Polymeric Delivery Research Articles

Photothermal‐Mediated In Situ Delivery of Polycations Into Bacteria via Alternating Polymer‐Modified Nanoparticles for Targeted Bacterial Killing and Enhanced Biofilm Penetration

AbstractTo achieve targeted clearance of bacteria and their biofilms, a straightforward strategy to integrate antimicrobial alternating polymers with photothermal polydopamine nanoparticles (PDA NPs) is proposed. By manipulating the alternating distribution of electrostatic, hydrophobic, and hydrogen bonding units in the polymer backbone, the thermal stability of polymer‐particle interaction can be tuned, enabling photothermal‐mediated in situ delivery of cationic antimicrobial polymers into bacteria. The alternating polymer coating significantly enhances the penetration capability of NPs into the Methicillin‐resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli) biofilm, achieving a 99% bactericidal rate within the biofilm at a low concentration after 10 min of near‐infrared irradiation, whereas pristine PDA NPs shows negligible effects. The in‐vitro co‐culture model demonstrates that alternating‐polymer‐loaded NPs selectively eradicate 1 × 107 CFU mL−1 of MRSA and E. coli while preserving over 75% viability of the mammalian cells, including mice fibroblasts, human kidney cells, human cervical cancer cells, and macrophages. The efficacy of these biocompatible NPs in targeting bacteria is further validated in a mouse MRSA‐infected wound model. This approach represents a significant advancement in developing safe and efficient antimicrobial therapies with targeted bacterial killing and minimal off‐target effects based on alternating cationic polymers.

Advances in Colon-Targeted Drug Delivery Systems: Innovative Strategies for Treating Colonic Disorders and Prospects for the Future.

Colon-specific targeting delivery systems have drawn a great deal of attention because they represent potential vehicles for treating colonic disorders like diverticulitis, colitis, salmonellosis, Crohn's disease, etc. with less systemic adverse effects as well as for the better oral delivery of many therapeutics that are prone to enzymatic and acidic deterioration in the upper GI tract. Smart polymeric delivery systems in particular have been investigated as "intelligent" delivery systems capable of releasing entrapped pharmaceuticals at the proper time & site of action in response to certain physiological stimuli. The creation of novel polymers & crosslinkers with improved biodegradability and biocompatibility would expand and enhance applications now in use. The development of polymeric systems could result in more precise and programmable drug delivery/therapies. In addition, newer advancements have led to the development of numerous ground-breaking techniques for directing a medication molecule to the colon. This review highlighted formulation techniques pH-dependent, time-dependent, enzyme sensitive, magnetically dependent, ligand-receptor mediated, and microflora-activated systems. Moreover, several methods have been put forth that make use of the innovative idea of such delivery systems, and mechanisms in which the release of drugs is regulated by pH and time as well as pH and the colon's bacteria.

Development and Analysis of Colon-Specific, pH-Responsive Polymer Delivery of Irinotecan Hydrochloride Tablets for Colon Cancer Treatment.

For the formulation of enteric-coated tablets containing irinotecan hydrochloride, this thesis focuses on HPMC and ethylcellulose, both of which are pH- and oxidation-resistant polymers. The integrated polymer-drug tablet mixture was coated with 15% of eudragit S100 and L100, which is a methacrylic acid copolymers, that’s soluble at pH 7. Both the physical characteristics with the invitro release kinetics pattern of the enteric-coated tablets were characterized. In the invitro release study, different pH environments were used, comparable to the gastrointestinal tract (GIT): 0.1 N HCl solution for two hours, pH 6.8 phosphate buffer for three hours, and pH 7.4 phosphate buffer for six hours. Using this device, you can simulate the pH level of the mouth, the digestive tract, and the urinary tract. As a result of consistent release studies, formulation F7 released 88.2% of the drug after 12 hours. Models such as Higuchi, Korsmeyer-Peppas, and zero-order reactions were used to analyze the GIT. This directed the development of a sustained delivery pattern that may be perfect for colonic IRT administration in the eventual treatment of colon cancer. Among the nine formulations, F7 formulated with EC and HPMC extended best sustained release pattern of drug, hence it is suitable for treating colon cancer.

Therapeutic impacts of GNE‑477‑loaded H2O2 stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma.

Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel H2O2 stimulus‑responsive dodecanoic acid (DA)‑phenylborate ester‑dextran (DA‑B‑DEX) polymeric micelle delivery system for GNE‑477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE‑477 loaded DA‑B‑DEX (GNE‑477@DBD) tumor‑targeting drug delivery system was established and the release of GNE‑477 was measured. The cellular uptake of GNE‑477@DBD by three OS cell lines (MG‑63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA‑B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to H2O2, the DA‑B‑DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE‑477@DBD by cells with sustained release of GNE‑477. The in vitro experiments, including MTT assay, flow cytometry, western blotting and RT‑qPCR, demonstrated that GNE‑477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. In vivo, through the observation of mice tumor growth and the results of H&E staining, the GNE‑477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, H2O2‑responsive DA‑B‑DEX presents a promising delivery system for hydrophobic anti‑tumor drugs for OS therapy.

Broadening the Scope of Sapofection: Cationic Peptide-Saponin Conjugates Improve Gene Delivery In Vitro and In Vivo.

Gene therapies represent promising new therapeutic options for a variety of indications. However, despite several approved drugs, its potential remains untapped. For polymeric gene delivery, endosomal escape represents a bottleneck. SO1861, a naturally occurring triterpene saponin with endosomal escape properties isolated from Saponaria officinalis L., has been described as additive agent to enhance transfection efficiency (sapofection). However, the challenge to synchronize the saponin and gene delivery system in vivo imposes limitations. Herein, we address this issue by conjugating SO1861 to a peptide-based gene vector using a pH-sensitive hydrazone linker programmed to release SO1861 at the acidic pH of the endosome. Nanoplexes formulated with SO1861-equipped peptides were investigated for transfection efficiency and tolerability in vitro and in vivo. In all investigated cell lines, SO1861-conjugated nanoplexes have shown superior transfection efficiency and cell viability over supplementation of transfection medium with free SO1861. Targeted SO1861-equipped nanoplexes incorporating a targeting peptide were tested in vitro and in vivo in an aggressively growing neuroblastoma allograft model in mice. Using a suicide gene vector encoding the cytotoxic protein saporin, a slowed tumor growth and improved survival rate were observed for targeted SO1861-equipped nanoplexes compared to vehicle control.

Biopolymer-Based Nanomedicine for Cancer Therapy: Opportunities and Challenges.

Cancer, as the foremost challenge among human diseases, has plagued medical professionals for many years. While there have been numerous treatment approaches in clinical practice, they often cause additional harm to patients. The emergence of nanotechnology has brought new directions for cancer treatment, which can deliver anticancer drugs specifically to tumor areas. This article first introduces the application scenarios of nanotherapies and treatment strategies of nanomedicine. Then, the noteworthy characteristics exhibited by biopolymer materials were described, which make biopolymers stand out in polymeric nanomedicine delivery. Next, we focus on summarizing the state-of-art studies of five categories of proteins (Albumin, Gelatin, Silk fibroin, Zein, Ferritin), nine varieties of polysaccharides (Chitosan, Starch, Hyaluronic acid, Dextran, cellulose, Fucoidan, Carrageenan, Lignin, Pectin) and liposomes in the field of anticancer drug delivery. Finally, we also provide a summary of the advantages and limitations of these biopolymers, discuss the prevailing impediments to their application, and discuss in detail the prospective research directions. This review not only helps readers understand the current development status of nano anticancer drug delivery systems based on biopolymers, but also is helpful for readers to understand the properties of various biopolymers and find suitable solutions in this field through comparative reading.

Machine learning in drug delivery

For decades, drug delivery scientists have been performing trial-and-error experimentation to manually sample parameter spaces and optimize release profiles through rational design. To enable this approach, scientists spend much of their career learning nuanced drug-material interactions that drive system behavior. In relatively simple systems, rational design criteria allow us to fine tune release profiles and enable efficacious therapies. However, as materials and drugs become increasingly sophisticated and their interactions have non-linear and compounding effects, the field is suffering the Curse of Dimensionality which prevents us from comprehending complex structure-function relationships. In the past, we have embraced this complexity by implementing high-throughput screens to increase the probability of finding ideal compositions. However, this brute force method was inefficient and led many to abandon these fishing expeditions. Fortunately, methods in data science including artificial intelligence / machine learning (AI/ML) are providing ideal analytical tools to model this complex data and ascertain quantitative structure-function relationships. In this Oration, I speak to the potential value of data science in drug delivery with particular focus on polymeric delivery systems. Here, I do not suggest that AI/ML will simply replace mechanistic understanding of complex systems. Rather, I propose that AI/ML should be yet another useful tool in the lab to navigate complex parameter spaces. The recent hype around AI/ML is breathtaking and potentially over inflated, but the value of these methods is poised to revolutionize how we perform science. Therefore, I encourage readers to consider adopting these skills and applying data science methods to their own problems. If done successfully, I believe we will all realize a paradigm shift in our approach to drug delivery.

