Drug-loaded Polymeric Nanoparticles Research Articles

Development and Optimization of Polymeric Nanoparticles and their In vitro Deposition Studies Using Modified TSI

Background: To deliver the drug through the pulmonary route, polymers like oleoylcarboxymethyl chitosan (O-CMC), chitosan, and HPMC (hydroxypropyl methylcellulose) K4M are well known for their effective mucoadhesive properties. Drug-loaded polymeric nanoparticles have the potential for a therapeutic response for the targeted site is a beneficial approach. background: To deliver the drug through the pulmonary route, polymers like oleoyl-carboxymethyl chitosan (O-CMC), chitosan, and HPMC (hydroxypropyl methyl cellulose) K4M are well known for their effective mucoadhesive properties. Drug-loaded polymeric nanoparticles have potential for therapeutic response for the targeted site is a beneficial approach. Objective: The present study is to develop polymeric nanoparticles (PNPs) utilizing mucoadhesive polymers with varying concentrations as well as to develop the PNPs for pulmonary delivery. objective: The present study is to develop polymeric nanoparticles (PNPs) utilizing mucoadhesive polymers with varying concentrations as well as to developed the PNPs for pulmonary delivery. Methods: Polymeric nanoparticles are developed by homogenization and solvent evaporation methods and characterized by modified twin-stage impinger to study in vitro deposition. Results: The characterization of pirfenidone-loaded polymeric nanoparticles (PFD-PNPs) reveals that the mean particle size of O-CMC-PNPs is 140.8 nm ± 20, found to be less than CS-PNPs and HPMC-PNPs. The polydispersibility index reveals that the particles of all prepared formulations are homogenous. At the same time, the zeta potential of O-CMC-PNPs is 40.8 mV ± 5.64, and the entrapment efficiency is 91% ± 1.2, which is better as compared to Chitosan and HPMC K4M PNPs and makes them efficient for pulmonary delivery. Findings from the in vitro deposition study using modified TSI show that 88.5% of the drug delivered through nebulization from both the stage of right and left sides of the TSI suggests effective deposition in the lungs of O-CMC PNPs, and it may move to the deeper regions because of the lowest diameter of the particles. Sustaining release of the drug was found in the O-CMC PNPs for 8 hours, compared with 5 and 7 hours for HPMC PNPs and Chitosan PNPs, respectively. Conclusions: Overall, the results of the O-CMC-PNPs highlight that the prepared nanoparticles with O-CMC would be effective for pulmonary delivery instead of chitosan and HPMC K4M.

Synergic fabrication of dual drug-loaded polymeric nanoparticles system to improve the in vitro treatment of glioma metastasis specific targeting therapy

ABSTRACT Poor drug delivery to the tumour site and harmful drug effects on the nearby healthy tissue are the two main issues with chemotherapeutic treatments for glioma. This study tests the efficacy of a chitosan dual delivery system loaded with rutin and aucubin to treat glioma. It was shown in vitro that rutin/aucubin loaded chitosan nanoparticlesignificantly inhibited U87 cells and promoted apoptosis, and the combination therapy results were superior to those of each compound used alone. The rutin-aucubin combination decreased the glioma cell’s ability to migrate. The chitosan rutin-aucubin nanocomposites showed time dependent cell uptake in U87 cells when labelled with RBITC ANG. At a low dose of 0.156 μg/mL chitosan rutin-aucubin successfully inhibited tumour growth and adhesion and ~ 43% necrosis was observed in mitochondrial membrane potential (ΔΨm) assay. In conclusion, rutin and aucubin drugs were codelivered which inhibited tumour proliferation by inducing cellular apoptosis at a low dose. This showed the system’s potential to effectively enhance glioma therapy.

Formulation and Evaluation of Ocusert Embeded with Ciprofloxacin Loaded Nanoparticles

Formulation and Evaluation of Ocusert Embeded with Ciprofloxacin Loaded Nanoparticles

Targeted Delivery of Anticancer Drug Loaded Charged PLGA Polymeric Nanoparticles Using Electrostatic Field.

