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Smart Hydrogel Drug Delivery: Harnessing Dual Stimuli Sensitivity with Magnetic Nanoparticles for Targeted Antitumor Therapy BMEN 3321 Biomaterials Dr. Ecker Group 2 Introduction ● Tumor diseases pose a major challenge in medicine ○ ○ ○ ● Limitations of current antitumor treatments ○ ○ ○ ● High mortality rates Complexity & diversity Individual variability Ex: chemotherapy, surgery, radiation Low efficacy, side effects Can damage healthy tissues This research explores the use of nanoscale drug delivery systems (DDSs) & theranostics for improved cancer treatment ○ ○ ○ Targeted delivery = reduction in off-target effects Reduced toxicity Controlled Release Research Problem Can smart hydrogel localized drug delivery systems, responsive of the stimuli of temperature and alternating magnetic field (AMF) sensitivity be a potential carrier of the model antitumor drug paclitaxel (PTX)? Will this system allow for simultaneous hyperthermia treatment and chemotherapy with a controlled drug release profile? Thermosensitive Hydrogels for Drug Delivery ● Hydrogels are 3D polymeric structures that can absorb large amounts of water/biological fluids ● Advantages for drug delivery - Versatility high drug entrapment Controlled release ● Triblock copolymer (PCLA-PEG-PCLA) - Biocompatible & biodegradable Synthesis Process Characterization ● Ring-Opening Polymerization (ROP) ● Zirconium (IV) acetylacetonate catalyst Fig 1 The PCLA synthesis via the ROP process. ● Nuclear Magnetic Resonance (NMR) & Gel Permeation Chromatography (GPC) techniques used for successful synthesis confirmation Magnetic Hyperthermia for Cancer Treatment ● Uses magnetic fields to generate localized heat within tumor tissues which helps destroy cancer cells ● Advantages of local hyperthermia over whole-body hyperthermia ○ ○ ○ ● Reduced side effects Targeted treatment Low risk of complications Combining hyperthermia with chemotherapy or radiotherapy increases efficacy of treatment ○ ○ ○ ○ Increases sensitivity of cancer cells Reduced repair capability Improved blood flow Synergistic effects on tumor microenvironment Magnetic Nanoparticles for Hyperthermia ● ● MIONs convert AMF energy into heat through relaxation mechanisms ○ Neel Relaxation ○ Brownian Relaxation Magnetic iron oxide nanoparticles (MIONs) are widely used for magnetic hyperthermia therapy (MHT) due to: ○ Unique magnetic properties ○ Biocompatibility ○ Controlled synthesis & functionalization ○ Localized heat generation ○ Versatility in medical applications MIONs Synthesis & Characterization ● MIONs require surface modification to prevent agglomeration and improve biocompatibility ● Coprecipitation method for MIONs ○ Simple & scalable ○ Parameter control ● Successful synthesis with desired properties ○ Small diameter & narrow size distribution ● Analysis techniques ○ Transmission Electron Microscopy (TEM) ○ Dynamic Light Scattering (DLS) ○ Vibrating Sample Magnetometry (VSM) Fig 2. Micrographs of MIONs obtained using the TEM technique MIONs Heating Properties ● ● MIONs hysteresis loops were S shaped & narrow Values of Hc (low coercivity) and Br (remanence) are low Fig 3. Hysteresis loop of the resulting MIONs Heating Properties ● Desired temperature is achieved for hyperthermia within short time ○ ○ Ideal Temp 41-45℃ which is ΔT of 4.4-8.4℃ Less than 5 mins ● Relationship between ΔT and time (T) is linear in most cases ● Optimal MION concentration is 5 mg/mL ○ Time needed for minimal desirable increase in temperature is longer for 2 mg/mL Fig 4. Heating Curves for MION suspensions A Hydrogel Drug Delivery ● ● Drug loading ○ Paclitaxel (PTX) is a powerful chemotherapeutic agent used in cancer treatment ■ LDDS necessary due to side effects Drug Release Kinetics ○ Drug release occurs in phases ○ Released through diffusive and erosive mechanisms ○ Determining exact kinetics was not possible but was close to zero-order kinetics B Fig 5. (a) Degradation time profiles for PCLA-A1 and PCLA-A2 hydrogels. (b) Drug release profiles for PCLA-A1/PTX and PCLA-A2/PTX hydrogels Combining Hydrogels & MIONs ● ● ● ● Research proposes using dual-stimuli responsive hydrogels: temperature and AMF sensitive ○ System would allow for simultaneous hyperthermia treatment & controlled drug release Hydrogel would be a thermosensitive, biodegradable, and biocompatible ○ AMF sensitivity would be mediated by a suspension of Magnetic Iron Oxide Nanoparticles (MIONs) Matrices prepared by dissolving PCLA copolymer into MION suspension to obtain 25 wt. % solutions which were then homogenized. MIONs and hyperthermia had no significant effect on the drug release profiles of their hydrogels Fig 6. Drug release of PCLAA2/PTX/MIONs hydrogels under