Smart nanoparticles for cancer therapy

Application of smart nanoparticles as a potential platform for effective colorectal cancer therapy

Abstract: Although chemotherapy is frequently used against cancer, it has notable limitations. Patients often experience side effects which require them to limit their dosage or discontinue treatment altogether. One such issue is the accumulation of chemotherapy in healthy organs. Another is the lack of specificity by cancer cells, which leads to the use of non-targeted molecules. On the other hand, cancer cells may develop resistance mechanisms that prevent the treatment from working. To get over these restrictions and tackle therapeutic issues, smart drug delivery systems were created. One potential medication delivery platform for targeted cancer treatment is smart nanoparticles, which may either react to or be guided by biological signals. Furthermore, these strategies can be directed by surface molecules that bind to certain receptors on cancer cell membranes or to the tumour microenvironment, resulting in a strong affinity. Recent progress in cancer therapy medication delivery methods is summarised in this brief review. These methods include several smart nanocarriers that respond to single or multifunctional stimuli. Nanoparticles made of polymeric materials, micelles, dendrimers, protein, cell membrane, liposomes, quantum dots, mesoporous silica, carbon, black phosphorus, iron oxide, quantum dots, and MOF are just a few examples of the smart materials that have recently been developed. Additionally, we shared a brief overview of the many medication delivery modalities available for cancer therapy, including peptides, nucleic acids, small molecules, proteins, and even live cells. We covered the advantages and disadvantages of smart nanoparticles as well as their potential applications in medicine.

INTRODUCTION: Breast cancer patients and providers are increasingly interested in personalized cancer therapy. Information-seeking behaviors and knowledge about personalized cancer therapy, cancer genetics, and molecular testing may influence patients’ participation in clinical trials and decision making regarding their care. We evaluated breast cancer patients’ knowledge and information seeking behaviors regarding personalized cancer therapy (PCT). METHODS: The study population included newly registered female breast cancer patients at The University of Texas MD Anderson Cancer Center prior to their first clinical visit. Of 308 consecutive patients who were invited to participate, 100 (32%) completed a self-administered questionnaire assessing their knowledge and information seeking preferences regarding PCT. Knowledge regarding cancer genetics and PCT research was assessed using 16 true/false questions (Cronbach’s α=0.88). A knowledge score was computed from the total number of correct responses. RESULTS: Respondents were predominantly white (70%), older (median age 55 years; SD=12.9; range 26-84), educated (78% with college degree or higher) and higher incomes (54% >$50,000/year); 71% had been diagnosed with breast cancer for at most one year at time of participation. Knowledge regarding cancer genetics and PCT was moderate (M=8.68, SD=3.8). Although most participants (85%) could correctly identify the definition of PCT, many (59%) did not know that somatic mutations are not hereditary. Many (75%) knew that molecular testing can reveal risk for other hereditary cancers. Less than half (46.5%) knew about the availability of PCT in clinical trials. A minority (27%) indicated that they had sought information regarding PCT. They sought for information related to specific treatment options. Higher education (p<0.01) and income levels (p<0.05) were associated with higher knowledge scores and with seeking PCT information (p<0.01). Those who had previously undergone any genetic testing also were more likely to seek information about PCT (29.6% vs 9.9%, p<0.05). Other demographic and clinical variables like age, race, duration of illness, cancer stage did not correlate with the knowledge score or information seeking behavior. CONCLUSION: Study participants could define PCT, but had limited knowledge of its availability and underlying treatment principles. This may be due, in part, to the fact that few participants had sought information about PCT. Understanding patients’ knowledge and prior information seeking regarding PCT may inform clinicians, who are likely to be patients’ initial source of information about PCT. Citation Format: Deevakar Rogith, Rafeek A Yusuf, Shelley R Hovick, Bryan M Fellman, Susan K Peterson, Allison Burton-Chase, Yisheng Li, Elmer V Bernstam, Funda Meric-Bernstam. Knowledge and Information seeking about personalized breast cancer therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-12-13.

