Novel Therapeutic Modalities Using Nanofiber-Based “Intelligent” Drug Delivery

Development of novel materials platforms for controlled (“intelligent”) release of functional molecules has emerged in materials research for medical applications. Controlled release of functional molecules in response to external stimuli is the key for intelligent release. Coaxial electrospinning technique¹ is a versatile method to integrate multiple functional materials into novel delivery systems, producing core-sheath fibers with advanced features: (a) combination of multiple functional materials; (b) encapsulation of functional molecules (drug, proteins, etc.) with controlled release kinetics; (c) protection of encapsulated molecules from outer environment. Intrinsic properties of nanofiber membranes (high surface-to-volume ratio and porosity) enable much quicker response to external stimuli compared to equivalent solid films. Complex nanofibers produced by coaxial electrospinning have been used in various advanced platforms for chem/bio/medical applications.<br/>To obtain release triggered by external stimuli, self-immolative polymer (SIP) has been incorporated into the outer sheath layer encapsulating the releasing core materials.² As SIP is depolymerized (“unzip”) upon cleavage of the head-molecule by specific target, stimuli drug molecules are released. A multi-phased controlled release was developed by integrating two different pH-responsive polymers into core-sheath fibers.³ Fibers with Eudragit L100 core and S100 sheath provide 3-phase response within physiological pH range: pH &lt; 5, no release is observed from either core or sheath layer; pH=5-6, sustained release from the core is obtained with different release kinetics; pH &gt; 6, both core and sheath materials are quickly dissolved. This approach is very promising for targeted oral drug delivery because human organs have different pH values.<br/>Other methodologies utilizing electrospun fibers include transdermal patches of parylene coated PCL fibers containing the drug pramipexole. These patches have demonstrated long-term drug delivery, ease-of-use, and no first-pass effect. Without parylene, 100% pramipexole load is released within 12 h, while parylene coating provided only 52% release over 10 days.⁴ Microneedles loaded with electrosprayed nanoparticles for painless drug delivery via skin penetration were also demonstrated. Extremely small needles caused least pain to the host while directly delivering the loaded drug into the blood or interstitial fluid streams.⁵ While patches and microneedles were developed to minimize physical disruption, implantation into the body is needed for certain cases. We developed a nanofibrous implant for localized chemotherapy against brain cancers. To circumvent the blood-brain-barrier, implanting the drug delivery device after tumor resection provides highly effective drug delivery to the targeted area. Our implantable device provides continuous drug release up to 160 days, significant increase of median survival and long-term survival rates of 50%.⁶<br/>1. Han, D.; Steckl, A. J., Coaxial Electrospinning Formation of Complex Polymer Fibers and their Applications. <i>ChemPlusChem </i><b>2019,</b> <i>84</i>, 1453.<br/>2. Han, D. et. al, Stimuli-Responsive Self-Immolative Polymer Nanofiber Membranes Formed by Coaxial Electrospinning. <i>ACS Appl. Mater. Interfaces </i><b>2016,</b> <i>9</i>, 11858.<br/>3. Han, D. Steckl, A. J., Selective pH-Responsive Core–Sheath Nanofiber Membranes for Chem/Bio/Med Applications: Targeted Delivery of Functional Molecules. <i>ACS Appl. Mater. Interfaces </i><b>2017,</b> <i>9</i>, 42653.<br/>4. Tort, S. et. al, Controlled drug release of parylene-coated pramipexole nanofibers for transdermal applications. <i>Surface and Coatings Technology </i><b>2021,</b> <i>409</i>, 126831.<br/>5. Tort, S. et. al, In vitro and in vivo evaluation of microneedles coated with electrosprayed micro/nanoparticles for medical skin treatments. <i>J Microencapsul </i><b>2020,</b> <i>37</i>, 517.<br/>6. Han, D. et. al, Multi-layered core-sheath fiber membranes for controlled drug release in the local treatment of brain tumor. <i>Scientific Reports </i><b>2019,</b> <i>9</i>, 17936.