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.

Department of Pharmaceutical Sciences and Health Outcomes The Ben and Maytee Fisch College of Pharmacy The University of Texas at Tyler Tyler Texas 75799 United States

Institute of Macromolecular Chemistry Czech Academy of Sciences Prague 16200 Czech Republic

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Park J.; Fong P. M.; Lu J.; Russell K. S.; Booth C. J.; Saltzman W. M.; Fahmy T. M. PEGylated PLGA Nanoparticles for the Improved Delivery of Doxorubicin. Nanomed. Nanotechnol. Biol. Med. 2009, 5, 410–418. 10.1016/j.nano.2009.02.002. PubMed DOI PMC

Nguyen T. D. T.; Pitchaimani A.; Bahadur Koirala M.; Muhammad F.; Aryal S. Engineered Biomimetic Nanoabsorbent for Cellular Detoxification of Chemotherapeutics. RSC Adv. 2016, 6, 33003–33008. 10.1039/C6RA02026G. DOI

Swami A.; Reagan M. R.; Basto P.; Mishima Y.; Kamaly N.; Glavey S.; Zhang S.; Moschetta M.; Seevaratnam D.; Zhang Y.; Liu J.; Memarzadeh M.; Wu J.; Manier S.; Shi J.; Bertrand N.; Lu Z. N.; Nagano K.; Baron R.; Sacco A.; Roccaro A. M.; Farokhzad O. C.; Ghobrial I. M. Engineered Nanomedicine for Myeloma and Bone Microenvironment Targeting. Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 10287–10292. 10.1073/pnas.1401337111. PubMed DOI PMC

Hu C.-M. J.; Fang R. H.; Copp J.; Luk B. T.; Zhang L. A Biomimetic Nanosponge That Absorbs Pore-Forming Toxins. Nat. Nanotechnol. 2013, 8, 336–340. 10.1038/nnano.2013.54. PubMed DOI PMC

Aryal S.; Hu C.-M. J.; Fang R. H.; Dehaini D.; Carpenter C.; Zhang D.-E.; Zhang L. Erythrocyte Membrane-Cloaked Polymeric Nanoparticles for Controlled Drug Loading and Release. Nanomedicine 2013, 8, 1271–1280. 10.2217/nnm.12.153. PubMed DOI

Aryal S.; Hu C.-M. J.; Zhang L. Polymer–Cisplatin Conjugate Nanoparticles for Acid-Responsive Drug Delivery. ACS Nano 2010, 4, 251–258. 10.1021/nn9014032. PubMed DOI PMC

Aryal S.; Stigliano C.; Key J.; Ramirez M.; Anderson J.; Karmonik C.; Fung S.; Decuzzi P. Paramagnetic Gd(3+) Labeled Red Blood Cells for Magnetic Resonance Angiography. Biomaterials 2016, 98, 163–170. 10.1016/j.biomaterials.2016.05.002. PubMed DOI

Nguyen T. D. T.; Pitchaimani A.; Aryal S. Engineered Nanomedicine with Alendronic Acid Corona Improves Targeting to Osteosarcoma. Sci. Rep. 2016, 6, 3670710.1038/srep36707. PubMed DOI PMC

Ferrari M. Cancer Nanotechnology: Opportunities and Challenges. Nat. Rev. Cancer 2005, 5, 161–171. 10.1038/nrc1566. PubMed DOI

Chen H.; Shao L.; Li Q.; Wang J. Gold Nanorods and Their Plasmonic Properties. Chem. Soc. Rev. 2013, 42, 2679–2724. 10.1039/C2CS35367A. PubMed DOI

Arvizo R.; Bhattacharya R.; Mukherjee P. Gold Nanoparticles: Opportunities and Challenges in Nanomedicine. Expert Opin. Drug Delivery 2010, 7, 753–763. 10.1517/17425241003777010. PubMed DOI PMC

Farokhzad O. C.; Langer R. Impact of Nanotechnology on Drug Delivery. ACS Nano 2009, 3, 16–20. 10.1021/nn900002m. PubMed DOI