The current approaches used for the treatment of cancer face some clinical limitations such as induction of severe side effects, multidrug resistance (MDR), and low specificity toward metastatic cancer cells. Hybrid nanomaterials hold a great potential to overcome all these challenges. Among hybrid nanoparticles, those based on mesoporous silica and iron oxide nanoparticles (MSNs and IONPs) have gained a privileged place in the biomedical field because of their outstanding properties. There are many studies demonstrating their effectiveness as drug delivery systems, nanoheaters, and imaging contrast agents. This review summarizes the advances related to the utilization of IONPs and MSNs for reducing side effects, overcoming MDR, and inhibiting metastasis. Furthermore, we give a future perspective of the clinical application of these technologies.

Photodynamic therapy (PDT), as a minimally invasive and high‐efficiency anticancer approach, has received extensive research attention recently. Despite plenty of effort devoted to exploring various types of photodynamic agents with strong near‐infrared (NIR) absorbance for PDT and many encouraging progresses achieved in the area, effective and safe photodynamic photosensitizers with good biodegradability and biocompatibility are still highly expected. In this work, a novel nanocomposite has been developed by assembly of iron oxide (Fe3O4) nanoparticles (NPs) and Au nanoparticles on black phosphorus sheets (BPs@Au@Fe3O4), which shows a broad light absorption band and a photodegradable character. In vitro and in vivo assay indicates that BPs@Au@Fe3O4 nanoparticles are highly biocompatible and exhibit excellent tumor inhibition efficacy owing to a synergistic photothermal and photodynamic therapy mediated by a low‐power NIR laser. Importantly, BPs@Au@Fe3O4 can anticipatorily suppress tumor growth by visualized synergistic therapy with the help of magnetic resonance imaging (MRI). This work presents the first combination application of the photodynamic and photothermal effect deriving from black phosphorus nanosheets and plasmonic photothermal effect from Au nanoparticles together with MRI from Fe3O4 NPs, which may open the new utilization of black phosphorus nanosheets in biomedicine, optoelectronic devices, and photocatalysis.

Magnetic induction hyperthermia is a new “green” cancer therapy method, which can destroy the tumor cells and undamage healthy cells. However, the difficulty of in vivo temperature rise control limits its clinical application. In this paper, we prepare a kind of smart magnetic nanoparticles for magnetic induction hyperthermia. The smart nanoparticles can self-control the temperature at 59.9 °C in the hyperthermia due to the low Curie temperature of nanoparticles. The formation mechanism of the smart magnetic nanoparticles is investigated. On the other hand, owing to the low thermal conductivity of the cell membrane, it is reasonable to believe that the intracellular hyperthermia is superior to extracellular hyperthermia. As such, we also discuss the feasibility of intracellular hyperthermia using the obtained smart magnetic nanoparticles. The results indicate that the temperature changes of the cell can meet the requirement of hyperthermia temperature when a single cell internalizes 2 pg of the smart magnetic nanoparticles.

The research presented and discussed within involves the development of novel biological applications of mesoporous silica nanoparticles (MSN) and an investigation of mesoporous material by transmission electron microscopy (TEM). Mesoporous silica nanoparticles organically functionalized shown to undergo endocytosis in cancer cells and drug release from the pores was controlled intracellularly and intercellularly. Transmission electron microscopy investigations demonstrated the variety of morphologies produced in this field of mesoporous silica nanomaterial synthesis. A series of room-temperature ionic liquid (RTIL) containing mesoporous silica nanoparticle (MSN) materials with various particle morphologies, including spheres, ellipsoids, rods, and tubes, were synthesized. By changing the RTIL template, the pore morphology was tuned from the MCM-41 type of hexagonal mesopores to rotational moire type of helical channels, and to wormhole-like porous structures. These materials were used as controlled release delivery nanodevices to deliver antibacterial ionic liquids against Escherichia coli K12. The involvement of a specific organosiloxane function group, covalently attached to the exterior of fluorescein doped mesoporous silica nanoparticles (FITC-MSN), on the degree and kinetics of endocytosis in cancer and plant cells was investigated. The kinetics of endocystosis of TEG coated FITC-MSN is significantly quicker than FITC-MSN as determined by flow cytometry experiments. The fluorescence confocal microscopy investigation showed the endocytosis of TEG coated-FITC MSN triethylene glycol grafted fluorescein doped MSN (TEG coated-FITC MSN) into both KeLa cells and Tobacco root protoplasts. Once the synthesis of a controlled-release delivery system based on MCM-41-type mesoporous silica nanorods capped by disulfide bonds with superparamagnetic iron oxide nanoparticles was completed. The material was characterized by general methods and the dosage and kinetics of the antioxidant dependent release was measured. Finally, the biological interaction of the material was determined along with TEM measurements. An electron investigation proved that the pore openings of the MSN were indeed blocked by the Fe3O4 nanoparticles. The biological interaction investigation demonstrated Fe3O4-capped MSN endocytosis into HeLa cells. Not only does the material enter the cells through endocytosis, but it seems that fluorescein was released from the pores most probably caused by disulfide bond reducing molecules, antioxidants. In addition to endocytosis and release, the Fe3O4-capped MSN propelled the cells across a cuvette upon induction of a magnet force. Finally, an important aspect of materials characterization is transmission electron microscopy. A TEM investigation demonstrated that incorporating different functional groups during the synthesis (co-condensation) changed the particle and pore morphologies.