Pure positive electrostatic charges (PPECs) show suppressive effect on the proliferation and metabolism of invasive cancer cells without affecting normal tissues. PPECs are used for the delivery of drug-loaded polymeric nanoparticles (DLNs) capped with negatively charged poly(lactide-co-glycolide) (PLGA) and Poly(vinyl-alcohol) PVA into the tumor site of mouse models. The charged patch is installed on top of the skin in the mouse models'tumor region, and the controlled selective release of the drug is assayed by biochemical, radiological, and histological experiments on both tumorized models and normal rats' livers. It is found that DLNs synthesized by PLGA show great attraction to PPECs due to their stable negative charges, which would not degrade immediately in blood. The burst and drug release after less than 48h of this synthesized DLNs are 10% and 50%, respectively. These compounds can deliver the loaded-drug into the tumor site with the assistance of PPECs, and the targeted-retarded release will take place. Hence, local therapy can be achieved with much lower drug concentration (conventional chemotherapy [2mgkg-1 ] versus DLNs-based chemotherapy [0.75mgkg-1 ]) with negligible side effects in non-targeted organs. PPECs have many potential clinical applications for advanced-targeted chemotherapy with the lowest discernible side effects.

Abstract 832: Exosome-based hybrid nanosystem for targeted TNBC therapy

Abstract Treatment of metastatic Triple-Negative Breast Cancer (TNBC) remains a challenge despite an increasing number of newer drugs being approved in recent years. The major challenge for improved treatment outcomes for metastatic cancer originates from the fact that the drugs are unable to reach the targeted site and hence are not able to elicit the desired response. Recently, natural mesenchymal stem cells (MSC) cells and their exosomes have been shown to have tumor-homing properties. By exploiting these homing properties, we propose the development of an exosome-polymeric hybrid nanosystem (EPHN) by using exosomes for their targeting ability to enhance the targetability and thus the therapeutic efficacy of the drug against TNBC. In this study, we bioengineered MSC exosome-coated drug-loaded polymeric nanoparticles to deliver our chemotherapeutic drug in a targeted fashion. To isolate the MSC exosomes, we grew the cells in exosome-free media and used the ultracentrifugation standard method. The MSC exosomes had a size of approximately 70 ± 5 nm and a PDI of 0.3. Our exosome sample was positive for exosomal proteins and negative for all other extracellular vesicles. The optimal doxorubicin-loaded PLGA nanoparticles were prepared using a microfluidics method resulting in a higher entrapment efficiency of 42 ± 3% and a smaller size of 70 ± 3 nm and a PDI of 0.2. To make the exosome-coated NPs, we used the extrusion method. After extrusion, the zeta potential of our EPHN was closer to -11mV compared to PLGA NPs (-50mV), which demonstrates that our NPs were coated with an exosomal membrane. We were able to make MSC exosome-coated drug-loaded polymeric nanoparticles and show that they were stable and uniform in size. Microfluidics-assisted doxorubicin-loaded PLGA nanoparticles show uniform size and higher entrapment efficiency. Release kinetics showed a strong burst phase release over the first 8 hours and subsequent sustained release up to 72 hours. In vivo biodistribution of EPHN shows better tumor accumulation compared to PLGA NP. The next stage in this project is in vivo tumor efficacy testing in breast cancer tumor models. This targeted NP system can serve as a novel therapeutic platform for developing improved treatments for metastatic TNBC. Citation Format: Rohan Joshi, Jana Lampe, Jamboor K. Vishwanatha, Amalendu P. Ranjan. Exosome-based hybrid nanosystem for targeted TNBC therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 832.

AMLODIPINE BESYLATE LOADED POLYMERIC NANOPARTICLES: PREPARATION AND IN VITRO CHARACTERISATION

Objective: The present investigation aims to formulate the ideal drug formulation using different surfactants and optimize the amlodipine-loaded polymeric nanoparticles. Methods: The present work was to formulate the drug-loaded polymeric nanoparticles to enhance the dissolution rate of a poorly water-soluble drug, amlodipine besylate, using the anti-solvent precipitation method. The Characterisation studies include particle size (nm), Zeta potential (mV), polydispersity index, Drug entrapment efficiency (%), in vitro release drug release, and surface morphological studies like SEM and XRD. Results: The drug-loaded Polymeric nanoparticles of F3 containing PLGA and PVA shows the desired smaller particle size is 198.8±5.25, maximum zeta potential is-24.76±2.54 mv and the stable polydispersity index of 0.957±0.45. The drug entrapment efficiency is 93%, and the controlled dissolution of the ideal formulation pattern is about 94.88±2.45 in 24h. Conclusion: The release pattern observed that PNs significantly improved the dissolution character of amlodipine besylate. PNs have a controlled drug release pattern and can be used as a suitable drug delivery carrier for low solubility and poorly bioavailable drugs like amlodipine to improve its dissolution rate.