Behzadi S.; Serpooshan V.; Tao W.; Hamaly M. A.; Alkawareek M. Y.; Dreaden E. C.; Brown D.; Alkilany A. M.; Farokhzad O. C.; Mahmoudi M. Cellular Uptake of Nanoparticles: Journey Inside the Cell. Chem. Soc. Rev. 2017, 46, 4218–4244. 10.1039/c6cs00636a. PubMed DOI PMC

Sakamoto J. H.; van de Ven A. L.; Godin B.; Blanco E.; Serda R. E.; Grattoni A.; Ziemys A.; Bouamrani A.; Hu T.; Ranganathan S. I.; De Rosa E.; Martinez J. O.; Smid C. A.; Buchanan R. M.; Lee S.-Y.; Srinivasan S.; Landry M.; Meyn A.; Tasciotti E.; Liu X.; Decuzzi P.; Ferrari M. Enabling Individualized Therapy through Nanotechnology. Pharmacol. Res. 2010, 62, 57–89. 10.1016/j.phrs.2009.12.011. PubMed DOI PMC

Caron W. P.; Morgan K. P.; Zamboni B. A.; Zamboni W. C. A Review of Study Designs and Outcomes of Phase I Clinical Studies of Nanoparticle Agents Compared with Small-Molecule Anticancer Agents. Clin. Cancer Res. 2013, 19, 3309–3315. 10.1158/1078-0432.CCR-12-3649. PubMed DOI

Muhammad F.; Nguyen T. D. T.; Raza A.; Akhtar B.; Aryal S. A Review on Nanoparticle-Based Technologies for Biodetoxification. Drug Chem. Toxicol. 2017, 40, 489–497. 10.1080/01480545.2016.1277736. PubMed DOI

Akter M.; Sikder M. T.; Rahman M. M.; Ullah A. K. M. A.; Hossain K. F. B.; Banik S.; Hosokawa T.; Saito T.; Kurasaki M. A Systematic Review on Silver Nanoparticles-Induced Cytotoxicity: Physicochemical Properties and Perspectives. J. Adv. Res. 2018, 9, 1–16. 10.1016/j.jare.2017.10.008. PubMed DOI PMC

Wilhelm S.; Tavares A. J.; Dai Q.; Ohta S.; Audet J.; Dvorak H. F.; Chan W. C. W. Analysis of Nanoparticle Delivery to Tumours. Nat. Rev. Mater. 2016, 1, 16014.10.1038/natrevmats.2016.14. DOI

Shi J.; Kantoff P. W.; Wooster R.; Farokhzad O. C. Cancer Nanomedicine: Progress, Challenges and Opportunities. Nat. Rev. Cancer 2017, 17, 20–37. 10.1038/nrc.2016.108. PubMed DOI PMC

Kabanov A. V.; Gendelman H. E. Nanomedicine in the Diagnosis and Therapy of Neurodegenerative Disorders. Prog. Polym. Sci. 2007, 32, 1054–1082. 10.1016/j.progpolymsci.2007.05.014. PubMed DOI PMC

Chithrani D. B. Nanoparticles for Improved Therapeutics and Imaging in Cancer Therapy. Recent Pat. Nanotechnol. 2010, 4, 171–180. 10.2174/187221010792483726. PubMed DOI

Bala I.; Hariharan S.; Kumar M. N. V. R. PLGA Nanoparticles in Drug Delivery: The State of the Art. Crit. Rev. Ther. Drug Carrier Syst. 2004, 21, 387–422. 10.1615/CritRevTherDrugCarrierSyst.v21.i5.20. PubMed DOI

Danhier F.; Ansorena E.; Silva J. M.; Coco R.; Le Breton A.; Préat V. PLGA-Based Nanoparticles: An Overview of Biomedical Applications. J. Controlled Release 2012, 161, 505–522. 10.1016/j.jconrel.2012.01.043. PubMed DOI

FDA’s Regulatory Science Program for Generic PLA/PLGA-Based Drug Products. http://www.americanpharmaceuticalreview.com/Featured-Articles/188841-FDA-s-Regulatory-Science-Program-for-Generic-PLA-PLGA-Based-Drug-Products/ (accessed June 15, 2016).