Advances in Nanotechnology have led to the development of a variety of nanomaterials that are changing the way cancer therapy is carried out. A particularly important example is nanoparticle that can carry cargo to tumor. We are using mesoporous silica nanoparticles (MSNs) for cancer therapy. MSNs contain thousands of pores that provide storage space for anticancer drugs. These materials are biocompatible and safe. In addition, we have recently introduced biodegradability into MSNs.
 We have shown that MSNs exhibit excellent tumor targeting capability in two different animal model systems (chicken egg tumor model and mouse xenografts). This tumor targeting capability is partly due to its small size; these nano-sized particles can accumulate in tumor due to leaky tumor vasculature. In addition, we have carried out surface modifications to attach ligands that bind receptors present on the surface of cancer cells. For example, folate was attached to the surface that enables binding to folate receptors overexpressed on cancer cells.
 We have also conferred controlled anticancer drug release capability to MSNs in collaboration with Fraser Stoddart and Jeff Zink. This was accomplished by attaching nanovalves at the opening of the pores. Rotaxanes and pseudorotaxanes are used to prepare nanovalves. These chemical compounds consist of a stalk and a moving part. When the moving part is close to the pore opening, the nanovalve is closed. On the other hand, when the moving part is located away from the pore opening, the nanovalve is closed. In this way, the nanovalve provides an open and close function so that controlled release of anticancer drugs can be carried out.
 Light activated nanovalves were developed by incorporating azobenzene into nanovalves. Azobenzene changes conformation upon light exposure and this conformational change opens the nanovalve releasing anticancer drugs in a power and exposure time dependent manner. More recently, this system was modified by incorporating two-photon dyes that can capture energy from two-photon light and transfer to azobenzene to drive the release of anticancer drugs. This enables the system to work with tissue penetrating two-photon light.
 We have also developed nanoparticles that respond to oscillating magnetic field. This system was developed using MSNs that contain iron oxide core. Because of superparamagnetic property of iron oxide, the internal temperature of such nanoparticles increases when exposed to oscillating magnetic field. This temperature increase drives opening of nanovalves that are particularly designed for this purpose. 
 Development of nanoparticles that respond to external cues such as light and magnetic field may change the way cancer therapy is carried out. Implications on the future of cancer therapy will be discussed.

Novel water-soluble and pH-responsive anticancer drug nanocarriers: Doxorubicin–PAMAM dendrimer conjugates attached to superparamagnetic iron oxide nanoparticles (IONPs)

