Hyaluronic acid conjugates for topical treatment of skin cancer lesions

Abstract

Skin cancer is one of the most common types of cancer in the United States and worldwide. Topical products are effective for treating cancerous skin lesions when surgery is not feasible. However, current topical products induce severe irritation, light-sensitivity, burning, scaling, and inflammation. Using hyaluronic acid (HA), we engineered clinically translatable polymer-drug conjugates of doxorubicin and camptothecin termed, DOxorubicin and Camptothecin Tailored at Optimal Ratios (DOCTOR) for topical treatment of skin cancers. When compared to the clinical standard, Efudex, DOCTOR exhibited high cancer-cell killing specificity with superior safety to healthy skin cells. In vivo studies confirmed its efficacy in treating cancerous lesions without irritation or systemic absorption. When tested on patient-derived primary cells and live-skin explants, DOCTOR killed the cancer with a selectivity as high as 21-fold over healthy skin tissue from the same donor. Collectively, DOCTOR provides a safe and potent option for treating skin cancer in the clinic.

Predictive high-throughput screening of PEGylated lipids in oligonucleotide-loaded lipid nanoparticles for neuronal gene silencing

“…47 Diglyceride and ceramide lipid anchors are conjugated to PEG via ether and ester linkages, respectively. 47,62 In order to understand the impact of linker chemistry on ASO-LNP structure and function, multiple analogs from each of these PEGlipid families were included while also varying C-tail anchor lengths and/or PEG chain sizes (Fig. 1C).…”

Hyaluronic Acid Nanoparticles for Immunogenic Chemotherapy of Leukemia and T-Cell Lymphoma

“…A polydisperse size distribution was revealed for HA-DOX-CPT in PBS with a mean size ranging from 149 nm (Figure 1A). With TEM and AFM, a polydisperse spherical morphology was observed for these nanoparticles in PBS [23]. When incorporated on HA, the IC90 values of the single-drug nanoparticles increased for DOX and CPT compared to the values obtained for the free drugs (SI, Figure S2, and SI, Table S3A).…”

“…In addition to applications in multimodal in vivo imaging for disease diagnosis or single-drug delivery, nanotechnology can be used to achieve the ratiometric delivery of multiple chemotherapeutic agents [18][19][20]. Previously, we have shown the ability to achieve this ratiometric control by conjugating drug pairs at synergistic ratios to the glycopolymer, namely Hyaluronic Acid (HA), to form HA nanoparticles [21][22][23]. HA can bind specifically to CD44, a cell surface receptor that is typically expressed at high levels on blood-cancer cells [24,25].…”

“…HA can bind specifically to CD44, a cell surface receptor that is typically expressed at high levels on blood-cancer cells [24,25]. This could promote an increased uptake for the particles [21,23,26]. By incorporating the drug pair on to HA, the differential blood circulation properties, tissue biodistribution levels, and cell uptake rate of each drug are now normalized to the carrier itself.…”

“…Here, we propose an effective and personalized immunogenic chemotherapy by conjugating doxorubicin (DOX) and camptothecin (CPT) at different ratios to the HA polymer backbone (HA-DOX-CPT). Previously, HA nanoparticles have demonstrated efficacy in treating solid tumors in vivo [21][22][23]. DOX, an anthracycline, is widely used in the clinic to treat a variety of cancers.…”