Platel A.; Carpentier R.; Becart E.; Mordacq G.; Betbeder D.; Nesslany F. Influence of the Surface Charge of PLGA Nanoparticles on Their in Vitro Genotoxicity, Cytotoxicity, ROS Production and Endocytosis. J. Appl. Toxicol. 2016, 36, 434–444. 10.1002/jat.3247. PubMed DOI

Wu J.; Zhang J.; Deng C.; Meng F.; Cheng R.; Zhong Z. Robust, Responsive, and Targeted PLGA Anticancer Nanomedicines by Combination of Reductively Cleavable Surfactant and Covalent Hyaluronic Acid Coating. ACS Appl. Mater. Interfaces 2017, 9, 3985–3994. 10.1021/acsami.6b15105. PubMed DOI

Marasini R.; Thanh Nguyen T. D.; Rayamajhi S.; Aryal S. Synthesis and Characterization of a Tumor-Seeking LyP-1 Peptide Integrated Lipid–Polymer Composite Nanoparticle. Mater. Adv. 2020, 1, 469–480. 10.1039/D0MA00203H. DOI

Situ J.-Q.; Wang X.-J.; Zhu X.-L.; Xu X.-L.; Kang X.-Q.; Hu J.-B.; Lu C.-Y.; Ying X.-Y.; Yu R.-S.; You J.; Du Y.-Z. Multifunctional SPIO/DOX-Loaded A54 Homing Peptide Functionalized Dextran-g-PLGA Micelles for Tumor Therapy and MR Imaging. Sci. Rep. 2016, 6, 3591010.1038/srep35910. PubMed DOI PMC

Schleich N.; Sibret P.; Danhier P.; Ucakar B.; Laurent S.; Muller R. N.; Jérôme C.; Gallez B.; Préat V.; Danhier F. Dual Anticancer Drug/Superparamagnetic Iron Oxide-Loaded PLGA-Based Nanoparticles for Cancer Therapy and Magnetic Resonance Imaging. Int. J. Pharm. 2013, 447, 94–101. 10.1016/j.ijpharm.2013.02.042. PubMed DOI

Nguyen T. D. T.; Pitchaimani A.; Ferrel C.; Thakkar R.; Aryal S. Nano-Confinement-Driven Enhanced Magnetic Relaxivity of SPIONs for Targeted Tumor Bioimaging. Nanoscale 2018, 10, 284–294. 10.1039/c7nr07035g. PubMed DOI

Karfeld-Sulzer L. S.; Waters E. A.; Kohlmeir E. K.; Kissler H.; Zhang X.; Kaufman D. B.; Barron A. E.; Meade T. J. Protein Polymer MRI Contrast Agents: Longitudinal Analysis of Biomaterials in Vivo. Magn. Reson. Med. 2011, 65, 220–228. 10.1002/mrm.22587. PubMed DOI PMC

Zhang Y.; García-Gabilondo M.; Grayston A.; J Feiner I. V.; Anton-Sales I.; A Loiola R.; Llop J.; Ramos-Cabrer P.; Barba I.; Garcia-Dorado D.; Gosselet F.; Rosell A.; Roig A. PLGA Protein Nanocarriers with Tailor-Made Fluorescence/MRI/PET Imaging Modalities. Nanoscale 2020, 12, 4988–5002. 10.1039/C9NR10620K. PubMed DOI

Aryal S.; Key J.; Stigliano C.; Landis M. D.; Lee D. Y.; Decuzzi P. Positron Emitting Magnetic Nanoconstructs for PET/MR Imaging. Small 2014, 10, 2688–2696. 10.1002/smll.201303933. PubMed DOI

Aryal S.; Key J.; Stigliano C.; Ananta J. S.; Zhong M.; Decuzzi P. Engineered Magnetic Hybrid Nanoparticles with Enhanced Relaxivity for Tumor Imaging. Biomaterials 2013, 34, 7725–7732. 10.1016/j.biomaterials.2013.07.003. PubMed DOI

Mitragotri S.; Lahann J. Physical Approaches to Biomaterial Design. Nat. Mater. 2009, 8, 15–23. 10.1038/nmat2344. PubMed DOI PMC

Albanese A.; Tang P. S.; Chan W. C. W. The Effect of Nanoparticle Size, Shape, and Surface Chemistry on Biological Systems. Annu. Rev. Biomed. Eng. 2012, 14, 1–16. 10.1146/annurev-bioeng-071811-150124. PubMed DOI

