Biodegradable Polymeric Nanoparticles Research Articles

Mix and Shake: A Mild Way to Drug-Loaded Lysozyme Nanoparticles.

Biocompatible nanoparticles as drug carriers can improve the therapeutic efficiency of hydrophobic drugs. However, the synthesis of biocompatible and biodegradable polymeric nanoparticles can be time-consuming and often involves toxic solvents. Here, a simple method for protein-based stable drug-loaded particles with a narrow polydispersity is introduced. In this process, lysozyme is mixed with hydrophobic drugs (curcumin, ellipticine, and dasatinib) and fructose to prepare lysozyme-based drug particles of around 150 nm in size. Fructose is mixed with the drug to generate nanoparticles that serve as templates for the lysozyme coating. The effect of lysozyme on the physicochemical properties of these nanoparticles is studied by transmission electron microscopy (TEM) and scattering techniques (e.g., dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS)). We observed that lysozyme significantly stabilized the curcumin fructose particles for 7 days. Moreover, additional drugs, such as ellipticine and dasatinib, can be loaded to form dual-drug particles with narrow polydispersity and spherical morphology. The results also reveal that lysozyme dual ellipticine/dasatinib curcumin particles enhance the cytotoxicity and uptake on MCF-7 cells, RAW 264.7 cells, and U-87 MG cells due to the larger and rigid hydrophobic core. In summary, lysozyme in combination with fructose and curcumin can serve as a powerful combination to form protein-based stable particles for the delivery of hydrophobic drugs.

Development of clobetasol-loaded biodegradable nanoparticles as an endodontic intracanal medicament.

The aim of current study is the development and optimization of biodegradable polymeric nanoparticles (NPs) to be used in the field of Endodontics as intracanal medication in cases of avulsed teeth with extended extra-oral time, utilizing PLGA polymers loaded with the anti-inflammatory drug clobetasol propionate (CP). CP-loaded nanoparticles (CP-NPs) were prepared using the solvent displacement method. CP release profile from CP-NPs was assessed for 48 h against free CP. Using extracted human teeth, the degree of infiltration inside the dentinal tubules was studied for both CP-NPs and CP. The anti-inflammatory capacity of CP-NPs was evaluated invitro measuring their response and reaction against inflammatory cells, in particular against macrophages. The enzyme-linked immunosorbent assay (ELISA) was used to examine the cytokine release of IL-1β and TNF-α. Optimized CP-NPs displayed an average size below 200 nm and a monomodal population. Additionally, spherical morphology and non-aggregation of CP-NPs were confirmed by transmission electron microscopy. Interaction studies showed that CP was encapsulated inside the NPs and no covalent bonds were formed. Moreover, CP-NPs exhibited a prolonged and steady release with only 21% of the encapsulated CP released after 48 h. Using confocal laser scanning microscopy, it was observed that CP-NPs were able to display enhanced penetration into the dentinal tubules. Neither the release of TNF-α nor IL-1β increased in CP-NPs compared to the LPS control, displaying results similar and even less than the TCP after 48 h. Moreover, IL-1β release in LPS-stimulated cells, decreased when macrophages were treated with CP-NPs. In the present work, CP-NPs were prepared, optimized and characterized displaying significant increase in the degree of infiltration inside the dentinal tubules against CP and were able to significantly reduce TNF-α release. Therefore, CP-NPs constitute a promising therapy for the treatment of avulsed teeth with extended extra-oral time.