Synergistic Polymer Blending Informs Efficient Terpolymer Design and Machine Learning Discerns Performance Trends for pDNA Delivery.

Cationic polymers offer an alternative to viral vectors in nucleic acid delivery. However, the development of polymer vehicles capable of high transfection efficiency and minimal toxicity has remained elusive, and continued exploration of the vast design space is required. Traditional single polymer syntheses with large monomer bases are very time-intensive, limiting the speed at which new formulations are identified. In this work, we present an experimental method for the quick probing of the design space, utilizing a combinatorial set of 90 polymer blends, derived from 6 statistical copolymers, to deliver pDNA. This workflow facilitated rapid screening of polyplex compositions, successfully tailoring polyplex hydrophobicity, particle size, and payload binding affinity. This workflow identified blended polyplexes with high levels of transfection efficiency and cell viability relative to single copolymer controls and commercial JetPEI, indicating synergistic benefits from copolymer blending. Polyplex composition was coupled with biological outputs to guide the synthesis of single terpolymer vehicles, with high-performing polymers P10 and M20, providing superior transfection of HEK293T cells in serum-free and serum-containing media, respectively. Machine learning coupled with SHapley Additive exPlanations (SHAP) was used to identify polymer/polyplex attributes that most impact transfection efficiency, viability, and overall effective efficiency. Subsequent transfections on ARPE-19 and HDFn cells found that P10 and M20 were surpassed in performance by M10, contrasting with results in HEK293T cells. This cell type dependency reinforced the need to evaluate transfection conditions with multiple cell models to potentially identify moieties more beneficial to delivery in certain tissues. Overall, the workflow employed can be used to expedite the exploration of the polymer design space, bypassing extensive synthesis, and to develop improved polymer delivery vehicles more readily for nucleic acid therapies.

Controlled Delivery of Rosuvastatin or Rapamycin through Electrospun Bismuth Nanoparticle-Infused Perivascular Wraps Promotes Arteriovenous Fistula Maturation.

In the context of arteriovenous fistula (AVF) failure, local delivery enables the release of higher concentrations of drugs that can suppress neointimal hyperplasia (NIH) while reducing systemic adverse effects. However, the radiolucency of polymeric delivery systems hinders long-term in vivo surveillance of safety and efficacy. We hypothesize that using a radiopaque perivascular wrap to deliver anti-NIH drugs could enhance AVF maturation. Through electrospinning, we fabricated multifunctional perivascular polycaprolactone (PCL) wraps loaded with bismuth nanoparticles (BiNPs) for enhanced radiologic visibility and drugs that can attenuate NIH─rosuvastatin (Rosu) and rapamycin (Rapa). The following groups were tested on the AVFs of a total of 24 Sprague-Dawley rats with induced chronic kidney disease: control (i.e., without wrap), PCL-Bi (i.e., wrap with BiNPs), PCL-Bi-Rosu, and PCL-Bi-Rapa. We found that BiNPs significantly improved the wraps' radiopacity without affecting biocompatibility. The drug release profiles of Rosu (hydrophilic drug) and Rapa (hydrophobic drug) differed significantly. Rosu demonstrated a burst release followed by gradual tapering over 8 weeks, while Rapa demonstrated a gradual release similar to that of the hydrophobic BiNPs. In vivo investigations revealed that both drug-loaded wraps can reduce vascular stenosis on ultrasonography and histomorphometry, as well as reduce [18F]Fluorodeoxyglucose uptake on positron emission tomography. Immunohistochemical studies revealed that PCL-Bi-Rosu primarily attenuated endothelial dysfunction and hypoxia in the neointimal layer, while PCL-Bi-Rapa modulated hypoxia, inflammation, and cellular proliferation across the whole outflow vein. In summary, the controlled delivery of drugs with different properties and mechanisms of action against NIH through a multifunctional, radiopaque perivascular wrap can improve imaging and histologic parameters of AVF maturation.

Beyond Lipids: Exploring Advances in Polymeric Gene Delivery in the Lipid Nanoparticles Era.