We report a smart mesoporous silica nanoparticle (MSN) with a pore surface designed toundergo charge conversion in intracellular endosomal condition. The surface of mesoporesin the silica nanoparticles was engineered to have pH-hydrolyzable citraconicamide. Solid-state nuclear magnetic resonance (NMR), Fourier-transform infrared(FT-IR) spectroscopy, and Brunauer–Emmett–Teller (BET) analyses confirmed thesuccessful modification of the pore surfaces. MSNs (MSN–Cit) with citraconicamide functionality on the pore surfaces exhibited a negative zeta potential (−10 mV) at pH 7.4 because of the presence of carboxylate end groups. At cellular endosomal pH (∼5.0), MSN–Cit have a positive zeta potential (16 mV) indicating the dramatic chargeconversion from negative to positive by hydrolysis of surface citraconic amide. Cytochromec (Cyt c) of positive charges could be incorporated into the pores of MSN–Cit byelectrostatic interactions. The release of Cyt c can be controlled by adjusting the pH ofthe release media. At pH 7.4, the Cyt c release was retarded, whereas, at pH 5.0,MSN–Cit facilitated the release of Cyt c. The released Cyt c maintained theenzymatic activity of native Cyt c. Hemolytic activity of MSN–Cit over red blood cells(RBCs) was more pronounced at pH 5.0 than at pH 7.0, indicating the capability ofintracellular endosomal escape of MSN carriers. Confocal laser scanning microscopy(CLSM) studies showed that MSN–Cit effectively released Cyt c in endosomalcompartments after uptake by cancer cells. The MSN developed in this work may serveas efficient intracellular carriers of many cell-impermeable therapeutic proteins.

Iron oxide nanoparticle (IONPs) have become a subject of interest in various biomedical fields due to their magnetism and biocompatibility. They can be utilized as heat mediators in magnetic hyperthermia (MHT) or as contrast media in magnetic resonance imaging (MRI), and ultrasound (US). In addition, their high drug-loading capacity enabled them to be therapeutic agent transporters for malignancy treatment. Hence, smartening them allows for an intelligent controlled drug release (CDR) and targeted drug delivery (TDD). Smart magnetic nanoparticles (SMNPs) can overcome the impediments faced by classical chemo-treatment strategies, since they can be navigated and release drug via external or internal stimuli. Recently, they have been synchronized with other modalities, e.g., MRI, MHT, US, and for dual/multimodal theranostic applications in a single platform. Herein, we provide an overview of the attributes of MNPs for cancer theranostic application, fabrication procedures, surface coatings, targeting approaches, and recent advancement of SMNPs. Even though MNPs feature numerous privileges over chemotherapy agents, obstacles remain in clinical usage. This review in particular covers the clinical predicaments faced by SMNPs and future research scopes in the field of SMNPs for cancer theranostics.

One of the greatest challenges of nanoparticle cancer therapy is the delivery of adequate numbers of nanoparticles to the tumor site. Iron oxide nanoparticles (IONPs) have many favorable qualities, including their nontoxic composition, the wide range of diameters in which they can be produced, the cell-specific cytotoxic heating that results from their absorption of energy from a nontoxic, external alternating magnetic field (AMF), and the wide variety of functional coatings that can be applied. Although IONPs can be delivered via an intra-tumoral injection to some tumors, the resulting tumor IONP distribution is generally inadequate; additionally, local tumor injections do not allow for the treatment of systemic or multifocal disease. Consequently, the ultimate success of nanoparticle based cancer therapy likely rests with successful systemic, tumor-targeted IONP delivery. In this study, we used a surface-based, bilateral, noninvasive static magnetic field gradient produced by neodymium-boron-iron magnets (80 T/m to 130 T/m in central plane between magnets), a rabbit ear model, and systemically-delivered starch-coated 100 nm magnetic (iron oxide) nanoparticles to demonstrate a spatially-defined increase in the local tissue accumulation of IONPs. In this non-tumor model, the IONPs remained within the local vascular space. It is anticipated that this technique can be used to enhance IONP delivery significantly to the tumor parenchyma/cells.

pH-responsive pHLIP (pH low insertion peptide) nanoclusters of superparamagnetic iron oxide nanoparticles as a tumor-selective MRI contrast agent

Preface

Superparamagnetic iron oxide (SPIO) nanoparticles have become a popular strategy of cancer treatment and molecular imaging because of their versatile properties and biocompatibility. A variety of studies have shown the exciting potential of functionalized SPIO nanoparticles, such as surface-coated, targeted ligandconjugated, and/or drug-loaded SPIO nanoparticles, as powerful tools for targeted imaging and therapy. Moreover, the applications of SPIO nanoparticles that integrate diagnosis and therapy in SPIO nanoparticles facilitate the monitoring of therapeutic efficacy during treatment. In the present review, we primarily concentrate on the recent advancements in the field of SPIO nanoparticles in terms of synthesis, targeted therapy, and cancer imaging.