Abstract 5817: pH responsive delivery of gemcitabine/pirarubicin co-loaded biodegradable polymeric nanoparticles for synergistic anti-cancer therapy

Abstract Gemcitabine, a nucleoside antimetabolite, is a widely known chemotherapeutic agent being used as a first line treatment alone or in combination with other chemo drugs for different types of cancer. However, due to its extremely short half-life in the body caused by enzymatic degradation and poor pharmacokinetics, the I.V. dosage of administration is quite high i.e., >1000 mg/m2 for metastatic breast cancer treatment. Moreover, gemcitabine in combination with anthracyclines imparts synergy but free anthracyclines are reported to be associated with long term cardiac toxicity. Nanoparticle-based drug delivery systems have provided a befitted solution for improving the poor pharmacokinetic properties and systemic toxicity caused by the chemo drugs because of their ability to improve bioavailability of the drugs at the desired site as well as overcoming multi-drug resistance (MDR).In the present work, PLA-based biodegradable block copolymeric nanoparticles have been employed to co-load Gemcitabine and Pirarubicin for improved anti-cancer activity. Gemcitabine and Pirarubicin have been chemically conjugated to the amphiphilic block copolymer mPEG PLA via a pH responsive Schiff’s Base linkage using a linker molecule Levulinic acid. The prepared PIRA/GEM co-loaded nanoparticles exhibited an optimum size, zeta potential and polydispersity index i.e., 187 ± 3.5 nm, -10 ± 2.0 and < 0.1 PDI respectively. Further, in the drug release experiments, these Nps displayed sustained and higher drug release in lysosomal pH (pH 5.0) than in the physiological buffer environment (pH 7.4) attributed to the pH sensitive bonding. The co-loaded Nps were prepared in multiple ratios (Pira: Gem - 1:1, 1:3, and 3:1) and investigated for in-vitro cellular inhibition studies in comparison to singly loaded drug Nps and corresponding free drug formulations in various breast cancer cell lines. Additionally, apoptotic studies revealed significant enhancement in synergistic activity in the case of PIRA/GEM co-loaded Nps in comparison to conventional free drug formulations. In conclusion, this nano-formulation demonstrated excellent anti-cancer activity against breast cancer cells therefore it may be used as a potential candidate for therapeutic use. Citation Format: Priya Gupta, Surender M. Kharbanda, Harpal Singh. pH responsive delivery of gemcitabine/pirarubicin co-loaded biodegradable polymeric nanoparticles for synergistic anti-cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5817.

Synthesis of gold nanoparticle-immobilized biodegradable polymer nanoparticles and their degradation properties

Synthesis of gold nanoparticle-immobilized biodegradable polymer nanoparticles and their degradation properties

Rational design of biodegradable semiconducting polymer nanoparticles for NIR-II fluorescence imaging-guided photodynamic therapy

Rational design of biodegradable semiconducting polymer nanoparticles for NIR-II fluorescence imaging-guided photodynamic therapy

Aerosolizable Pyrazinamide-Loaded Biodegradable Nanoparticles for the Management of Pulmonary Tuberculosis.

Background: Pyrazinamide is a Biopharmaceutical Classification System class III antibiotic indicated for active tuberculosis. Methods: In the present work, pyrazinamide-loaded biodegradable polymeric nanoparticles (PNPs) based dry powder inhaler were developed using the double emulsion solvent evaporation technique and optimized using design of experiments to provide direct pulmonary administration with minimal side effects. Batches were characterized for various physicochemical and aerosol performance properties. Results: Optimized batch exhibited particle size of 284.5 nm, % entrapment efficiency of 71.82%, polydispersibility index of 0.487, zeta potential of -17.23 mV, and in vitro drug release at 4 hours of 79.01%. Spray-dried PNPs were evaluated for drug content, in vitro drug release, and kinetics. The particle mass median aerodynamic diameter was within the alveolar region's range (2.910 μm). In the trachea and lung, there was a 2.5- and 1.2-fold increase in in vivo deposition with respect to pure drug deposition, respectively. In vitro drug uptake findings showed that alveolar macrophages with pyrazinamide PNPs had a considerably higher drug concentration. Furthermore, accelerated stability studies were carried out for the optimized batch. Results indicated no significant change in the evaluation parameters, which showed stability of the formulation for at least a 6-month period. Conclusion: PNPs prepared using biodegradable polymers exhibited efficient pulmonary drug delivery with decent stability.

Biosecurity test of conjugated nanoparticles of chitosan-protoporphyrin IX-vitamin B9 for their use in photodynamic therapy.