The recent success of gene therapy during the COVID-19 pandemic has underscored the importance of effective and safe delivery systems. Complementing lipid-based delivery systems, polymers present a promising alternative for gene delivery. Significant advances have been made in the recent past, with multiple clinical trials progressing beyond phase I and several companies actively working on polymeric delivery systems which provides assurance that polymeric carriers can soon achieve clinical translation. The massive advantage of structural tunability and vast chemical space of polymers is being actively leveraged to mitigate shortcomings of traditional polycationic polymers and improve the translatability of delivery systems. Tailored polymeric approaches for diverse nucleic acids and for specific subcellular targets are now being designed to improve therapeutic efficacy. This review describes the recent advances in polymer design for improved gene delivery by polyplexes and covalent polymer-nucleic acid conjugates. The review also offers a brief note on novel computational techniques for improved polymer design. The review concludes with an overview of the current state of polymeric gene therapies in the clinic as well as future directions on their translation to the clinic.

Dynamic Covalent Boronate Chemistry Accelerates the Screening of Polymeric Gene Delivery Vectors via In Situ Complexation of Nucleic Acids.

Gene therapy provides exciting new therapeutic opportunities beyond the reach of traditional treatments. Despite the tremendous progress of viral vectors, their high cost, complex manufacturing, and side effects have encouraged the development of nonviral alternatives, including cationic polymers. However, these are less efficient in overcoming cellular barriers, resulting in lower transfection efficiencies. Although the exquisite structural tunability of polymers might be envisaged as a versatile tool for improving transfection, the need to fine-tune several structural parameters represents a bottleneck in current screening technologies. By taking advantage of the fast-forming and strong boronate ester bond, an archetypal example of dynamic covalent chemistry, a highly adaptable gene delivery platform is presented, in which the polycation synthesis and pDNA complexation occur in situ. The robustness of the strategy entitles the simultaneous evaluation of several structural parameters at will, enabling the accelerated screening and adaptive optimization of lead polymeric vectors using dynamic covalent libraries.

Sparsely PEGylated poly(beta-amino ester) polyplexes enhance antigen specific T-cell response of a bivalent SARS-CoV-2 DNA vaccine

DNA technology has emerged as a promising route to accelerated manufacture of sequence agnostic vaccines. For activity, DNA vaccines must be protected and delivered to the correct antigen presenting cells. However, the physicochemical properties of the vector must be carefully tuned to enhance interaction with immune cells and generate sufficient immune response for disease protection. In this study, we have engineered a range of polymer-based nanocarriers based on the poly(beta-amino ester) (PBAE) polycation platform to investigate the role that surface poly(ethylene glycol) (PEG) density has on pDNA encapsulation, formulation properties and gene transfectability both in vitro and in vivo. We achieved this by synthesising a non-PEGylated and PEGylated PBAE and produced formulations containing these PBAEs, and mixed polyplexes to tune surface PEG density. All polymers and co-formulations produced small polyplex nanoparticles with almost complete encapsulation of the cargo in all cases. Despite high gene transfection in HEK293T cells, only the fully PEGylated and mixed formulations displayed significantly higher expression of the reporter gene than the negative control in dendritic cells. Further in vivo studies with a bivalent SARS-CoV-2 pDNA vaccine revealed that only the mixed formulation led to strong antigen specific T-cell responses, however this did not translate into the presence of serum antibodies indicating the need for further studies into improving immunisation with polymer delivery systems.

Polymeric Nanoparticles for Wound Healing.

Skin injury is one of the most prevalent lesions in humans, and many such wounds, including deep burns and chronic skin wounds, are notoriously difficult to heal. It has been established by medical practitioners that current wound therapies are not perfectly effective and are far from satisfactory. Meanwhile, nanotechnologies have made it possible to develop pharmaceutical formulations that can elevate the effectiveness of conventional pharmacotherapies to entirely new heights. Most nanostructured biomaterials used to treat wounds, including those that have helped establish this fascinating subject, have been polymeric. The bibliographic analysis presented here shows a steady growth in the research output of studies on the use of polymeric nanoparticles in wound healing therapies. This article provides an overview of polymeric nanoparticles for the treatment of wounds with an emphasis on different chemistries and polymer-drug combinations that have been proven the most effective. The wound age, pathophysiology, wound healing treatments of the present and past, as well as the physicochemical nature and methods for the synthesis of polymeric nanoparticles, are all covered in the opening parts of the review. The existing polymeric nano-drug delivery systems with the greatest promise for wound healing and skin regeneration are subsequently addressed and their potentials summarized.

