drug loading. Despite various liposomal applications, such as drug, vaccine/gene delivery, biosensors fabrication, diagnosis, and food products applications, their use encounters many limitations due to physico-chemical instability as their stability is vigorously affected by the constituting ingredients wherein cholesterol performs a vital role in the stability of the liposomal membrane. It has well established that cholesterol exerts its impact by controlling fluidity, permeability, membrane strength, elasticity and stiffness, transition temperature (Tm), drug retention, phospholipid packing, and plasma stability. Although the undetermined optimum amount of cholesterol for preparing a stable and controlled release vehicle has been the downside, but researchers are still focused on cholesterol as a promising material for the stability of liposomes necessitating explanation for the stability promotion of liposomes. Herein, the prior art pertaining to the liposomal appliances, especially for drug delivery in cancer therapy, and their stability emphasizing the roles of cholesterol.

Recent Advances in Exosome-Based Drug Delivery for Cancer Therapy.

Simple SummaryExosomes derived from various sources can deliver therapeutic agents such as small molecule drugs, nucleic acids, and proteins to cancer cells by passive or active targeting. These exosomes can encapsulate drugs inside the exosomes, extending drug half-life and increasing drug release stability. In addition, exosomes are highly biocompatible due to their endogenous origin and can be used as nanocarriers for tissue-specific targeted delivery. This review discusses recent advances in exosome-based drug delivery for cancer therapy.Exosomes are a class of extracellular vesicles, with a size of about 100 nm, secreted by most cells and carrying various bioactive molecules such as nucleic acids, proteins, and lipids, and reflect the biological status of parent cells. Exosomes have natural advantages such as high biocompatibility and low immunogenicity for efficient delivery of therapeutic agents such as chemotherapeutic drugs, nucleic acids, and proteins. In this review, we introduce the latest explorations of exosome-based drug delivery systems for cancer therapy, with particular focus on the targeted delivery of various types of cargoes.

Black phosphorus nanosheet-based new drug delivery system for the anticancer agents: A review

Cancer has been one among the main threats to the lives of citizenry for hundreds of years. Traditional drug therapy has certain defects such as poor targeting, easy degradation, high side effects, etc. Therefore, to enhance the treatment efficiency of anticancer agents, there is need of developing new drug delivery systems. Black phosphorus is a member of the 2D family, and it possess the potential to construct drug delivery system by virtue of its photothermal therapy, photodynamic therapy, and biodegradable properties. Due to their special structure BP are considered to be the best platform for drug delivery. They have shown large potential as near-infrared photothermal therapy agents and drug delivery for cancer therapy. The present review covered advances in BP- based drug delivery system along with its advantages and applications in cancer therapy.

Polymeric micelles functionalized with cell penetrating peptides as potential pH-sensitive platforms in drug delivery for cancer therapy: A review

Improving the intrinsic pharmacodynamics or pharmacokinetic of drugs is regarded as a crucial step in developing potential drug therapies. In this context, the development of nanostructured-based drug delivery systems (DDSs) responsive to exogenous or endogenous stimuli demonstrate an outstanding platform to clinical applications. Polymeric micelles (PM)-based DDSs are often modified with selective short peptides like cell penetrating peptides (CPPs) for highly efficient cellular internalization. In this review, we discussed recent achievements in the design and development of nanoscale pH-responsive micelles modified with CPPs to provide controlled drug release in the tumor cells. An overview on the application of micelles, especially PMs as promising engineered nanocarriers to combine pharmaceutical agents with CPPs are presented. Afterwards, the peptide-based transfection method as one of the promising approaches for drug delivery and therapeutic agents was explained. Subsequently, conjugation of pH-responsive micelles with CPPs as a novel DDS in cancer therapy was surveyed. Finally, the current challenges and future application of stimuli-sensitive nanoplatforms conjugated with CPP were discussed. In conclusion, the application of controlled delivery using pH-sensitive PMs-based DDSs conjugated with peptides can be considered as a potential approach to improve the therapeutic index of anticancer drugs.

Targeted Delivery of Cabazitaxel Using Cyclic Cell-Penetrating Peptide and Biomarkers of Extracellular Matrix for Prostate and Breast Cancer Therapy