The main obstacle of Photodynamic Therapy (PDT) to damage and destroy abnormal cells is that most photosensitizers (Ps) have a highly hydrophobic nature with a tendency to aggregate in aqueous solutions and the non-specificity towards target cells. Nanotechnology proposes new tactics for the development of monomeric Ps nanotransporters and active targeting molecules with the use of biodegradable polymeric nanoparticles to improve the specificity towards target cells. However, these products must comply with safety tests to be endorsed as therapeutic alternatives by regulatory organizations. The goal of this work was to optimize the synthesis of chitosan polymeric nanoparticles conjugated with protoporphyrin IX and vitamin B9 (CNPs-PpIX-B9) by the ionic gelation method from the established protocol previously carried out by our laboratory with 1.74 times fold of efficiency. They were characterized by ultraviolet light-visible light, infrared spectroscopy and transmission electron microscopy. In addition, in CHO-K1 cells the biosafety (cytotoxicity and genotoxicity) of conjugate was assessed following the recommendations of the chromosomal aberrations test by OEDC 473 (2016) guideline. The conjugate did not show evidence of genotoxicity (clastogenicity). Surprisingly, the significant differences between the treatments performed and the negative control do not represent increases in chromosomal aberrations, whereby the safe concentrations to use the conjugate without inducing cytotoxic or genotoxic effects are less than 0.25 mg / mL. Since it induced a significant decrease of structural chromosomal aberrations, generating a positive effect on the genomic stability of CHO-K1 cells cultured in this test system.

Design and optimization of chitosan-alginate nanoparticles for plant growth hormone indole-3-acetic acid

Excessive use of agrochemicals can lead to environmental degradation, and thus, a potential solution is to control their release using biodegradable polymeric nanoparticles. This study aimed to fabricate indole-3-acetic acid chitosan/alginate nanoparticles (IAA-CANPs) through o/w emulsification and ionotropic gelation, employing a Box-Behnken design (BBD) to evaluate the influence of various factors (alginate: chitosan mass ratio (ALG:CS), TweenTM 80, and IAA concentration) on particle size, zeta potential, and encapsulation efficiency (EE). Response surface methodology (RSM) was used to determine the optimum conditions for nanoparticle fabrication, which were ALG:CS mass ratio of 1:0.10, TweenTM 80 of 1.5% w/v, and IAA of 15 mg/mL. The IAA-CANPs produced under these optimal conditions exhibited an average particle size of 275 ± 19 nm, a polydispersity index (PDI) of 0.37 ± 0.9, a zeta potential of -23.8 ± 0.8 mV, and an EE of 68.5 ± 1.4%. The IAA-CANPs also demonstrated superior physico-chemical stability under UV irradiation exposure compared to free IAA. The IAA-CANPs had stability up to 3 months at 4°C. The release pattern in dissolution media at pH 5.5 and 7.5 indicated a sustained-release behavior, which fit well with the Peppas-Sahlin kinetic model, indicating anomalous diffusion, a non-Fickian diffusion mechanism. These findings suggest that CANPs could be a promising approach for encapsulating and controlling the release of IAA, exhibiting excellent physicochemical stability and potential for agricultural applications.

Abstract A031: Development of poly lactic acid based biodegradable nanoparticles for co-delivery of pirarubicin and gemcitabine for synergistic anti-tumor efficacy