Cytotoxicity, Antidiabetic and Anticancer Studies of Insulin and Curcumin-Loaded Polymeric Nanoparticles

Cytotoxicity measurement is needed for all drug-loaded nanoparticles. Because, if the nanoparticles have toxicity means, the drug-loaded polymeric nanoparticles cannot be used for the drug delivery. Generally cell viability is measured in the cytotoxicity measurement. In this work, the nanoparticle have synthesized from the natural polymeric material. These nanoparticles have been prepared using a nano-precipitation technique. Drugs, Insulin and Curcumin are added to these synthesized nanoparticles. This drug was coated on the surface of the nanoparticles to enhance the biocompatibility. These drug-loaded polymeric nanoparticles are used for the drug delivery. L929 cells have been to prove the cytotoxicity of these drug loaded polymeric nanoparticles by Neutral red assay method. From the cytotoxicity assay TPIG, TPCG and CCIG, CCCG nanoparticles are not cytotoxic. Insulin-loaded Tapioca/pectin and a Casein/chitosan nanoparticle were used to study the anti- diabetic assay. Curcumin-loaded Tapioca/pectin and Casein/Chitosan nanoparticle were used for Anti-cancer studies, by making use of Human Osteosarcoma cells (HOS). From these studies, the Insulin and Curcumin-loaded Tapioca/pectin and Casein/chitosan nanoparticles are not cytotoxic, and they can be used for drug delivery.

COMPUTATIONAL TOOLS ASSISTED FORMULATION OPTIMIZATION OF NEBIVOLOL HYDROCHLORIDE LOADED PLGA NANOPARTICLES BY 32 FACTORIAL DESIGNS

Objective: The aim of the present study was to formulate and optimize the PLGA polymeric nanoparticle of Nebivolol Hydrochloride for sustain release of drug Methods: The drug-excipients interaction was explored by molecular docking studies by in silico tools. The drug-loaded polymeric nanoparticles prepared by emulsion solvent evaporation method using 32 factorial design and characterized for particle size, zeta potential, and entrapment efficiency. Shape and surface morphology was analysed by SEM and TEM. In vitro drug release study was performed by using a diffusion membrane. Results: The docking analysis inferred that the drug has interacted well with PLGA and PF-68, which could prevent the drug crystal formation. The optimized polymeric nanoparticles had a particle size of 291 nm and entrapment efficiency of 83.4% and were found to be within 95% of CI of the predicted value, which is acceptable. SEM and TEM studies showed that the formed polymeric nanoparticles were smooth, spherical in shape and uniform in size. In vitro drug release study of optimized formulation showed sustained release for prolonged time period Conclusion: Based on the computational studies and in vitro release studies, the developed Nebivolol hydrochloride loaded in PLGA nanoparticles could be a promising formulation in oral drug delivery for the treatment of hypertension.

Preparation and Evaluation of Eprosartan Mesylate loaded PLGA Nanostructures

In modern medication, drug-loaded novel polymeric nanoparticles have potential advantages over conventional dosage forms. The present study focused on the formulation development and evaluation of newly introduced angiotensin receptor blocker (ARB) eprosartan mesylate loaded biodegradable acid terminated poly(lactide-co-glycolide) (50:50) nanoparticle using double emulsion solvent evaporation technique. This methodology was found to improve the therapeutic efficacy as Eprosartan Mesylate belongs to BCS class-II and water-insoluble antihypertensive drug with 13% bioavailability. In the earlier stage, screening was performed to find out the suitable combination of excipients (Polyvinyl alcohol, Dichloromethane and Ethanol) to formulate the nanoparticles. In this present study, the physical and chemical properties of polymer and drug were determined before and after the formulation of nanoparticles using experimental techniques, such as Differential Light Scattering (DLS), zeta potential, X-ray Deffractometry (XRD), Fourier-Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and Liquid Chromatography-Mass Spectrometry (LC-MS/MS) analysis. The eprosartan mesylate loaded PLGA nanoparticles showed fairly monodispersive, as determined from DLS (average particle diameter 136 nm, Poly Dispesity Index = 0.3). The zeta potential was found to be -10.8mV. This formulation showed a prolonged improved drug release (82.03%) for 360 hours in phosphate buffer (pH7.4) as compared to the conventional marketed dosage form. In-vitro release kinetics data of NPs (R2=0.8979) and diffusion exponent values (n=0.3328) suggested that optimized followed the Korsmeyer-Peppas model with Fickian mechanism.

