Functionalization of Metal and Carbon Nanoparticles with Potential in Cancer Theranostics

Cancer theranostics is a new concept of medical approach that attempts to combine in a unique nanoplatform diagnosis, monitoring and therapy so as to provide eradication of a solid tumor in a non-invasive fashion. There are many available solutions to tackle cancer using theranostic agents such as photothermal therapy (PTT) and photodynamic therapy (PDT) under the guidance of imaging techniques (e.g., magnetic resonance—MRI, photoacoustic—PA or computed tomography—CT imaging). Additionally, there are several potential theranostic nanoplatforms able to combine diagnosis and therapy at once, such as gold nanoparticles (GNPs), graphene oxide (GO), superparamagnetic iron oxide nanoparticles (SPIONs) and carbon nanodots (CDs). Currently, surface functionalization of these nanoplatforms is an extremely useful protocol for effectively tuning their structures, interface features and physicochemical properties. This approach is much more reliable and amenable to fine adjustment, reaching both physicochemical and regulatory requirements as a function of the specific field of application. Here, we summarize and compare the most promising metal- and carbon-based theranostic tools reported as potential candidates in precision cancer theranostics. We focused our review on the latest developments in surface functionalization strategies for these nanosystems, or hybrid nanocomposites consisting of their combination, and discuss their main characteristics and potential applications in precision cancer medicine.     

Mesoporous silica nanoparticles for 19F magnetic resonance imaging,fluorescence imaging,and drug delivery

Multifunctional mesoporous silica nanoparticles (MSNs) are good candidates for multimodal applications in drug delivery, bioimaging, and cell targeting. In particular, controlled release of drugs from MSN pores constitutes one of the superior features of MSNs. In this study, a novel drug delivery carrier based on MSNs, which encapsulated highly sensitive ¹⁹F magnetic resonance imaging (MRI) contrast agents inside MSNs, was developed. The nanoparticles were labeled with fluorescent dyes and functionalized with small molecule-based ligands for active targeting. This drug delivery system facilitated the monitoring of the biodistribution of the drug carrier by dual modal imaging (NIR/¹⁹F MRI). Furthermore, we demonstrated targeted drug delivery and cellular imaging by the conjugation of nanoparticles with folic acid. An anticancer drug (doxorubicin, DOX) was loaded in the pores of folate-functionalized MSNs for intracellular drug delivery. The release rates of DOX from the nanoparticles increased under acidic conditions, and were favorable for controlled drug release to cancer cells. Our results suggested that MSNs may serve as promising ¹⁹F MRI-traceable drug carriers for application in cancer therapy and bio-imaging.     

Effects of surface modifications on the physicochemical properties of iron oxide nanoparticles and their performance as anticancer drug carriers

Surface of iron oxide nanoparticles were modified with citric acid (CA), chitosan (CS) and folic acid conjugated chitosan (FA-g-CS), respectively. Their physicochemical properties, doxorubicin loading capacity, drug release patterns and in vitro cytotoxicity were comparatively studied.     

Radio-immunoconjugated,Dox-loaded,surface-modified superparamagnetic iron oxide nanoparticles (SPIONs) as a bioprobe for breast cancer tumor theranostics