Abstract Nanoparticles based drug delivery systems have provided a befitted solution for the poor pharmacokinetic properties and systemic toxicity caused by the chemo drugs because of their ability to improve bioavailability of the drugs at the desired site and thereby decreasing extracellular toxicity. The present work investigates the single or dual chemo drugs loaded PLA-based biodegradable polymeric nanoparticles for improved anti-tumor efficacy as compared to free drug formulations. For the study, an amphiphilic block copolymer; mPEG PLA has been synthesized and characterized using Gel permeation chromatography (GPC) for its molecular weight and poly dispersity index as well as with Nuclear magnetic resonance (NMR) and Fourier-transform Infrared (FT-IR) spectroscopies. Thereafter, two different chemo drugs Pirarubicin (PIRA, THP analogue of Doxorubicin) and Gemcitabine (GEM) have been chemically conjugated individually to mPEG PLA block copolymer via a linker molecule, Levulinic acid to give an acid labile polymer-drug conjugate and the % drug conjugation efficiency has been calculated using High performance liquid chromatography (HPLC). The synthesized polymer-drug conjugates have been employed to prepare PIRA/GEM single or dual-loaded nanoparticles via nanoprecipitation technique and the physiochemical properties including size, zeta potential, and stability were analyzed using Dynamic Light Scattering (DLS) and High-resolution transmission electron microscopy (HR-TEM). To carry out toxicity assessment of the mPEG PLA nanoparticles, both cytocompatibility and hemocompatibility were checked using MTT assay and Hemolysis assay respectively. Moreover, the cellular internalization studies of dye-loaded mPEG PLA nanoparticles were done using Confocal microscopy on SUM-149, breast cancer cells. Besides, the drug release kinetic studies of the free PIRA/GEM from the PIRA/GEM single or dual-loaded nanoparticles were carried out in different pH environments; pH 7.4 and pH 5.0. The in-vitro cell proliferation inhibition studies of PIRA/GEM or dual-loaded nanoparticles were carried out on different human and murine breast cancer cell lines including MCF-7, MDA-MB-468, SUM 149, MDA-MB-231 and 4T1 and half-maximal inhibitory concentrations (IC50 values) were compared to that of respective free drug formulations. The overall results suggested that the prepared sub-nano sized PIRA/GEM single or dual-loaded particles are highly stable, uniformly spherical in size and biocompatible in nature. They were found to possess high cellular uptake, sustained drug release rate and synergistic efficacy and potential against both human and murine breast cancer cells in-vitro conditions. Citation Format: Priya Gupta. Development of poly lactic acid based biodegradable nanoparticles for co-delivery of pirarubicin and gemcitabine for synergistic anti-tumor efficacy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A031.

Design-of-Experiment-Assisted Fabrication of Biodegradable Polymeric Nanoparticles: In Vitro Characterization, Biological Activity, and In Vivo Assessment.

Berberine (BER) is an alkaloid obtained from berberis plant having broad biological activities including anticancer. BER-encapsulated alginate (ALG)/chitosan (CHS) nanoparticles (BER-ALG/CHS-NPs) were developed for long-acting improved treatment in breast cancer. The surface of the NPs was activated by a conjugation reaction, and thereafter, the BER-ALG/CHS-NP surface was grafted with folic acid (BER-ALG/CHS-NPs-F) for specific targeting in breast cancer. BER-ALG/CHS-NPs-F was optimized by applying the Box-Behnken design using Expert design software. Moreover, formulations are extensively evaluated in vitro for biopharmaceutical performances and tested for cell viability, cellular uptake, and antioxidant activity. The comparative pharmacokinetic study of formulation and free BER was carried out in animals for estimation of bioavailability. The particle size recorded for the diluted sample using a Malvern Zetasizer was 240 ± 5.6 nm. The ζ-potential and the predicted % entrapment efficiency versus (vs) observed were +18 mV and 83.25 ± 2.3% vs 85 ± 3.5%. The high % drug release from the NPs was recorded. The analytical studies executed using infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction expressed safe combinations of the components in the formulation and physical state of the drug revealed to be amorphous in the formulation. Cytotoxicity testing demonstrated that the formulation effectively lowered the cell viability and IC50 of the tested cell line in comparison to a raw drug. The cellular uptake of BER-ALG/CHS-NPs-F was 5.5-fold higher than that of BER-suspension. The antioxidant capacities of BER-ALG/CHS-NPs-F vs BER-suspension by the DPPH assay were measured to be 62.3 ± 2.5% vs 30 ± 6%, indicating good radical scavenging power of folate-conjugated NPs. The developed formulation showed a 4.4-fold improved oral bioavailability compared to BER-suspension. The hemolytic assay intimated <2% destruction of erythrocytes by the developed formulation. The observed experimental characterization results such as cytotoxicity, cellular uptake, antioxidant activity, and improved absorption suggested the effectiveness of BER-ALG/CHS-NPs-F toward breast cancer.