Targeted drug delivery for cancer therapy is an emerging area of research. Cancer cells overexpress certain biomarkers that can be exploited for their targeted therapy. Cyclic cell-penetrating peptides (cCPP) are increasingly assessed for intracellular cargo delivery in cancer cells. In this study, we have conjugated cabazitaxel (CBT) to the cCPP via an ester bond to assist CBT release in the tumor's acidic environment. Integrin targeting (RGDC, TP1) and extra domain B of fibronectin (EDB-Fn) targeting (CTVRTSAD, TP2) peptides were linked to the peptide-drug conjugate (cCPP-CBT) via a disulfide bond to provide targeting ability to the conjugates until they reach the tumor site. Conjugate 11 (TP1-cCPP-CBT) and conjugate 16 (TP2-cCPP-CBT) showed approximately 3-4-fold less antiproliferative activity on integrin and EDB-FN overexpressing cancer cell lines as compared to the CBT analogue used for comparison (CBT-GA, 5). Conjugates (11 and 16) were less toxic (31-34-fold less antiproliferative activity) to the normal human embryonic kidney (HEK-293) cells as compared to CBT. The flow cytometry and quantitative confocal microscopy data further confirm the selective efficacy of conjugates (TP1-cCPP-FAM (10) and TP1-cCPP-FAM (15)) toward biomarker overexpressing cancer cells. Furthermore, the stability and release studies of conjugate 11 revealed its therapeutic potential under different conditions, such as human plasma, different pHs, and redox conditions. This conjugation strategy was proven to enhance chemotherapeutics agents' efficacy and targeting and can be applied to other chemotherapeutic agents.

Chitosan–dipeptide hydrogels as potential anticancer drug delivery systems

A novel chitosan–dipeptide hydrogel was fabricated through a combination of self-assembly of 9-fluorenylmethoxycarbonyl-modified diphenylalanine (Fmoc–FF) and its electrostatic interaction with glycol chitosan (GCS). Hydrogel strength and stability depended on its composition. The highest gel strength was observed at a Fmoc–FF mass fraction (ϕFF) of 0.85, whereby the highest combined strength of the two interactions was achieved. As the ϕFF increased above 0.6, gel stability decreased in buffered solution at pH 7.46. The incorporation of doxorubicin (DOX) as a cationic model drug significantly increased the stability of the complex hydrogels. DOX-loaded hydrogels exhibited slow DOX release, probably due to the drug's strong binding to Fmoc–FF via electrostatic attraction and the high gel stability. These hydrogels also exhibited excellent thixotropic features that facilitated the development of injectable self-healing drug delivery systems. Notably, DOX release was significantly accelerated as the pH of the medium decreased from 7.46 to 5.5 and 4.0, possibly due to hydrogel components' protonation. The DOX-loaded hydrogel exhibited notable cytotoxicity against A549 human lung cancer cells, which suggests the newly developed hydrogel to be a promising candidate vehicle for the localized and controlled drug delivery in cancer therapy.

Studies on drug-assisted silver nanoparticles to reduce granulocytopenia and improve drug delivery for cancer therapy

Chemotherapy is accompanied by suppression of the immune system of a patient, which is usually handled through the judicial use of antibiotic therapy. Through clinical conditions like granulocytopenia, antibiotic treatment is given along with chemotherapeutic drugs. Granulocytopenic infection, which is associated with three bacteria, i.e., Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, causes the granulocyte count to fall below 500/mm3, thereby causing complications and resulting in the death of cancer patients. In this study, one-pot synthesis is used to incorporate the anticancer and antibiotic drugs into silver nanoparticles by using a chemical reduction method. The morphological data indicate the size of ampicillin-mediated silver nanoparticles (i.e., Amp-Ag NPs) as ~ 25 nm, which further, after adding paclitaxel (i.e., AT-Ag NPs) in the reaction mixture, increase to ~ 42 nm. The antimicrobial studies of synthesized NPs show a synergistic effect toward the infection-causing bacteria. Imaging studies represent the accumulation of nanoparticles and pores formation into the bacterial membrane. Biological assay and apoptosis assay predict the positive efficacy of paclitaxel, keeping the therapy intact. Hence, the robust drug delivery system in cancer therapy with minimal side effects and improved antimicrobial and anticancer activity is proposed.

Efficient, enzyme responsive and tumor receptor targeting gelatin nanoparticles decorated with concanavalin-A for site-specific and controlled drug delivery for cancer therapy