In this research, we develop dual modality molecular imaging and also radio-immunotherapy (RIT) bioprobes, in the form of modified superparamagnetic iron oxide nanoparticles (SPIONs) conjugated to radiolabeled antibodies, for PET and MRI of HER2 expressing cancers as well as a PH sensitive drug carrier by embedded an anticancer agent for cancer therapeutic applications. The bioprobes were developed by conjugating ⁶⁴Cu labeled trastuzumab (herceptin) and rituximab (Anti CD-20) antibodies to modified SPIONs. The SPIONs were modified with carboxymethyl chitosan and functionalized with acrylic acid (AA). Also, with the purpose of identifying more effective bifunctional chelator (BFC), we compared the properties of novel BFC, p-NO₂-Bn-PCTA with the commonly used DOTA-NHS for radio-immunoconjugate preparations. Moreover, a chemotherapy drug, doxorubicin, was then loaded onto engineered nanoparticles for targeted intracellular drug delivery and selective cancer cell killing. Resulting radio-immunoconjugated-SPIONs were evaluated for molecular imaging and effective targeting of the HER2+ receptors in SKBR3 cell lines and breast tumor bearing Balb/C mice. Therefore, our biocompatible SPIONs could serve as a promising multifunctional theranostics nanoplatform in dual modality imaging guided RIT of HER2 overexpressing cancer applicable to drug delivery and controlled drug release for trigger both intrinsic and extrinsic pathways of apoptosis.     

Development and physicochemical characterization of doxorubicin-encapsulated hydroxyapatite–polyvinyl alcohol nanocomposite for repair of osteosarcoma-affected bone tissues

Nowadays locoregional therapy for cancer treatment can be associated with nanocomposite drug delivery systems. Coated nanoparticles have versatile applications for delivering chemotherapeutic drugs to the targeted part of the body. In this study, a ceramic carrier like nanosized hydroxyapatite (HAp) was synthesized by the in situ precipitation method followed by coating with anticancer drug like doxorubicin (DOX) and polyvinyl alcohol (PVA) polymer. The physicochemical characterization of the prepared polymer-coated drug ceramic nanocomposite (DOX-HAp-PVA) was carried out using Fourier transform infrared spectroscopy, X-ray diffraction, transmission electron spectroscopy, and particle size distribution. Furthermore, the biocompatibility and the anticancer activity of the nanocomposite were explored by MTT assay study. Successfully synthesized DOX-HAp-PVA nanocomposite exhibited a remarkable cytotoxicity toward osteosarcoma cells (MG 63), which may be potentially used as an anticancer agent against osteosarcoma.     

Biocompatible APTES–PEG Modified Magnetite Nanoparticles: Effective Carriers of Antineoplastic Agents to Ovarian Cancer

Magnetite nanoparticles are particularly attractive for drug delivery applications because of their size-dependent superparamagnetism, low toxicity, and biocompatibility with cells and tissues. Surface modification of iron oxide nanoparticles with biocompatible polymers is potentially beneficial to prepare biodegradable nanocomposite-based drug delivery agents for in vivo and in vitro applications. In the present study, the bare (10 nm) and polyethylene glycol (PEG)–(3-aminopropyl)triethoxysilane (APTES) (PA) modified (17 nm) superparamagnetic iron oxide nanoparticles (SPIO NPs) were synthesized by coprecipitation method. The anticancer drugs, doxorubicin (DOX) and paclitaxel (PTX), were separately encapsulated into the synthesized polymeric nanocomposites for localized targeting of human ovarian cancer in vitro. Surface morphology analysis by scanning electron microscopy showed a slight increase in particle size (27?±?0.7 and 30?±?0.45 nm) with drug loading capacities of 70 and 61.5 % and release capabilities of 90 and 93 % for the DOX- and PTX-AP-SPIO NPs, respectively (p?<?0.001). Ten milligrams/milliliter DOX- and PTX-loaded AP-SPIO NPs caused a significant amount of cytotoxicity and downregulation of antiapoptotic proteins, as compared with same amounts of free drugs (p?<?0.001). In vivo antiproliferative effect of present formulation on immunodeficient female Balb/c mice showed ovarian tumor shrinkage from 2,920 to 143 mm³ after 40 days. The present formulation of APTES–PEG-SPIO-based nanocomposite system of targeted drug delivery proved to be effective enough in order to treat deadly solid tumor of ovarian cancer in vitro and in vivo.     