Wang J.; Byrne J. D.; Napier M. E.; DeSimone J. M. More Effective Nanomedicines through Particle Design. Small 2011, 7, 1919–1931. 10.1002/smll.201100442. PubMed DOI PMC

Pitchaimani A.; Nguyen T. D. T.; Koirala M.; Zhang Y.; Aryal S. Impact of Cell Adhesion and Migration on Nanoparticle Uptake and Cellular Toxicity. Toxicol. In Vitro 2017, 43, 29–39. 10.1016/j.tiv.2017.05.020. PubMed DOI

Win K. Y.; Feng S.-S. Effects of Particle Size and Surface Coating on Cellular Uptake of Polymeric Nanoparticles for Oral Delivery of Anticancer Drugs. Biomaterials 2005, 26, 2713–2722. 10.1016/j.biomaterials.2004.07.050. PubMed DOI

Urbánek T.; Trousil J.; Rak D.; Gunár K.; Konefał R.; Šlouf M.; Sedlák M.; Šebestová Janoušková O.; Hrubý M. γ-Butyrolactone Copolymerization with the Well-Documented Polymer Drug Carrier Poly(Ethylene Oxide)-Block-Poly(ε-Caprolactone) to Fine-Tune Its Biorelevant Properties. Macromol. Biosci. 2020, 20, 190040810.1002/mabi.202070009. PubMed DOI

Crucho C. I. C.; Barros M. T. Formulation of Functionalized PLGA Polymeric Nanoparticles for Targeted Drug Delivery. Polymer 2015, 68, 41–46. 10.1016/j.polymer.2015.04.083. DOI

Eshete M.; Bailey K.; Nguyen T. D. T.; Aryal S.; Choi S.-O. Interaction of Immune System Protein with PEGylated and Un-PEGylated Polymeric Nanoparticles. Adv. Nanopart. 2017, 06, 103.10.4236/anp.2017.63009. DOI

Fang R. H.; Chen K. N. H.; Aryal S.; Hu C.-M. J.; Zhang K.; Zhang L. Large-Scale Synthesis of Lipid–Polymer Hybrid Nanoparticles Using a Multi-Inlet Vortex Reactor. Langmuir 2012, 28, 13824–13829. 10.1021/la303012x. PubMed DOI

Aryal S.; Hu C.-M. J.; Fu V.; Zhang L. Nanoparticle Drug Delivery Enhances the Cytotoxicity of Hydrophobic–Hydrophilic Drug Conjugates. J. Mater. Chem. 2012, 22, 994–999. 10.1039/C1JM13834K. DOI

Makadia H. K.; Siegel S. J. Poly Lactic-Co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polymers 2011, 3, 1377–1397. 10.3390/polym3031377. PubMed DOI PMC

Schliecker G.; Schmidt C.; Fuchs S.; Wombacher R.; Kissel T. Hydrolytic Degradation of Poly(Lactide-Co-Glycolide) Films: Effect of Oligomers on Degradation Rate and Crystallinity. Int. J. Pharm. 2003, 266, 39–49. 10.1016/S0378-5173(03)00379-X. PubMed DOI

Engineer C.; Parikh J.; Raval A. Effect of Copolymer Ratio on Hydrolytic Degradation of Poly(Lactide-Co-Glycolide) from Drug Eluting Coronary Stents. Chem. Eng. Res. Des. 2011, 89, 328–334. 10.1016/j.cherd.2010.06.013. DOI

Vainshtein I.; Roskos L. K.; Cheng J.; Sleeman M. A.; Wang B.; Liang M. Quantitative Measurement of the Target-Mediated Internalization Kinetics of Biopharmaceuticals. Pharm. Res. 2015, 32, 286–299. 10.1007/s11095-014-1462-8. PubMed DOI PMC

Krishnamoorthy K.; Mahalingam M. Selection of a Suitable Method for the Preparation of Polymeric Nanoparticles: Multi-Criteria Decision Making Approach. Adv. Pharm. Bull. 2015, 5, 57–67. 10.5681/apb.2015.008. PubMed DOI PMC

Uribe-Querol E.; Rosales C. Phagocytosis: Our Current Understanding of a Universal Biological Process. Front. Immunol. 2020, 11, 106610.3389/fimmu.2020.01066. PubMed DOI PMC

Lee H.-J.; Woo Y.; Hahn T.-W.; Jung Y. M.; Jung Y.-J. Formation and Maturation of the Phagosome: A Key Mechanism in Innate Immunity against Intracellular Bacterial Infection. Microorganisms 2020, 8, 1298.10.3390/microorganisms8091298. PubMed DOI PMC

Doxorubicin – FDA Prescribing Information, Side Effects and Uses. http://www.drugs.com/pro/doxorubicin.html.