The tumor targeting and stimuli responsiveness behavior of intelligent drug delivery systems imparts effective therapeutic delivery and decreases the toxicity of conventional chemotherapeutic agents in off-target organs. To achieve the receptor targeting and smart drug release, several strategies have been employed to engineer nano-carrier with stimulus sensitivity. In this work, mannose receptor-targeted and matrix metalloproteinase (MMP) responsive gelatin nanoparticles were developed and assessed for its receptor targeting and “on-demand” controlled drug delivery in lung cancer therapeutics. MMPs are protease enzymes and over-expressed in tumorous tissues in all the stages of cancer. The cancer cells also have over-expressed mannose receptors on the cell surface. The surface decoration of gelatin nanoparticles with concanavalin A (con-A) tends to bind with mannose moiety of cell surface glycoproteins which enhances the cancer cell-specific higher uptake of nanoparticles. Gelatin nanoparticles have attracted significant attraction in recent years as a potential drug carrier because of its good biocompatibility and versatile physicochemical properties desirable to deliver the drug. Cisplatin was complexed with the gelatin matrix (CG-NP) to evaluate stimuli responsiveness with the lung cancer cells and its release pattern. In this smart inhalable delivery system, cisplatin loaded gelatin nanoparticles were surface decorated with con-A (CCG-NP). In tumorous cells, con-A coating is expected to enhance mannose receptor-specific cellular internalization of CCG-NP, and subsequently high level of MMP in tumor tissues would help to release cisplatin in response and ensures controlled drug release. The synthesized CCG-NP has shown enzyme triggered drug release and favorable endocytosis after incubation of 12 h compare to uncoated nanoparticles. The efficacy of CCG-NP significantly increased in presence of MMP-2 enzyme in lung cancer cell line A549 cells. It also significantly enhanced reactive oxygen species generation, cell cycle arrest in S and G2/M phase, and apoptosis in cancer cells. Therefore, inhalable CCG-NP promises a pragmatic approach to construct a receptor targeting and an “on-demand” drug delivery system to efficiently deliver the drug at the tumor site only.

Exosome-Based Delivery of Natural Products in Cancer Therapy.

A rapidly growing research evidence has begun to shed light on the potential application of exosome, which modulates intercellular communications. As donor cell released vesicles, exosomes could play roles as a regulator of cellular behaviors in up-taken cells, as well as a delivery carrier of drugs for targeted cells. Natural product is an invaluable drug resources and it is used widely as therapeutic agents in cancers. This review summarizes the most recent advances in exosomes as natural product delivery carriers in cancer therapy from the following aspects: composition of exosomes, biogenesis of exosomes, and its functions in cancers. The main focus is the advantages and applications of exosomes for drug delivery in cancer therapy. This review also summarizes the isolation and application of exosomes as delivery carriers of natural products in cancer therapy. The recent progress and challenges of using exosomes as drug delivery vehicles for five representative anti-cancer natural products including paclitaxel, curcumin, doxorubicin, celastrol, and β-Elemene. Based on the discussion on the current knowledge about exosomes as delivery vehicles for drugs and natural compounds to the targeted site, this review delineates the landscape of the recent research, challenges, trends and prospects in exosomes as delivery vehicles for drugs and natural compounds for cancer treatment.

Facile synthesis of biodegradable mesoporous functionalized-organosilica nanoparticles for enhancing the anti-cancer efficiency of cordycepin

Cordycepin, a major compound of Cordyceps sp., has been shown to have anticancer potential. However, its low solubility in water is a hurdle in drug delivery in the human body and for cellular uptake. This study focuses on the ability to load cordycepin onto a biodegradable silica nanoparticle as an effective nanocarrier. Biodegradable tetrasulfide-based organosilica nanomaterial with homogeneously spherical particles, average particle size of approximately 50 nm, and pore size of 3.56 nm were successfully synthesized. The nanomaterial could efficiently load cordycepin with a loading capacity up to 755.02 mg g−1. The release profile of cordycepin-loaded nanoparticles at pH 5.5 showed a burst release within the first 1 h and a gradually slow rate thereafter. Moreover, the results of in vitro toxicity of the drug-loaded material against two malignant cancer cell lines including gastric (AGS) and lung (A549) indicated the potential of the nanosystem for drug delivery in cancer therapy.

Functional Choline Phosphate Lipids for Enhanced Drug Delivery in Cancer Therapy

Liposome formulations by zwitterionic lipids (e.g., phosphatidyl choline (PC)) have been widely applied in the clinical translation of nanomedicines. However, poor bioorthogonality in the PC lipid backbone and limited cellular uptake potency significantly impede the development of a therapeutic strategy. Herein, we synthesized a novel bioorthogonal zwitterionic lipid named choline phosphate (CP), with reversed PC charge orientation via a phospholane derivative ring-opening reaction. CP lipids can assemble into liposomes with excellent biocompatibility and stable physical and chemical properties similar to PC liposomes. Due to supramolecular ionic pair interactions with the cell membrane, doxorubicin (Dox)-loaded CP liposomes (CP-Dox) were preferentially taken up and accumulated in cells compared to PC-Dox, which significantly enhanced the cytotoxicity in cancer cells and inhibited tumor growth. Furthermore, we determined the bioorthogonality of the CP lipids by conjugating folate in situ using a “click” reaction, which showed specificity in targeting treatment for breast cancer. Our studies provide a new proof of concept that functional liposomes can be designed at the molecular level. We also expect that CP lipids may have potential in other applications, including biosensors, antifouling coatings, cell membrane mimetic engineering, and artificial cells.