Synthesis and characterization of folic acid‐modified carboxymethyl chitosan‐ursolic acid targeted nano‐drug carrier for the delivery of ursolic acid and 10‐hydroxycamptothecin

Carboxymethyl chitosan (CMCS), as a water‐soluble, biocompatible, and biodegradable polymer, is an excellent carrier for a sustained drug delivery system. In this study, a amphiphilic carboxymethyl chitosan‐ursolic acid nano‐drug carrier modified by folic acid (FPCU) were prepared, and then the nano‐drug carrier wrapped another anticancer drug 10‐hydroxycamptothecin were self‐assembled into nanoparticles (FPCU/HCPT NPs). The FPCU/HCPT NPs had a suitable size, high drug loading efficiency of ursolic acid (6.4%) and 10‐hydroxycamptothecin (14.1%). The drug release study in vitro indicated that the nanoparticles have obviously sustained effect and pH sensitive behaviors, the drug release amount was higher at pH 5.5 than at pH 7.4. in vitro and in vivo study showed that the nanoparticles displayed a high antitumor efficiency to tumor cells compared with free drug. The nano delivery system as a carrier for ursolic acid (UA) and 10‐hydroxycamptothecin (HCPT) has good application prospects in cancer treatment.     

Differential Effects of Polymer‐Surface Decoration on Drug Delivery,Cellular Retention,and Action Mechanisms of Functionalized Mesoporous Silica Nanoparticles

Polymer‐surface decoration has been found to be an effective strategy to enhance the biological activities of nanomedicine. Herein, three different types of polymers with a cancer‐targeting ligand Arg‐Gly‐Asp peptide (RGD) have been used to decorate mesoporous silica nanoparticles (MSNs) and the functionalized nanosystems were used as drug carriers of oxaliplatin (OXA). The results showed that polymer‐surface decoration of the MSNs nanosystem by poly(ethylene glycol) (PEG) and polyethyleneimine (PEI) significantly enhanced the anticancer efficacy of OXA, which was much higher than that of chitosan (CTS). This effect was closely related to the enhancement of the cellular uptake and cellular drug retention. Moreover, PEI@MSNs‐OXA possessed excellent advantages in penetrating ability and inhibitory effects on SW480 spheroids that were used to simulate the in vivo tumor environments. Therefore, this study provides useful information for the rational design of a cancer‐targeted MSNs nanosystem with polymer‐surface decoration.     

Target delivery of photo-triggered nanocarrier for externally activated chemo-photodynamic therapy of prostate cancer

Objective therapeutics such as photodynamic therapy (PDT) play an imperative role where targeted delivery of nanotherapeutics could achieve the highest level of therapeutic efficiency for the treatment of cancer. For an effective combination of chemotherapy and PDT, a multimodal-targeted system is vital to achieving effective therapeutic efficacy to counter cancer. In this study, an upconversion nanoparticle-based dual-mode nanocarrier was established where doxorubicin, a chemotherapeutic drug, and tetra carboxy zinc phthalocyanine, a reactive oxygen species (ROS) generator, were successfully embedded onto metal-organic framework (ZIF-8) for synergistic photodynamic therapy. For controlled drug release, amine-PEG was wrapped around UCNPs@MOF. In addition, targeting efficiency was enhanced by employing a prostate cancer-specific ligand (folic acid, FA), which is recognized by prostate-specific membrane antigen (PSMA). Indeed, the nanocomposite-coupled FA was uptaken more in LNCaP (PSMA positive) cells compared to DU145 (PSMA negative) cells. Interestingly, coating the nanocomposite with biocompatible polyethylene glycol significantly inhibited doxorubicin (DOX) release even under a lower pH condition. This effect is abrogated by near-infrared irradiation, whereupon NIR irradiation, the nanocomposite accelerates the production of ROS, as well as chemotherapeutic drug release. These results suggest that the release of DOX was more tightly controlled by a polymer coating. As observed by in vitro cytotoxicity experiment, LNCaP cells showed descending pattern in the cell viability than DU145 cells under the NIR irradiation condition. All these results, taken together, show a promising system for NIR-based targeted PDT where burst release of drug and ROS is achieved to improve the synergistic therapeutics.     