Rational Design of Polymeric mRNA Delivery Vectors to Achieve Excellent Room-Temperature Storage Stability and Delivery Efficiency

Rational Design of Polymeric mRNA Delivery Vectors to Achieve Excellent Room-Temperature Storage Stability and Delivery Efficiency

Advancements in microsponges for the management of vaginal and colorectal diseases: A comprehensive review

The controlled-release drug delivery systems have risen dramatically allowing various factors such as the prohibitive cost of developing new entities, the expiration of existing international patents, and the discovery of new polymeric materials suitable for prolonged drug release and improvement in therapeutic efficacy. Microsponges are the porous microspheres-based polymeric delivery system that allows controlled drug release at a specific site. Microsponges are developed for the efficient delivery of active ingredients at a low dose. They help in improving stability by modifying drug release kinetics, reducing side effects, and enhancing the retention of drug entities. Microsponge compositions are stable throughout a wide pH and temperature range, making them more compatible with numerous vehicles, and ingredients. Several studies have shown that microsponges are non-irritant, non-toxic, non-mutagenic, and non-allergic with self-sterilizing properties. They are typically used for topical administration but have lately been used for oral, vaginal, and colorectal administration as well. The current review contains basic information about microsponges, their method of preparation, and various characterization parameters. The review also discusses the application of microsponges in vaginal and colorectal diseases. The latter portion of the script includes various patents and preclinical trials.

Integrated anti-vascular and immune-chemotherapy for colorectal carcinoma using a pH-responsive polymeric delivery system

Colorectal carcinoma (CRC) has become one of the most prevalent malignant tumors and exploring a potential therapeutic strategy with diminished drug-associated adverse effects to combat CRC is urgent. Herein, we designed a pH-responsive polymer to efficiently encapsulate a stimulator of interferon genes (STING) agonist (5,6- dimethylxanthenone-4-acetic acid, termed ASA404) and a common clinically used chemotherapeutic agent (1-hexylcarbamoyl-5-fluorouracil, termed HCFU). Investigations in vitro demonstrated that polymer encapsulation endowed the system with a pH-dependent disassembly behavior (pHt 6.37), which preferentially selected cancerous cells with a favorable dose reduction (dose reduction index (DRI) of HCFU was 4.09). Moreover, the growth of CRC in tumor-bearing mice was effectively suppressed, with tumor suppression rates up to 94.74%, and a combination index (CI) value of less than one (CI = 0.41 for CT26 cell lines), indicating a significant synergistic therapeutic effect. Histological analysis of the tumor micro-vessel density and enzyme-linked immunosorbent assay (ELISA) tests indicated that the system increased TNF-α and IFN-β levels in serum. Therefore, this research introduces a pH-responsive polymer-based theranostic platform with great potential for immune-chemotherapeutic and anti-vascular combination therapy of CRC.

Combating bone marrow failure with polymer materials.

Bone marrow failure (BMF) has become one of the most studied autoimmune disorders, particularly due to its prevalence both as an inherited disease, but also as a result of chemotherapies. BMF is associated with severe symptoms such as bleeding episodes and susceptibility to infections, and often has underlying characteristics, such as anemia, thrombocytopenia, and neutropenia. The current treatment landscape for BMF requires stem cell transplantation or chemotherapies to induce immune suppression. However, there is limited donor cell availability or dose related toxicity associated with these treatments. Optimizing these treatments has become a necessity. Polymer-based materials have become increasingly popular, as current research efforts are focused on synthesizing novel cell matrices for stem cell expansion to solve limited donor cell availability, as well as applying polymer delivery vehicles to intracellularly deliver cargo that can aid in immunosuppression. Here, we discuss the importance and impact of polymer materials to enhance therapeutics in the context of BMF.

Sustained adenosine release: Revealing its impact on osteogenic signalling pathways of human mesenchymal stromal cells

Non-healing fractures, a global health concern arising from trauma, osteoporosis, and tumours, can lead to severe disabilities. Adenosine, integral to cellular energy metabolism, gains prominence in bone regeneration via adenosine A2B receptor activation. This study introduces a controlled-release system for localized adenosine delivery, fostering human mesenchymal stromal cell (hMSC) differentiation into functional bone cells. The study investigates how the ratio of lactic acid to glycolic acid in microparticles can influence adenosine release and explores the downstream effects on gene expression and metabolic profiles of osteogenic differentiation in hMSCs cultured in growth and osteoinductive media. Insights into adenosine-modulated signalling pathways during MSC differentiation, with osteogenic factors, provide a comprehensive understanding of the pathways involved. Analysing gene expression and metabolic profiles unravels adenosine's regulatory mechanisms in MSC differentiation. Sustained adenosine release from microparticles induces mineralization, synergizing with osteogenic media supplements, showcasing the potential of adenosine for treating critical bone defects and metabolic disorders. This study highlights the efficacy of a polymeric microparticle-based delivery system, offering novel strategies for bone repair. Unveiling adenosine's roles and associated signalling pathways advances our comprehension of molecular mechanisms steering bone regeneration, propelling innovative biomaterial, combined with metabolites, approaches for clinical use.