PH-Sensitive nanogels for drug delivery in cancer therapy.

As a commonly used treatment method for cancer, chemotherapy is greatly limited by the side effects of chemotherapy drugs and the multiple drug resistance that develops. Nanogels are considered ideal drug carriers due to their high stability, high water content and excellent drug loading capacities. To achieve more precise and intelligent drug delivery in tumor tissues, various environmentally responsive nanogels have been widely developed. Compared to normal tissue, tumor tissue exhibits a lower pH value. Therefore, the pH gradients between the tumor microenvironment and the normal physiological environment can be used to design pH-sensitive nanogels to regulate the delivery and release of antitumor drugs. This article mainly introduces the application of pH-sensitive nanogels in cancer treatment, hoping to provide a reference for the development of cancer treatment.

Stimuli-responsive nanocarriers for therapeutic applications in cancer.

Cancer has become a very serious challenge with aging of the human population. Advances in nanotechnology have provided new perspectives in the treatment of cancer. Through the combination of nanotechnology and therapeutics, nanomedicine has been successfully used to treat cancer in recent years. In terms of nanomedicine, nanocarriers play a key role in delivering therapeutic agents, reducing severe side effects, simplifying the administration scheme, and improving therapeutic efficacies. Modulations of the structure and function of nanocarriers for improved therapeutic efficacy in cancer have attracted increasing attention in recent years. Stimuli-responsive nanocarriers penetrate deeply into tissues and respond to external or internal stimuli by releasing the therapeutic agent for cancer therapy. Notably, stimuli-responsive nanocarriers reduce the severe side effects of therapeutic agents, when compared with systemic chemotherapy, and achieve controlled drug release at tumor sites. Therefore, the development of stimuli-responsive nanocarriers plays a crucial role in drug delivery for cancer therapy. This article focuses on the development of nanomaterials with stimuli-responsive properties for use as nanocarriers, in the last few decades. These nanocarriers are more effective at delivering the therapeutic agent under the control of external or internal stimuli. Furthermore, nanocarriers with theranostic features have been designed and fabricated to confirm their great potential in achieving effective treatment of cancer, which will provide us with better choices for cancer therapy.

Ultrasound-Mediated Drug Delivery in Cancer Therapy: A Review.

The use of ultrasound as a medical diagnostic tool began in the 1940s. Ever since, the medical applications of ultrasound have included imaging, tumor ablation, and lithotripsy; however, an ever-increasing body of literature demonstrates that ultrasound has potential in other medical applications, including targeted drug delivery. Site-specific drug delivery involves delivering drugs to diseased areas with a high degree of precision, which is particularly advantageous in cancer treatment as it would minimize the adverse side effects experienced by patients. This review addresses the ability of ultrasound to induce localized and controlled drug release from nanocarriers, namely micelles and liposomes, utilizing thermal and/or mechanical effects. The interactions of ultrasound with micelles and liposomes, the effects of the lipid composition, and ultrasound parameters on the release of encapsulated drugs are discussed. In addition, a survey of the literature detailing some in vitro and in vivo ultrasound triggered drug delivery systems is presented.

Novel biomimetic nanostructured lipid carriers for cancer therapy: preparation, characterization, and in vitro/in vivo evaluation

Nanostructured lipid carriers (NLC) have become a research hotspot, wherein cancer-targeting effects are enhanced and side effects of chemotherapy are overcome. Usually, accelerated blood clearance (ABC) occurs after repeated injections, without changing the immunologic profile, despite PEGylation which prolongs the circulation function. To overcome these problems, we designed a red blood cell-membrane-coated NLC (RBCm-NLC), which was round-like, with a particle size of 60.33 ± 3.04 nm and a core-shell structure. Its stability was good, the drug paclitaxel (PTX) release from RBCm-PTX-NLC was less than 30% at pH7.4 and pH6.5, and the integrity of RBC membrane surface protein was maintained before and after preparation. Additionally, in vitro assays showed that, with the RBCm coating, the cellular uptake of the NLC by cancer cells was significantly enhanced. RBCm-NLC can avoid recognition by macrophage cells and prolong circulation time in vivo. In S180 tumor-bearing mice, the DiR-labeled RBCm-NLC group showed a stronger fluorescence signal and longer retention in tumor tissues, indicating a prompt tumor-targeting effect and extended blood circulation. Importantly, RBCm-PTX-NLC enhanced the antitumor effect and extended the survival period significantly in vivo. In summary, biomimetic NLC offered a novel strategy for drug delivery in cancer therapy.

Charge Switchable Polymer Micelles: A Smart Strategy for Safe and Efficient Drug Delivery in Cancer Therapy

Charge Switchable Polymer Micelles: A Smart Strategy for Safe and Efficient Drug Delivery in Cancer Therapy