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Shirisha Bellala,1,* Karthika Viswanathan,2,* Ujwala Guntakanti,3 Anitha Kowthalam,1 Sung Soo Han,4 Madhusudana Rao Kummara,4 Sreekanth Reddy Obireddy,1,5 Wing-Fu Lai5– 7 1Department of Chemistry, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh, 515003, India; 2Department of Nanoscience and Technology, Alagappa University, Karaikudi, Tamil Nadu, 630 003, India; 3Department of Chemistry, G. Pulla Reddy Engineering College, Kurnool, Andhra Pradesh, 518 007, India; 4School of Chemical Engineering, Yeungnam University, Gyeongsan, 38541, Republic of Korea; 5Department of Urology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Zhejiang, 310014, China; 6School of Food Science and Nutrition, University of Leeds, Leeds, LS2 9JT, UK; 7Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong Special Administrative Region, China*These authors contributed equally to this workCorrespondence: Wing-Fu Lai, Email rori0610@graduate.hku.hk; Sreekanth Reddy Obireddy, Email sreekanthchem7@gmail.comPurpose: The purpose of this study is to address the need for efficient drug delivery with high drug encapsulation efficiency and sustained drug release. We aim to create nanoparticle-loaded microgels for potential applications in treatment development.Methods: We adopted the process of ionic gelation to generate microgels from sodium alginate and carboxymethyl cellulose. These microgels were loaded with doxorubicin-conjugated amine-functionalized zinc ferrite nanoparticles (AZnFe-NPs). The systems were characterized using various techniques. Toxicity was evaluated in MCF-7 cells. In vitro release studies were conducted at different pH levels at 37 oC, with the drug release kinetics being analyzed using various models.Results: The drug encapsulation efficiency of the created carriers was as high as 70%. The nanoparticle-loaded microgels exhibited pH-responsive behavior and sustained drug release. Drug release from them was mediated via a non-Fickian type of diffusion.Conclusion: Given their high drug encapsulation efficiency, sustained drug release and pH-responsiveness, our nanoparticle-loaded microgels show promise as smart carriers for future treatment applications. Further development and research can significantly benefit the field of drug delivery and treatment development.Keywords: sodium alginate, carboxymethyl cellulose, doxorubicin, zinc ferrite nanoparticles, microgels

Boddu Adilakshmi,1 Obireddy Sreekanth Reddy,2– 4 Duddekunta Hemalatha,1 Kummari SV Krishna Rao,1 Wing-Fu Lai2,3 1Polymer Biomaterial Design and Synthesis Laboratory, Department of Chemistry, Yogi Vemana University, Kadapa, Andhra Pradesh, 516005, India; 2Department of Urology, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Zhejiang, 310012, People’s Republic of China; 3Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong Special Administrative Region, People’s Republic of China; 4Department of Chemistry, Sri Krishnadevaraya University, Anantapuramu, Andhra Pradesh, 515003, IndiaCorrespondence: Wing-Fu Lai; Kummari SV Krishna Rao, Email rori0610@graduate.hku.hk; ksvkr@yogivemanauniversity.ac.inPurpose: Site-specific drug delivery systems can contribute to the development and execution of effective cancer treatment. Due to its favorable features (including high biocompatibility, high hydrophilicity and ease of functionalization), poly(ethylene glycol) (PEG) has been widely adopted to design drug carriers. Generating carriers for delivery of hydrophobic anticancer agents, however, is still a challenge in carrier design.Methods: In the first step, PEG is functionalized with dialdehyde to generate PEG-(CHO)2 using EDC/NHS chemistry. In the second step, Fe3O4 nanoparticles are functionalized with amino groups to generate Fe3O4-NH2. In the third step, PEG-(CHO)2, Fe3O4-NH2 and doxorubicin (DOX) react in an acidic environment to yield a drug conjugate (PEGDA-MN-DOX), which is subsequently characterized by FT-IR, 1H-NMR, SEM, TEM, DLS, TGA, and DSC.Results: The chemical functionalities of the drug conjugate are confirmed by FTIR, H-NMRand XRD analysis.The release pattern of PEGDA-MN-DOX is investigated at 25 and 37 °C at different pH values. The results indicate that the developed drug conjugate cannot only behave as a sustained-release carrier, but can also generate a significant level of reactive oxygen species (ROS), leading to a high level of toxicity against MCF-7 cells while still showing excellent biocompatibility in 3T3 cells.Conclusion: The reported conjugate shows anticancer potential, cancer-targeting ability, and ROS-generating capacity for effective drug encapsulation and sustained release in chemotherapy.Graphical Abstarct: Keywords: PEG, doxorubicin, magnetic nanoparticles, anti-cancer, biocompatibility, drug delivery