Biocompatible Magnetic Hydrogel Nanocomposite Based on Carboxymethylcellulose: Synthesis,Cell Culture Property and Drug Delivery

In this report, the synthesis of a novel biocompatible magnetic hydrogel nanocomposite based on carboxymethyl cellulose (CMC), as an eco-friend, biocompatible and green polysaccharide, is described via a facile one pot approach using magnetic iron oxide nanoparticles (MIONs) as a crosslinker. The structure of the prepared MION–CMC hydrogel nanocomposite was examined by various analytical techniques such as FTIR spectroscopy, TGA thermal analysis, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM). The MIONs were generated in situ during the hydrogel formation with an average diameter size of 10 nm and a narrow size distribution. The sample was superparamagnetic with large saturation magnetization at room temperature. MION–CMC hydrogel nanocomposite showed a good ability for releasing of doxorubicin as an anticancer drug at pH 7 with case II (relaxational) transport mechanism. This outcome demonstrated that MION–CMC hydrogel nanocompositeis an attractive biocompatible candidate for widespread biomedical applications, particularly in controlled drug-targeting delivery.     

Cyclodextrin Polymers as Delivery Systems for Targeted Anti-Cancer Chemotherapy

In the few last years, nanosystems have emerged as a potential therapeutic approach to improve the efficacy and selectivity of many drugs. Cyclodextrins (CyDs) and their nanoparticles have been widely investigated as drug delivery systems. The covalent functionalization of CyD polymer nanoparticles with targeting molecules can improve the therapeutic potential of this family of nanosystems. In this study, we investigated cross-linked γ- and β-cyclodextrin polymers as carriers for doxorubicin (ox) and oxaliplatin (Oxa). We also functionalized γ-CyD polymer bearing COOH functionalities with arginine-glycine-aspartic or arginine moieties for targeting the integrin receptors of cancer cells. We tested the Dox and Oxa anti-proliferative activity in the presence of the precursor polymer with COOH functionalities and its derivatives in A549 (lung, carcinoma) and HepG2 (liver, carcinoma) cell lines. We found that CyD polymers can significantly improve the antiproliferative activity of Dox in HepG2 cell lines only, whereas the cytotoxic activity of Oxa resulted as enhanced in both cell lines. The peptide or amino acid functionalized CyD polymers, loaded with Dox, did not show any additional effect compared to the precursor polymer. Finally, studies of Dox uptake showed that the higher antiproliferative activity of complexes correlates with the higher accumulation of Dox inside the cells. The results show that CyD polymers could be used as carriers for repositioning classical anticancer drugs such as Dox or Oxa to increase their antitumor activity.     

Rational Chemical Multifunctionalization of Graphene Interface Enhances Targeted Cancer Therapy

The synthesis of a drug delivery platform based on graphene was achieved through a step‐by‐step strategy of selective amine deprotection and functionalization. The multifunctional graphene platform, functionalized with indocyanine green, folic acid, and doxorubicin showed an enhanced anticancer activity. The remarkable targeting capacity for cancer cells in combination with the synergistic effect of drug release and photothermal properties prove the great advantage of a combined chemo‐ and phototherapy based on graphene against cancer, opening the doors to future therapeutic applications of this type of material.     

