Kaila Javius-Jones, Pharmaceutical Sciences graduate student (Hong Research Group), will be defending his PhD research thesis:

Targeted dendritic-lipid nanoparticles for combination cancer therapy

Drug delivery systems for hybrid delivery of multiple therapeutics is largely under investigation as we grow to understand the synergistic benefits from combination cancer therapies. To offer optimal delivery of multiple therapeutics, a drug delivery platform is necessary to tune the biodistribution of two or more drugs into one singular distribution profile. Increasing the occurrence of dual drug delivery within a cell, can also increase chances of attacking multiple tumorigenic pathways concurrently, thus cooperatively decreasing cancer cell growth. A major challenge in this integrated approach is the lack of effective nanoparticle (NP)-mediated delivery systems that are capable of transporting multiple therapeutics in a controlled manner. 

In the first approach, we have developed a novel nanocarrier platform based on lipid nanoparticles containing dendritic polymers, noted as dendritic-lipid nanoparticles (dLNPs). This platform was functionalized with PD-L1 targeting peptides (pPD-L1), siRNA that silences PD-L1, and doxorubicin (DOX).  With this targeted immunomodulation approach, we can provide active tumor targeting and immune checkpoint blockade through cancer cell PD-L1 expression. This NP-mediated integration of immunotherapy alongside conventional chemo- and gene therapy, can offer the potential to improve clinical efficacy of anti-tumor immunity. Thus, this nanoformulation was optimized by implementing 2.5% w/w of targeted unimers (pPD-L1-dLNPs) within nanoparticles and shown to elicit robust cell targeting as a 4.7-fold increase was observed in the transfection of  DNA encoding green fluorescent protein (GFP) compared to non-targeted samples (p = 0.017).  In addition, delivery of DOX encapsulated pPD-L1-dLNPs and free drug elicited a 28.7% and 34.3% reduction in the viability of mouse oral cancer (MOC1) cells, respectively, after 48-hour incubation.  However, the co-delivery of a sublethal dose of DOX and PD-L1 siRNA using pPD-L1-dLNPs offered synergistic results in the inhibition of cancer cell proliferation, as a 56.4% reduction in cell viability was observed compared to untreated cells (p < 0.01). 

In the second approach, we present a novel hybrid drug delivery system where our dLNPs are embedded into gelatin-methacrylate (GelMA) based hydrogels to allow for slow and sustained delivery of drugs to cells. We determined the optimal dLNP formulation by testing the effect of dendron generation (generation 3-5) on the capability to deliver drug to murine triple negative breast cancer cells, 4T1. Results indicated acetylated NP formulations had high biocompatibility (>90% viability) and all dLNP formulations could outcompete a linear copolymer, PCL_3.5K-PEG_5K, in DOX loading (>17% loading vs 7% loading, respectively), in vitro drug release and cytotoxicity. Generation 4 and 5 amine-terminated dLNPs also showed similar proton buffering capacity to generation 4 PAMAM dendrimers while enhancing biocompatibility 4-fold and 2.9-fold, respectively, at 100 µg/mL of NP. Optimal GelMA conditions were also validated by testing various GelMA hydrogels (1-10 wt % GelMA) and confirmed 10 wt % of GelMA elicited a hydrogel that offered a porous structure with high biocompatibility (>80% viability) and slow release of DOX-loaded G5 dLNPs as 58% of DOX was released after 72 hours compared to 77% release in DOX-loaded hydrogels alone (p < 0.01).

Together, these findings offer insight into the chemical and structural features necessary to design next-generation dendritic-lipid nanoparticles for personalized combination cancer treatment.

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