Pu Zhang1 *, Haibao Zhang2 *, Bin Zheng1 *, Heng Wang,1 Xiaolong Qi,1 Shuai Wang,1 Zhenghong Liu,1 Li Sun,1 Yang Liu,3 Xiaowen Qin,1 Weijiao Fan,1 Minghai Ma,2 Wing-Fu Lai,1 Dahong Zhang1 1Urology & Nephrology Center, Department of Urology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang People’s Republic of China; 2Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 3Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang People’s Republic of China*These authors contributed equally to this workCorrespondence: Dahong Zhang; Wing-Fu Lai, No. 138 Shang Tang Road, Hangzhou, 310014, People’s Republic of China, Tel +86-13705711671, Email zppurology@163.com; rori0610@graduate.hku.hkIntroduction: Bladder cancer (BCa) is among the most prevalent cancers worldwide. However, the effectiveness of intravesical therapy for BCa is limited due to the short dwell time and the presence of the permeation barrier.Methods: Nanocomplexes were self-assembled between DNA and hendeca-arginine peptide (R11). Stepwise intravesical instillation of R11 and the generated nanocomplexes significantly enhanced the targeting capacity and penetration efficiency in BCa therapy. The involved mechanism of cellular uptake and penetration of the nanocomplexes was determined. The therapeutic effect of the nanocomplexes was verified preclinically in murine orthotopic BCa models.Results: Nanocomplexes exhibited the best BCa targeting efficiency at a nitrogen-to-phosphate (NP) ratio of 5 but showed a lack of stability during cellular uptake. The method of stepwise intravesical instillation not only increased the stability and target specificity of the DNA component but also caused the delivered DNA to more effectively penetrate into the glycosaminoglycan layer and plasma membrane. The method promotes the accumulation of the delivered DNA in the clathrin-independent endocytosis pathway, directs the intracellular trafficking of the delivered DNA to nonlysosome-localized regions, and enables the intercellular transport of the delivered DNA via a direct transfer mechanism. In preclinical trials, our stepwise method was shown to remarkably enhance the targeting and penetration efficiency of DNA in murine orthotopic BCa models.Conclusion: With this method, a stepwise intravesical instillation of self-assembled nanocomplexes, which are generated from hendeca-arginine peptides, was achieved; thus, this method offers an effective strategy to deliver DNA to target and penetrate BCa cells during gene therapy and warrants further development for future intravesical gene therapy in the clinical context.Graphical Abstract: Keywords: bladder cancer, intravesical therapy, DNA delivery, direct transfer

Sreekanth Reddy Obireddy,1,2 Wing-Fu Lai2 1Department of Chemistry, Sri Krishnadevaraya University, Anantapur, 515003, India; 2Ciechanover Institute of Precision and Regenerative Medicine, The Chinese University of Hong Kong (Shenzhen), Shenzhen, 518172, People’s Republic of ChinaCorrespondence: Wing-Fu LaiCiechanover Institute of Precision and Regenerative Medicine, The Chinese University of Hong Kong (Shenzhen), Shenzhen, 518172, People’s Republic of China, Email rori0610@graduate.hku.hkPurpose: Magnetic nanoparticles have been used in diverse pharmaceutical applications because they can potentially be used to target specific sites. In the present work, a new type of nanocomposites is designed as a carrier of controlled bioactive agent delivery.Methods: Amine-functionalized magnetic nanoparticles (amine-MNPs) are coupled with carboxymethyl chitosan (CMC) to generate the nanocomposites, namely MNPs-CMC, which can be further loaded with doxorubicin (DOX) to produce MNPs-CMC-DOX. The generated nanocomposites are characterized by using various techniques (including FTIR, 1H-NMR, DSC, TGA, SEM, TEM and XRD). In vitro drug release studies are conducted in PBS with different pH values (1.2 and 6.8) at different temperatures (25°C and 37°C). The toxicity of the nanocomposites is tested in MCF-7 and 3T3 cells. The ROS-generating capacity of the nanocomposites is determined in treated cells using 2’,7’-dichlorodihydrofluorescein diacetate.Results: The structures of MNPs, CMC, and nanocomposites are confirmed by FTIR, XRD, and 1H-NMR data reveals the formation of CMC from chitosan (CS). The size of MNPs is estimated by TEM to be around 25 nm. After conjugation with CMC, the size of the nanocomposites increases to 46– 57 nm. Based on the release profiles of MNPs-CMC-DOX, our nanocomposites are pH-responsive. In addition, our nanocomposites show reactive oxygen species (ROS)-generating capacity and cell type-dependent toxicity.Conclusion: Our nanocomposites show high potential for use in bioactive agent delivery. Along with their ROS-generating capacity, they warrant further development as pH-responsive carriers for therapeutic applications.Keywords: nanocomposites, drug delivery, controlled release, biocompatibility