Dual-Targeting Biomimetic Semiconducting Polymer Nanocomposites for Amplified Theranostics of Bone Metastasis

Bone metastasis is a type of metastatic tumors that involves the spreads of malignant tumor cells into skeleton, and its diagnosis and treatment remain a big challenge due to the unique tumor microenvironment. We herein develop osteoclast and tumor cell dual-targeting biomimetic semiconducting polymer nanocomposites (SPFeN_OC) for amplified theranostics of bone metastasis. SPFeN_OC contain semiconducting polymer and iron oxide (Fe₃O₄) nanoparticles inside core and surface camouflaged hybrid membrane of cancer cells and osteoclasts. The hybrid membrane camouflage enables their targeting to both metastatic tumor cells and osteoclasts in bone metastasis through homologous targeting mechanism, thus achieving an enhanced nanoparticle accumulation in tumors. The semiconducting polymer mediates near-infrared (NIR) fluorescence imaging and sonodynamic therapy (SDT), and Fe₃O₄ nanoparticles are used for magnetic resonance (MR) imaging and chemodynamic therapy (CDT). Because both cancer cells and osteoclasts are killed synchronously via the combinational action of SDT and CDT, the vicious cycle in bone metastasis is broken to realize high antitumor efficacy. Therefore, 4T1 breast cancer-based bone metastasis can be effectively detected and cured by using SPFeN_OC as dual-targeting theranostic nanoagents. This study provides an unusual biomimetic nanoplatform that simultaneously targets osteoclasts and cancer cells for amplified theranostics of bone metastasis.     

Tuning the In Vivo Transport of Anticancer Drugs Using Renal‐Clearable Gold Nanoparticles

Precise control of in vivo transport of anticancer drugs in normal and cancerous tissues with engineered nanoparticles is key to the future success of cancer nanomedicines in clinics. This requires a fundamental understanding of how engineered nanoparticles impact the targeting‐clearance and permeation‐retention paradoxes in the anticancer‐drug delivery. Herein, we systematically investigated how renal‐clearable gold nanoparticles (AuNPs) affect the permeation, distribution, and retention of the anticancer drug doxorubicin in both cancerous and normal tissues. Renal‐clearable AuNPs retain the advantages of the free drug, including rapid tumor targeting and high tumor vascular permeability. The renal‐clearable AuNPs also accelerated body clearance of off‐target drug via renal elimination. These results clearly indicate that diverse in vivo transport behaviors of engineered nanoparticles can be used to reconcile long‐standing paradoxes in the anticancer drug delivery.     

Folic Acid Modified Polymeric Micelles for Intravesical Instilled Chemotherapy

In this study,a targeting micellar drug delivery system was developed for intravesical instilled chemotherapy of bladder cancer.The amphiphilic diblock copolymer poly(ε-caprolactone)-block-poly(ethylene glycol) (PCL-b-PEO) with functional amino group (NH2) at the end of PEO block was synthesized.Then the copolymer was conjugated with folic acid (FA) and fluorescein isothiocyannate (FITC) via the PEO-NH2 terminus,and then assembled into micelles with the target moiety and fluorescence labeling.In addition,drug loaded micelles were also fabricated with anticancer drug doxorubicin (DOX) encapsulated in the hydrophobic core.The micelles were characterized in terms of size,drug loaded efficiency and critical micellization concentration (CMC) by means ofDLS,UV and fluorescence spectra.In vitro cellular uptake and cytotoxicity studies showed that FA modified PCL-b-PEO-FA micelles have a greater targeting efficiency to human bladder cancer cell (T-24 cell) compared to PCL-b-PEO-NH2 micelles due to the conjugation of FA on the surface,while no targeting effect to normal tissue originated human embryonic kidney 293 (HEK-293) cells was observed,enabling the micelles a promising drug carrier for intravesical instilled chemotherapy of bladder cancer.     

One-step fabrication of polymeric Janus nanoparticles for drug delivery

With its unique structure of two compartments, Janus particles can be used for many applications for which monomorphic particles are inadequate, including to be used as a drug delivery system to deliver multiple payloads with widely different solubility. Here we report on a fluidic nanoprecipitation system (FNPS), capable of fabricating biocompatible Janus polymeric nanoparticles comprised of the FDA-approved polymer poly(lactic-co-glycolic acid) (PLGA). The FNPS contains dual inlets, one for each half of the particle, that insert into the precipitation stream. The system provides a one-step approach for production of Janus polymeric particles with submicrometer diameters and is likely amenable to substantial scale-up. To the best of our knowledge, this is the first demonstration of biocompatible Janus nanoparticles that encapsulate a hydrophobic drug (paclitaxel) on one side and a hydrophilic drug (doxorubicin hydrochloride) on the other.     