Precise engineering of dual drug-loaded polymeric nanoparticles system to improve the treatment of glioma-specific targeting therapy

We have fabricated a novel method to achieve therapy- triggered changes in tumor cells by using promising effects concerning dual chemotherapeutic drugs. Dual-drug conveyance of Salinomycin (SAL) and Doxorubicin (DOX) exhibits a great anti-tumor ability, as SAL improves the impact of DOX management of glioma cells by supplying stability of the microenvironment. Nevertheless, encapsulations of SAL and DOX fanatical by (lactic-co-glycolic acid (PLGA) and polyethylene glycol (PEG)- based nanoparticles (NPs) is incompetents due to inappropriateness between the dual drug SAL and DOX polymeric framework. At the present, we show DOX and SAL can be formulated with dioleoylphosphatide acid (DOPA) through the hydrophobic covering of drug centers. In PEG-PLGA NPs, the DOPA- enclosed DOX can be co-incorporating in addition to SAL to encourage superior cancer activities. The DOX revealed seductively that the SAL encapsulations in PEG-PLGA NPs (SAL-DOX NPs) were improved. The transmission microscopy (TEM) studied the morphology of SAL NPs, DOX NPs, SAL-DOX NPs, and nanoparticle size. SAL-DOX NPs also induced major apoptosis in vitro human glioma cells such as LN229 and U251. Different biochemical trials such as AO-EB, Hoechst staining, and annexin V-FITC have confirmed morphological observations and apoptosis. The findings indicate that the SAL-DOX NPs is one of the promising caregivers of therapeutic candidates for human glioma cancer worth further study.

Engineering of hybrid anticancer drug-loaded polymeric nanoparticles delivery system for the treatment and care of lung cancer therapy

Chemotherapy with combination drugs has become one of the most commonly used cancer prevention treatments, with positive clinical results. The goal of this study was to develop compostable polymeric nanomaterials (NMs) for the delivery of puerarin (PRN) and 5-fluorouracil (5FU), as well as to investigate the anticancer activity of the drug delivery system (PRN-5FU NMs) against in vitro and in vivo lung cancer cells. Since double antitumor drugs PRN and 5FU are insufficiently compressed in polymer-based bio-degradable nanoparticles, encapsulation of PRN and 5FU antitumor drugs were co-encapsulated with polyethylene glycol and polylactidecoglycolide nanoparticles (NMs) is efficient. The arrangement of PRN NMs, 5FU NMs, and PRN-5FU NMs, as well as the nanoparticles shape and scale, were studied using transmission electron microscopy (TEM). 5FU-PRN NMs triggered apoptosis in lung carcinoma cell lines such as HEL-299 and A549 in vitro. Acridine orange/ethidium bromide (AO/EB) and nuclear damaging staining techniques were used to observe morphologies and cell death. The mechanistic analysis of apoptosis was also confirmed by flow cytometry analysis using dual staining. When compared to free anticancer products, the hemolysis analysis findings of the 5FU-PRN NMs showed excellent biocompatibility. Taken together the advantages, this combination drug conveyance strategy exposed that 5FU-PRN NMs could have a significant promising to improve the effectiveness of lung cancer cells.

Drug-loaded polymeric nanoparticles: a review

Polymeric nanoparticles are one of the most studied strategies in modern medicine for drug encapsulation. The researchers' main interest is a formulation capable of administering the medication in a controlled mode and specific site. In this context, stimulus-responsive nanoparticles are highlighted, as these systems can have long circulation times, achieve the disease site, and improve intracellular medication administration. Therefore, this review addressed trends in drug delivery mechanisms and the influence of internal and external stimulus sources on the stimulus-responsive nanocarriers. Moreover, conventional and emerging methods for the synthesis of polymeric nanoparticles were reviewed.

Biodegradable Nanoparticles Based on Pseudo-Proteins Show Promise as Carriers for Ophthalmic Drug Delivery.