Preparation of biodegradable polymer nanoparticles stabilized with the poly (vinyl alcohol)-sodium dodecyl sulfate mixture: Effect of the lactide/glycolide molar ratio

Preparation of biodegradable polymer nanoparticles stabilized with the poly (vinyl alcohol)-sodium dodecyl sulfate mixture: Effect of the lactide/glycolide molar ratio

Development of an oral nanovaccine for dogs against Echinococcus granulosus

Dogs are the main source of animal and human cystic echinococcosis caused by the Cestode parasite Echinococcus granulosus. Dog vaccination seems to be a good strategy to control this parasitic disease. Here we present the development of a polymeric nanoparticle-based oral vaccine for dogs against Echinococcus granulosus delivered in enteric-coated capsules. To achieve our target, we encapsulated two recombinant antigens into biodegradable polymeric nanoparticles in the presence of Monophosphoryl lipid A as an adjuvant to ensure efficient delivery and activation of a protective mucosal immune response. The formulated delivery system showed a nanoparticle size less than 200 nm with more than 80 % antigen encapsulation efficiency and conserved integrity and immunogenicity. The nanoparticle surface was coated with chitosan to enhance adhesion to the gut mucosa and a subsequent antigen delivery. Chitosan-coated nanoparticles showed a higher cell internalization in murine macrophages and dendritic cells as well as a higher penetration into Caco-2 cells in vitro. Antigen-loaded nanoparticles were freeze-dried and enteric-coated capsules were filled with the obtained powder. The obtained results show a promising nanoparticles delivery system for oral vaccination.

Red-Light-Photosensitized NO Release and Its Monitoring in Cancer Cells with Biodegradable Polymeric Nanoparticles.

The role of nitric oxide (NO) as an "unconventional" therapeutic and the strict dependence of biological effects on its concentration require the generation of NO with precise spatiotemporal control. The development of precursors and strategies to activate NO release by excitation in the so-called "therapeutic window" with highly biocompatible and tissue-penetrating red light is desirable and challenging. Herein, we demonstrate that one-photon red-light excitation of Verteporfin, a clinically approved photosensitizer (PS) for photodynamic therapy, activates NO release, in a catalytic fashion, from an otherwise blue-light activatable NO photodonor (NOPD) with an improvement of about 300 nm toward longer and more biocompatible wavelengths. Steady-state and time-resolved spectroscopic and photochemical studies combined with theoretical calculations account for an NO photorelease photosensitized by the lowest triplet state of the PS. In view of biological applications, the water-insoluble PS and NOPD have been co-entrapped within water-dispersible, biodegradable polymeric nanoparticles (NPs) of mPEG-b-PCL (about 84 nm in diameter), where the red-light activation of NO release takes place even more effectively than in an organic solvent solution and almost independently by the presence of oxygen. Moreover, the ideal spectroscopic prerequisites and the restricted environment of the NPs permit the green-fluorescent co-product formed concomitantly to NO photorelease to communicate with the PS via Förster resonance energy transfer. This leads to an enhancement of the typical red emission of the PS offering the possibility of a double color optical reporter useful for the real-time monitoring of the NO release through fluorescence techniques. The suitability of this strategy applied to the polymeric NPs as potential nanotherapeutics was evaluated through biological tests performed by using HepG2 hepatocarcinoma and A375 melanoma cancer cell lines. Fluorescence investigation in cells and cell viability experiments demonstrates the occurrence of the NO release under one-photon red-light illumination also in the biological environment. This confirms that the adopted strategy provides a valuable tool for generating NO from an already available NOPD, otherwise activatable with the poorly biocompatible blue light, without requiring any chemical modification and the use of sophisticated irradiation sources.

Effect of Nanoparticle Weight on the Cellular Uptake and Drug Delivery Potential of PLGA Nanoparticles.