An iGlu Receptor Antagonist and Its Simultaneous Use with an Anticancer Drug for Cancer Therapy

Glutamate receptor antagonists have been known to play a crucial role in the treatment of many neuronal diseases. Recently, these antagonists have also shown therapeutic effects in the treatment of cancer. In this study, an ionotropic glutamate (iGlu) receptor antagonist, 4‐hydroxyphenylacetyl spermine ( L1 ), was used concurrently with a common anticancer drug, doxorubicin (Dox), for simultaneous cancer therapy. Mesoporous silica nanoparticles (MSNPs) were employed as the delivery vehicle for both L1 and Dox by conjugating the iGlu receptor antagonist on the surface and encapsulating Dox within the mesopores. Dox was then trapped within the mesopores by functionalizing a redox‐cleavable capping group on the MSNP surface, and it could be released upon exposure to the reductive glutathione. In vitro studies on B16F10 and NIH3T3 cell lines revealed that the iGlu receptor antagonist L1 exhibited therapeutic as well as targeting effects. In addition, the simultaneous use of therapeutic L1 and Dox proved to be synergistic in the treatment of cancer. The present work demonstrated the feasibility of employing a delivery system to deliver both neuroprotective drug and anticancer drug for efficient anticancer treatment.     

Construction of a graphene oxide based noncovalent multiple nanosupramolecular assembly as a scaffold for drug delivery

A multiple supramolecular assembly, in which a folic acid-modified β-cyclodextrin (1) acted as a target unit, an adamantanyl porphyrin (2) acted as a linker unit, and graphene oxide acted as a carrier unit, was successfully fabricated through non-covalent interactions and comprehensively investigated by means of UV/Vis, fluorescence, and X-ray photoelectron spectroscopies, and electron microscopy. Significantly, the graphene oxide unit could associate with the anticancer drug doxorubicin through π-π interactions, and the folic acid-modified β-cyclodextrin unit could recognize the folic acid receptors in cancer cells. Owing to the cooperative contribution of these three units, the resulting multiple supramolecular assembly, after association with doxorubicin, exhibited better drug activity and much lower toxicity than free doxorubicin in vivo.     

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

PH-responsive drug release system based on the conjugates of PAMAM dendrimers-doxorubicin (PAMAM-DOX) and superparamagnetic iron oxide (Fe(3)O(4)) nanoparticles (IONPs) has been constructed and characterized. The IONPs were stabilized by mPEG-G2.5 PAMAM dendrimers. The anticancer drug DOX was conjugated to the dendrimer segments of amino-stabilized IONPs using hydrazine as the linker via hydrazone bonds, which is acid cleavable and can be used as an ideal pH-responsive drug release system. The drug release profiles of DOX-PAMAM dendrimer conjugates were studied at pH 5.0 and 7.4. The results showed that the hydrolytic release profile can be obtained only at the condition of lysosomal pH (pH=5.0), and IONPs participated in carrying DOX to the tumor by the Enhanced Permeability and Retention (EPR) effect. These novel DOX-conjugated IONPs have the potential to enhance the effect of MRI contrast and cancer therapy in the course of delivering anticancer drugs to their target sites. Although the dendrimer-DOX-coated IONPs do not have any targeting ligands attached on their surface, they are potentially useful for cancer diagnosis in vivo.     

Temperature-sensitive polypeptide brushes-coated mesoporous silica nanoparticles for dual-responsive drug release

A multifunctional nanohybrid based on mesoporous silica nanoparticle and biocompatible polypeptide was fabricated for targeted and dual-responsive therapy of tumor cells.