Purpose: Drug delivery to treat ocular diseases still is a challenge in ophthalmology. One way to achieve drug delivery that is investigated currently is topical administration of drug-loaded polymeric nanoparticles (NPs) that are able to penetrate ocular barriers. The purpose of this study was optimal preparation of NPs made from pseudo-proteins and evaluation of their ability to penetrate ocular tissues. Methods: Biodegradable NPs of various types were prepared by nanoprecipitation of pseudo-protein composed of l-leucine (L), 1,6-hexanediol (6), and sebacic acid (8) (8L6). Arginine-based cationic polyester amides 8R6 and comb-like polyester amide containing lateral PEG-2000 chains along with 8L6 anchoring fragments in the backbones were used to construct positively charged and PEGylated NPs. They were loaded with fluorescein diacetate (FDA) or rhodamine 6G (Rh6G) as fluorescent probes. Suspensions of the NPs were given to cultivated microglial cells and retinal pigment epithelial (RPE) cells as well as topically on eyes of C57BL/6 mice. Penetration of NPs into the eyes was checked by fluorescence analysis. Results: NPs were prepared, and their properties were characterized. Cultured microglial cells and RPE cells took up the NPs. After topical administration, penetration of NPs into the cornea of the eyes was clearly seen. Small amounts of fluorescent dyes were also found in the lens, the retina, and the sclera depending on the type of NPs. Conclusions: The results showed that the new NPs penetrate ocular tissues after topical administration and are internalized by the cells. This raises confidence that the NPs may be useful carriers of therapeutic agents for ocular delivery.

Abstract TMIM-083: A TWO-STEP TARGETING STRATEGY UTILIZING GLYCOENGINEERED MESENCHYMAL STEM CELLS FOR OVARIAN CANCER

Abstract Current tumor targeted drug delivery systems suffer from a lack of selectivity for tumor cells. We propose a two-step tumor targeting strategy to improve the delivery of therapeutic agents to metastatic ovarian cancer. The two-step targeting approach relies on the introduction of non-natural targets (azide functional groups) in the tumor tissue, followed by the delivery of drug-loaded polymeric nanoparticles that are surface modified (with dibenzyl cyclooctyne; DBCO) and have high affinity for these synthetic targets. The objective of the present study was to determine the in vivo efficacy of two-step targeting in a clinically-realistic, patient-derived xenograft (PDX) model of ovarian cancer. The DBCO functionalized, paclitaxel (PTX)-loaded nanoparticles (16.2% w/w PTX; diameter 320 ± 10 nm; and zeta potential -11.5 ± 1.3 mV) were formulated using the FDA approved, biodegradable and biocompatible polymer, poly (DL-lactide-co-glycolide) (PLGA), by emulsion-solvent evaporation method. Glycoengineered mesenchymal stem cells (MSC-Az) were generated by culturing MSCs in N-azidoacetylmannosamine-tetraacylated supplemented media without affecting their viability or tumor homing properties. Anticancer efficacy of MSC-Az mediated two-step targeting strategy was evaluated in female athymic nude mice bearing PDX tumors. Mice with generation 2 tumors were randomly divided into four groups receiving intravenous injection of saline, PTX solution, DBCO-PTX nanoparticles, and intravenous injection of MSC-Az followed by intravenous injection of DBCO-PTX nanoparticles (MSC-Az + DBCO-PTX). We observed significantly reduced tumor growth (p <0.05) and improved survival in the group receiving MSC-Az + DBCO-PTX compared to all other groups. Furthermore, immunohistochemical analysis of the tumor tissues demonstrated that the animals treated with MSC-Az + DBCO-PTX had extensive necrosis compared to other groups, suggesting the potential of MSCs for improved tumor targeting and inhibition. In summary, our results demonstrate the potential of two-step tumor targeting strategy to enhance tumor specific delivery of conventional chemotherapeutic drugs resulting in significantly improved anti–cancer efficacy. Citation Format: Buddhadev Layek, Mihir Shetty, Tim Starr, Swayam Prabha. A TWO-STEP TARGETING STRATEGY UTILIZING GLYCOENGINEERED MESENCHYMAL STEM CELLS FOR OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-083.

Application of statistical design to evaluate critical process parameters and optimize formulation technique of polymeric nanoparticles.