Biodegradable and biocompatible polymeric nanoparticles (NPs) stand out as a key tool for improving drug bioavailability, reducing the inherent toxicity, and targeting the intended site. Most importantly, the ease of polymer synthesis and its derivatization to add functional properties makes them potentially ideal to fulfill the requirements for intended therapeutic applications. Among many polymers, US FDA-approved poly(l-lactic-co-glycolic) acid (PLGA) is a widely used biocompatible and biodegradable co-polymer in drug delivery and in implantable biomaterials. While many studies have been conducted using PLGA NPs as a drug delivery system, less attention has been given to understanding the effect of NP weight on cellular behaviors such as uptake. Here we discuss the synthesis of PLGA NPs with varying NP weights and their colloidal and biological properties. Following nanoprecipitation, we have synthesized PLGA NP sizes ranging from 60 to 100 nm by varying the initial PLGA feed in the system. These NPs were found to be stable for a prolonged period in colloidal conditions. We further studied cellular uptake and found that these NPs are cytocompatible; however, they are differentially uptaken by cancer and immune cells, which are greatly influenced by NPs' weight. The drug delivery potential of these nanoparticles (NPs) was assessed using doxorubicin (DOX) as a model drug, loaded into the NP core at a concentration of 7.0 ± 0.5 wt % to study its therapeutic effects. The results showed that both concentration and treatment time are crucial factors for exhibiting therapeutic effects, as observed with DOX-NPs exhibiting a higher potency at lower concentrations. The observations revealed that DOX-NPs exhibited a higher cellular uptake of DOX compared to the free-DOX treatment group. This will allow us to reduce the recommended dose to achieve the desired effect, which otherwise required a large dose when treated with free DOX. Considering the significance of PLGA-based nanoparticle drug delivery systems, we anticipate that this study will contribute to the establishment of design considerations and guidelines for the therapeutic applications of nanoparticles.

Biodegradable NIR-II Pseudo Conjugate Polymeric Nanoparticles Amplify Photodynamic Immunotherapy via Alleviation of Tumor Hypoxia and Tumor-Associated Macrophage Reprogramming.

Photodynamic therapy (PDT) has achieved great success in cancer treatment. Despite its great promise, the efficacy of photodynamic immunotherapy can be limited by the hypoxia in solid tumors which is closely related to the abnormal tumor vasculature. These abnormal vasculatures are a hallmark of most solid tumors and facilitate immune evasion. Therefore, tumor vascular normalization is developed as a promising strategy to overcome tumor hypoxia, resulting in improved cancer therapy. Here, a NIR-II bio-degradable pseudo-conjugate polymer (PSP)-based photodynamic polymer is designed to deliver a vascular normalization agent, i.e., regorafenib (Reg) in nanoparticles (NP-PDT@Reg). NP-PDT@Reg under 808nm laser irradiation (NP-PDT@Reg + L) can efficiently release Reg to improve the tumor hypoxia via vascular normalization, making more NP-PDT@Reg and oxygen enter the tumors. Moreover, NP-PDT@Reg + L can further result in generation of more reactive oxygen species (ROS) to eradicate tumor cells while inducing immunogenic cell death (ICD) to activate anti-tumor immune responses. In addition, Reg can reprogram TAM from a pro-tumor M2 phenotype to a tumor-killing M1 phenotype as well, thereby reversing the immunosuppressive tumor microenvironment. Taken together, the current study provides an innovative perspective on the development of novel nanomaterials to overcome the limitations in photodynamic immunotherapy.

Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination

Nanoparticle (NP)-based mRNA cancer vaccines hold great promise to realize personalized cancer treatments. To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester) nanocarriers with quadpolymer architecture. The platform is agnostic to the mRNA sequence, with one-step self-assembly allowing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid-based adjuvants. We examined structure-function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the polymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. Treatment with engineered NPs codelivering antigen-encoding mRNA and toll-like receptor agonist adjuvants led to robust antigen-specific CD8+ T cell responses, resulting in efficient antitumor therapy in invivo models of murine melanoma and colon adenocarcinoma.