Reductive prodrug and AIE copolymer nanoparticle for monitoring and chemotherapy

Polymeric micelle systems for drug delivery, monitor and chemotherapy have gained significant attention, and reductive polymeric micelle systems have become particularly attractive due to their controlled release behavior without additional assistance. However, there are challenges in accurately controlling drug and probe release from the nanoparticles and determining the loading content of drug and probe. To address these issues, we have developed a reduction-responsive Pt(IV) prodrug-based polymeric delivery system that can be dynamically monitored using aggregation-induced emission luminogens (AIE) based bioprobes. These polymeric micelle can self-assemble into nanoparticles and release both bio-active Pt(II) drug and bio-probe upon reduction activation. TPE molecules released in the inner endo/lysosomal microenvironment aggregate and fluoresce upon irradiation, thus allowing real-time tracking of drug biodistribution without additional contrast agents. Advantages of this system include position-specific chemical bond cleavage, control of platinum content, and monitoring of drug reduction and biodistribution.

Abstract 5734: Polymeric delivery with dual drug payloads for hepatocellular carcinoma (HCC) therapy

Abstract Background: The long-term survival of hepatocellular carcinoma (HCC) patients is hampered by high recurrence and drug resistance. Targeting sonic hedgehog (SHH) pathways can overcome drug resistance in HCC. In this study, we co-loaded SHH inhibitor, cyclopamine (CPA) and paclitaxel (PTX) in a novel polymeric nanomicellar drug delivery system (M-CPA/PTX), to overcome the drug resistance in HCC tumor models. Method: The combinational effect in vitro was studied by treating HCC with CPA and PTX. The combinational index was calculated using CalcuSyn Biosoft software to determine the additive or synergistic effect of the combination. Three formulations (F0, F5, and F16) were selected for further testing based on formulation optimization using central composition design (CCD). The storage stability of M-CPA/PTXs at room temperature and 4 °C was evaluated by measuring the changes in micelle size, PDI, and encapsulation efficiency (EE) over pre-determined periods. In the pharmacokinetics (PK) study, nude mice were IP-injected with 5 mg/kg of PTX equivalent F0 and F16. Additionally, the toxicity of F0 was investigated using healthy Sprague Dawley rats, in which rats were intravenously injected with a single F0 dose of 1, 2, and 4 mg/kg/drug of M-CPA/PTX. Results: Combinational effect study suggested that CPA and PTX, demonstrated synergistic effect in Hep3B and HepG2 cells compared to the mono-treatment, thus overcoming resistance. F0, F5, and F16 exhibited particle sizes of 75.27 ± 1.06, 54.63 ± 0.85, and 70.63 ± 3.39 nm, respectively. The release kinetics of both drugs from these micelles displayed significantly slow-release profiles from the micelles, with less than 10% cumulative release within 24 hours in plasma. The stability study indicated that both drugs' micelle size and EE were not appreciably changed over 6 weeks at room temperature and 4 °C. Notably, the biodistribution studies showed that F16 achieved significantly greater accumulations of CPA in the liver, kidney, and spleen compared to F0 (P < 0.05). Additionally, the maximal tolerable dose of F0 in rats was 4 mg/kg/drug for the M-CPA/PTX combination, which did not result in treatment-related mortality. Conclusion: The combination of CPA and PTX offered promising synergistic effects on HCC treatment. F0, F5, and F16 were developed and characterized with the desired physicochemical properties and demonstrated controlled release characteristics for both payloads, suggesting their potential for sustained drug delivery in HCC therapy. Enhanced liver accumulation of F16 suggested favorable biodistribution for the site of action. Lastly, the safe toxicity profile supports the first choice of F0 among other lead candidates for further pre-clinical efficacy studies. Citation Format: Lu Dai, Guodong Zhang, Fatima Dagher, Airong Li, Amir Mohammad Gholizadeh, Chun Li, Diana S- Chow. Polymeric delivery with dual drug payloads for hepatocellular carcinoma (HCC) 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 5734.