In advanced medication, drug-loaded polymeric nanoparticles (NPs) appeared as a novel drug delivery system with lots of advantages over conventional medicines. Despite all the advantages, NPs do not gain popularity for manufacturing hurdles. The study focused on the formulation difficulties and implementation of statistical design to establish an effective model for manufacturing NPs. In this study, physico-chemical properties of the drug and polymer (PLGA) were incorporated to understand the mechanistic insights of nanoformulations. Primarily, the process controlling parameters were screened by Plackett–Burman design and the critical process parameters (Cpp) were further fabricated by Box–Behnken design (BBD). The TLM-PLGA-NPs (telmisartan loaded PLGA NPs) exhibited particle size, encapsulation efficiency and zeta potential of 232.4 nm, 79.21% and −9.92 mV respectively. The NPs represented drug loading of 76.31%. Korsmeyer–Peppas model (R2 = 0.925) appeared to be the best fitted model for in vitro release kinetics of NPs. The model identified Fickian diffusion of TLM from the polymeric nanoparticles. The ANOVA results of variables indicate that BBD is a suitable model for the development of polymeric NPs. The study successfully identified and evaluated the correlation of significant parameters that were directly or indirectly influencing the formulations which deliberately produce desired nanoparticles with the help of statistical design.

Abstract 987: Glycoengineered MSCs for targeting platinum resistant ovarian tumors

Abstract Tumor-targeted delivery of chemotherapeutics can improve efficacy while mitigating their debilitating side effects. However, current drug delivery approaches rely on inefficient passive accumulation of delivery systems in the tumor and suffer from significant non-specific distribution. Here, we propose a novel two-step tumor targeting strategy that can improve delivery of cytotoxic agents to both primary tumor as well as metastatic lesions, resulting in effective tumor inhibition. This strategy involves introduction of non-natural targets in the tumor tissue via glycoengineered mesenchymal stem cells (MSCs expressing targetable synthetic azide groups) followed by the delivery of drug-loaded polymeric nanoparticles (surface functionalized with dibenzyl cyclooctyne; DBCO) that have high affinity for these synthetic targets. DBCO surface functionalized, paclitaxel (PTX)-loaded nanoparticles (DBCO-PTX NP; 17.6% w/w PTX; diameter 313.7 ± 13 nm; and zeta potential -12.5 ± 1.9 mV) were formulated using poly (DL-lactide-co-glycolide) (PLGA) polymer by emulsion-solvent evaporation method. Glycoengineered MSCs (MSC-Az) were generated by culturing MSCs in N-azidoacetylmannosamine-tetraacylated supplemented media without affecting their viability or tumor homing properties. Binding of MSC-Az to DBCO-PTX NP was confirmed with confocal microscopy and flow cytometry analysis. Anticancer efficacy of two-step targeting strategy was evaluated in murine model of platinum-resistant orthotopic ovarian C200-luc tumors. Treatment with MSC-Az + DBCO-PTX nanoparticles resulted in significant inhibition of the tumor growth (p < 0.05) and improved survival (p < 0.05) compared to that with other controls. In summary, our results demonstrate the potential of two-step tumor targeting strategy to enhance the anticancer efficacy of conventional chemotherapeutic drugs. Citation Format: Buddhadev Layek, Drishti Sehgal, Jayanth Panyam, Swayam Prabha. Glycoengineered MSCs for targeting platinum resistant ovarian tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 987.

Paclitaxel Magnetic Core⁻Shell Nanoparticles Based on Poly(lactic acid) Semitelechelic Novel Block Copolymers for Combined Hyperthermia and Chemotherapy Treatment of Cancer.

Magnetic hybrid inorganic/organic nanocarriers are promising alternatives for targeted cancer treatment. The present study evaluates the preparation of manganese ferrite magnetic nanoparticles (MnFe2O4 MNPs) encapsulated within Paclitaxel (PTX) loaded thioether-containing ω-hydroxyacid-co-poly(d,l-lactic acid) (TEHA-co-PDLLA) polymeric nanoparticles, for the combined hyperthermia and chemotherapy treatment of cancer. Initially, TEHA-co-PDLLA semitelechelic block copolymers were synthesized and characterized by 1H-NMR, FTIR, DSC, and XRD. FTIR analysis showed the formation of an ester bond between the two compounds, while DSC and XRD analysis showed that the prepared copolymers were amorphous. MnFe2O4 MNPs of relatively small crystallite size (12 nm) and moderate saturation magnetization (64 emu·g−1) were solvothermally synthesized in the sole presence of octadecylamine (ODA). PTX was amorphously dispersed within the polymeric matrix using emulsification/solvent evaporation method. Scanning electron microscopy along with energy-dispersive X-ray spectroscopy and transmission electron microscopy showed that the MnFe2O4 nanoparticles were effectively encapsulated within the drug-loaded polymeric nanoparticles. Dynamic light scattering measurements showed that the prepared nanoparticles had an average particle size of less than 160 nm with satisfactory yield and encapsulation efficiency. Diphasic PTX in vitro release over 18 days was observed while PTX dissolution rate was mainly controlled by the TEHA content. Finally, hyperthermia measurements and cytotoxicity studies were performed to evaluate the magnetic response, as well as the anticancer activity and the biocompatibility of the prepared nanocarriers.