DOE supported optimization of biodegradable polymeric nanoparticles based dry powder inhaler for targeted delivery of afatinib in non-small cell lung cancer

Poly (lactic-co-glycolic acid) (PLGA) based nanoparticles are increasingly being used to deliver anticancer agents directly to the lungs. This approach offers targeted delivery of the drug, which minimizes the risk of side effects associated with oral administration. Afatinib-loaded PLGA nanoparticles were fabricated with a double emulsification solvent evaporation method and optimized by a factorial design (32) approach. The optimized batch of afatinib-loaded polymeric nanoparticles exhibited suitable entrapment efficiency (78.15 ± 2.20% w/w), drug loading (3.90 ± 0.11% w/w), particle size (198.1 ± 3.5 nm), and zeta potential (−0.519 ± 0.197 mV). A dry powder-based inhaled drug delivery platform is rapid-acting, handy, and self-administered that is expected to enhance patient compliance. The lyophilization method was used to convert afatinib-loaded PLGA nanoparticles into dry powder form. The formulated afatinib-loaded PLGA nanoparticles dry powder inhaler (PLGA NDPI) demonstrated good flow properties with 77.86 ± 3.02% drug content and 6.883 ± 0.369 μm particle size distribution. With more than 85% of the dosage released from an inhaler device in the eight-stage cascade impactor through an in-vitro lung deposition investigation, the particles also proved their capacity to penetrate the deeper area of the lung. Further, the in-vitro drug release study demonstrated more than 80% drug release from PLGA NDPI at different pH of phosphate buffer solutions. A549 adenocarcinoma cell line cytotoxicity investigation revealed that PLGA NDPI has a stronger potential for suppressing tumour cell proliferation than pure drug solution. Fluorescein isothiocyanate (FITC) encapsulated afatinib PLGA NDPI formulation was more effectively absorbed intracellularly by adenocarcinoma cells than plain FITC dye. Taken together, the results suggest that, the formulated afatinib PLGA NDPI can be a promising approach for targeted lung delivery of the anticancer agent.

Quality by Design Enabled Systematic Optimization of Calcineurin Inhibitor loaded Polymeric Nanoparticles for Sustained Topical Delivery in Psoriasis

Background: The present work describes the systematic development and optimization of cyclosporine-A loaded biodegradable polymeric nanoparticulate system using quality by design paradigm, to achieve an effective and sustained release of the cyclosporine-A to the targeted lesion of plaque psoriasis. Methods: The polymeric nanoparticles were formulated using the solvent emulsification method using Polycaprolactone and Hyaluronic acid as polymers. An Ishikawa fishbone diagram was constructed for risk assessment and to describe various plausible product and process variables influencing the quality target product profile. Critical process and product parameters were further optimized by Response surface methodology using Central Composite Design by Minitab 19 Software. The development and optimization of cyclosporine-A loaded biodegradable polymeric nanoparticles were further carried out by developing the relationship of independent variables viz. amount of polymers polycaprolactone and hyaluronic acid on dependent variables viz. particle size, zeta potential, and entrapment efficiency and exploring their interactions. Validation of the model was done by checkpoint analysis method. Results: The particle size, zeta potential, and Entrapment efficiency of the optimized polymeric nanoparticles were found to be 317.2 ± 1.271, -0.249 ± 0.903 mV and 83.33 ± 1.124%, respectively. SEM images of the lyophilized nanoparticles showed spherical particles. In-vitro drug release study showed a slow and sustained release of 88.52 ± 1.10% of drugs up to 14 days. Conclusion: The nanoparticulate system would also help in overcoming the problem associated with poor water solubility and low permeability of the drug and will explore drug loaded biodegradable polymeric nanoparticles as a novel platform for effective therapy of psoriasis.