Tejada-Berges T.; Granai C. O.; Gordinier M.; Gajewski W. Caelyx/Doxil for the Treatment of Metastatic Ovarian and Breast Cancer. Expert Rev. Anticancer Ther. 2002, 2, 143–150. 10.1586/14737140.2.2.143. PubMed DOI

Tsai L.-H.; Yen C.-H.; Hsieh H.-Y.; Young T.-H. Doxorubicin Loaded PLGA Nanoparticle with Cationic/Anionic Polyelectrolyte Decoration: Characterization, and Its Therapeutic Potency. Polymers 2021, 13, 693.10.3390/polym13050693. PubMed DOI PMC

Mukherjee S.; Kotcherlakota R.; Haque S.; Bhattacharya D.; Kumar J. M.; Chakravarty S.; Patra C. R. Improved Delivery of Doxorubicin Using Rationally Designed PEGylated Platinum Nanoparticles for the Treatment of Melanoma. Mater. Sci. Eng. C 2020, 108, 11037510.1016/j.msec.2019.110375. PubMed DOI

Siegal T.; Horowitz A.; Gabizon A. Doxorubicin Encapsulated in Sterically Stabilized Liposomes for the Treatment of a Brain Tumor Model: Biodistribution and Therapeutic Efficacy. J. Neurosurg. 1995, 83, 1029–1037. 10.3171/jns.1995.83.6.1029. PubMed DOI

Tian G.; Sun X.; Bai J.; Dong J.; Zhang B.; Gao Z.; Wu J. Doxorubicin-loaded Dual-functional Hyaluronic Acid Nanoparticles: Preparation, Characterization and Antitumor Efficacy in Vitro and in Vivo. Mol. Med. Rep. 2019, 19, 133–142. 10.3892/mmr.2018.9687. PubMed DOI PMC

Clawson C.; Ton L.; Aryal S.; Fu V.; Esener S.; Zhang L. Synthesis and Characterization of Lipid–Polymer Hybrid Nanoparticles with PH-Triggered Poly (Ethylene Glycol) Shedding. Langmuir 2011, 27, 10556–10561. 10.1021/la202123e. PubMed DOI PMC

Trousil J.; Filippov S. K.; Hrubý M.; Mazel T.; Syrová Z.; Cmarko D.; Svidenská S.; Matějková J.; Kováčik L.; Porsch B.; Konefał R.; Lund R.; Nyström B.; Raška I.; Štěpánek P. System with Embedded Drug Release and Nanoparticle Degradation Sensor Showing Efficient Rifampicin Delivery into Macrophages. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 307–315. 10.1016/j.nano.2016.08.031. PubMed DOI

Trousil J.; Syrová Z.; Dal N.-J. K.; Rak D.; Konefał R.; Pavlova E.; Matějková J.; Cmarko D.; Kubíčková P.; Pavliš O.; Urbánek T.; Sedlák M.; Fenaroli F.; Raška I.; Štěpánek P.; Hrubý M. Rifampicin Nanoformulation Enhances Treatment of Tuberculosis in Zebrafish. Biomacromolecules 2019, 20, 1798–1815. 10.1021/acs.biomac.9b00214. PubMed DOI

Trousil J.; Pavliš O.; Kubíčková P.; Škorič M.; Marešová V.; Pavlova E.; Knudsen K. D.; Dai Y.-S.; Zimmerman M.; Dartois V.; Fang J.-Y.; Hrubý M. Antitubercular Nanocarrier Monotherapy: Study of In Vivo Efficacy and Pharmacokinetics for Rifampicin. J. Controlled Release 2020, 321, 312–323. 10.1016/j.jconrel.2020.02.026. PubMed DOI