How to unravel the chemical structure and component localization of individual drug-loaded polymeric nanoparticles by using tapping AFM-IR.

AFM-IR is a photothermal technique that combines AFM and infrared (IR) spectroscopy to unambiguously identify the chemical composition of a sample with tens of nanometer spatial resolution. So far, it has been successfully used in contact mode in a variety of applications. However, the contact mode is unsuitable for soft or loosely adhesive samples such as polymeric nanoparticles (NPs) of less than 200 nm of wide interest for biomedical applications. We describe here the theoretical basis of the innovative tapping AFMIR mode that can address novel challenges in imaging and chemical mapping. The new method enables gaining information not only on NP morphology and composition, but also reveals drug location and core-shell structures. Whereas up to now the locations of NP components could only be hypothesized, tapping AFM-IR allows accurately visualizing both the location of the NPs' shells and that of the incorporated drug, pipemidic acid. The preferential accumulation of the drug in the NPs' top layers was proved, despite its low concentration (<1 wt%). These studies pave the way towards the use of tapping AFM-IR as a powerful tool to control the quality of NP formulations based on individual NP detection and component quantification.

Co-delivery of cisplatin and CJM-126 via photothermal conversion nanoparticles for enhanced synergistic antitumor efficacy

Polymeric biomaterials that can be smartly disassembled through the cleavage of the covalent bonds in a controllable way upon an environmental stimulus such as pH change, redox, special enzymes, temperature, or ultrasound, as well as light irradiation, but are otherwise stable under normal physiological conditions have attracted great attention in recent decades. The 2-(4-aminophenyl) benzothiazole molecule (CJM-126), as one of the benzothiazole derivatives, has exhibited a synergistic effect with cisplatin (CDDP) and restrains the bioactivities of a series of human breast cancer cell lines. In our study, novel NIR-responsive targeted binary-drug-loaded nanoparticles encapsulating indocyanine green (ICG) dye were prepared as a new co-delivery and combined therapeutic vehicle. The prepared drug-loaded polymeric nanoparticles (TNPs/CDDP-ICG) are stable under normal physiological conditions, while burst drugs release upon NIR laser irradiation in a mild acidic environment. The results further confirmed that the designed co-delivery platform showed higher cytotoxicity than the single free CDDP due to the synergistic treatment of CJM-126 and CDDP in vitro. Taken together, the work might provide a promising approach for effective site-specific antitumor therapy.

Light-Responsive Nanoparticles for Highly Efficient Cytoplasmic Delivery of Anticancer Agents.

Stimuli-responsive nanostructures have shown great promise for intracellular delivery of anticancer compounds. A critical challenge remains in the exploration of stimuli-responsive nanoparticles for fast cytoplasmic delivery. Herein, near-infrared (NIR) light-responsive nanoparticles were rationally designed to generate highly efficient cytoplasmic delivery of anticancer agents for synergistic thermo-chemotherapy. The drug-loaded polymeric nanoparticles of selenium-inserted copolymer (I/D-Se-NPs) were rapidly dissociated in several minutes through reactive oxygen species (ROS)-mediated selenium oxidation upon NIR light exposure, and this irreversible dissociation of I/D-Se-NPs upon such a short irradiation promoted continuous drug release. Moreover, I/D-Se-NPs facilitated cytoplasmic drug translocation through ROS-triggered lysosomal disruption and thus resulted in highly preferable distribution to the nucleus even in 5 min postirradiation, which was further integrated with light-triggered hyperthermia for achieving synergistic tumor ablation without tumor regrowth.