hyperthermia conditions. Methodology ● ● ● ● ● ● In vitro drug release studies performed under various conditions ○ Concentrations determined with HPLC analysis Hydrolytic Degradation ○ Calculated using weight loss of the hydrogels Optimization of thermosensitive PCLA copolymers for hydrogel formation Hydrogel properties ○ Gel forming temperatures, mechanical strength, etc Cytotoxicity and genotoxicity assays to assess hydrogel safety Synthesis & characterization of PEG coated MIONs for magnetic hyperthermia Fig 7. Magnetically assisted sedimentation of MIONs Results ● Successful synthesis & optimization of PCLA copolymers with desired gel-forming properties ● Hydrogels exhibited high mechanical strength and biocompatibility ● PEG coated MIONs were obtained with spherical shape and narrow size distribution ● LDDS showed controlled release of PTX in response to temperature and AMF Discussion ● The structure of the resulting products of PCLA copolymers produced via ROP with zirconium catalyst and PEG initiator were confirmed by NMR ○ High monomer conversion & repeatability ○ Narrow dispersity ● Improved Stability & biocompatibility of hydrogels ○ Random microstructure ○ Low critical solution temperature (LCST) ○ No cytotoxicity or genotoxicity in synthesized matrices Discussion ● Synthesis/Characterization of MIONs ○ Coprecipitation method resulted in nanoparticle diameter of 10 nm ○ 30% PEG 6000 concentration was optimal for coating and stability in aqueous media ○ ○ VSM analysis showed MIONs had superparamagnetic properties ■ Low coercivity (Hc) ■ Narrow hysteresis loop Nanoparticles reached appropriate temperature increase for hyperthermia treatment at a low concentration of 5 mg/mL ● PTX release profile was prolonged & well controlled ○ Followed zero order kinetics Conclusion ● ● ● ● ● ● Copolymers synthesized were water soluble and temperature sensitive, making them suitable as an injectable material. Copolymers were found to be neither cyto- nor genotoxic MIONs were found to be close to superparamagnetic MIONs were able to achieve the appropriate temperature conditions within 5 minutes, making them potentially useful as a hyperthermia device. PTX release was well controlled, achieving release close to zero-order kinetics. The simulated hyperthermia treatment conditions had no effect on release profiles ○ In specific the PCLA-A2/PTX/MIONs hydrogels were the most promising due to the degradation rate and specific drug release kinetics ○ Indicates that the developed dual-stimuli-sensitive smart hydrogel is promising as a potential antitumor drug LDDS. Future Directions ● ● ● ● ● Further testing is expected ○ Study only performed in vitro drug release tests, further in vitro and eventually in vivo studies will likely be performed if they reach that stage Evidence for MIONs combined with hydrogel drug delivery is limited Smart hydrogel systems for antitumor drug delivery has still not seen use in clinical practice Evaluation with other antitumor drugs Further evaluation of properties in different contexts Citations Kasiński, A., Świerczek, A., Zielińska-Pisklak, M., Kowalczyk, S., Plichta, A., Zgadzaj, A., Oledzka, E., & Sobczak, M. (2023). Dual-Stimuli-Sensitive Smart Hydrogels Containing Magnetic Nanoparticles as Antitumor Local Drug Delivery Systems-Synthesis and Characterization. International journal of molecular sciences, 24(8), 6906. https://doi.org/10.3390/ijms24086906 Contributions Name: Group Number: Title of your Presentation Abstract Please use this template for your abstract. Typically, an abstract for a paper or presentation is one or two paragraphs long (120 – 500 words). Abstracts usually spend: • 25% of their space on the purpose and importance of the research (Introduction) • 25% of their space on what you did (Methods) • 35% of their space on what you found (Results) • 15% of their space on the implications of the research Reference(s):
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Smart Hydrogel Drug Delivery
Abstract
Cancer has become one of the most demanding issues in medical treatment today, not only due to
its high mortality rates but also because it enters into the cells and spreads with an aggressive
nature. In addition, the tumor variegation makes the application of the current treatment regimen
complex. The main choices of anticancer therapies, i.e., chemotherapy, surgery, and radiotherapy,
though broad, have been marred by low efficacy, severe side effects and high recurrence
rates. These therapies are usually not related to the molecular mechanisms of cancer cells and do
not distinguish the healthy tissue, which leads to widespread systemic toxicity (Kasiński et al.,
2023). On account of ...


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