Biomedical application of polymer based nanomaterials: Vaccines & drugs

Polymer nanoparticles have drawn attention worldwide due to their extensive use in many domains like physics, chemistry, and biology. Drug development greatly benefits from the use of nanotechnology. Vaccine antigens, therapeutic proteins, and other substances can be delivered to the site of action using polymeric nanoparticles. When administered via the mucosa, polymeric nanoparticles with low cytotoxicity can prevent the breakdown of antigens or medicines. Due to their ability to extend the duration of the vaccination antigen, nanoparticles are frequently used in vaccine delivery systems. The biocompatibility and biodegradability of biodegradable polymer nanoparticles in various delivery methods are their key features. Shortly, more drug delivery methods utilizing nanoparticles are anticipated to become accessible.

Abstract 2718: Co-loading of a novel PI3-Kdelta/HDAC6 dual inhibitor and navitoclax into QuatramerTM biodegradable polymeric nanoparticles synergistically inhibit growth of ER+breast cancer

Abstract Progression and metastasis of ER+ breast cancer depends on multiple signaling cascades. The available conventional treatment options have limited efficacy in ER+ breast cancer. Simultaneous targeting and inhibition of multiple pathways in ER+ cancer may result in effective therapeutic outcomes. However, combining two or more drugs to treat cancer leads to unsynchronized pharmacokinetics, toxicity and eventual development of drug resistance. To overcome these limitations, a novel nano-formulation of PI3-Kδ/HDAC6 dual inhibitor in combination with Navitoclax (NAV; BCL-2 and BCL-xL inhibitor) is developed using Pluronic modified PLA based hybrid block copolymers (QuatramersTM). The prepared dual drug loaded PI3-Kδ/HDAC6-NAV-Quatramers have shown high encapsulation efficiency, optimum size and polydispersity index (PDI) of ~93%, 159 ± 2.6 nm and 0.13 ± 0.05, respectively. These PI3-Kδ/HDAC6-NAV-Quatramers exhibit slow and sustained release profile of PI3-Kδ/HDAC6 and NAV in a non-physiological buffer (PBS, pH 7.4). Multiple ratios (PI3-Kδ/HDAC6:NAV = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug-loaded Quatramers. The in-vitro proliferation inhibition studies conducted with PI3-Kδ/HDAC6-NAV-Quatramers on ER+ breast cancer cell lines have shown synergistic effect with substantially lower IC50 values as compared to individual PI3-Kδ/HDAC6-Quatramers and NAV-Quatramers. The results also demonstrate that, in contrast to 1:1 and 3:1, treatment of ER+ breast cancer cells with 1:3 ratio of PI3-Kδ/HDAC6:NAV dual drug-loaded Quatramenrs, was associated with substantial inhibition of growth in vitro. The efficacy of PI3-Kδ/HDAC6-NAV-Quatramers was assessed in ER+ breast cancer syngeneic mouse tumor model (EAC). Mice were treated either with PI3-Kδ/HDAC6-Quatramers, NAV-Quatramers or PI3-Kδ/HDAC6-NAV-dual drug loaded Quatramers at 4 mg/kg, i.v, twice a week for 3 weeks. Interestingly, in contrast to PI3-Kδ/HDAC6-Quatramers or NAV-Quatramers alone, the results demonstrate that there was nearly a complete tumor growth inhibition when mice were treated with PI3-Kδ/HDAC6-NAV-Quatramers. Additionally, the treatment with PI3-Kδ/HDAC6-NAV-Quatramers at the efficacious dose of 4 mg/kg did not show any significant body weight loss, confirming no overt toxicity. Taken together, these results demonstrate that a unique formulation of a novel PI3-Kδ/HDAC6 dual inhibitor in combination with Navitoclax in a dual drug-loaded Quatramers in a particular ratio of 1:3, represents an excellent strategy for efficient treatment option for ER+ breast cancer. Citation Format: Surender M. Kharbanda, Sachchidanand Tiwari, Harshdeep Kaur, Anees Mohammad, Priya Gupta, Harpal Singh. Co-loading of a novel PI3-Kdelta/HDAC6 dual inhibitor and navitoclax into QuatramerTM biodegradable polymeric nanoparticles synergistically inhibit growth of ER+breast cancer [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 2718.