Small molecule drug conjugates (SMDCs) have been developed in the clinical field as a useful option that can overcome various limitations of antibody-drug conjugates (ADCs), such as low tumor penetration and high cost of antibody. Although SMDCs provide several advantages over ADCs, including chemical stability, facile synthesis, relatively low cost manufacturing, and high solid tumors penetration, their short half-lives hamper effective delivery into tumor tissue and ultimately lead to limited therapeutic potential of SMDCs. In order to improve the blood circulation time and tumor penetration of SMDCs, nanoparticle-assisted delivery system arose as a rational strategy. In this sense, the development of stimuli responsive therapeutic nanoparticles is considered critical for the successful clinical translation of SMDCs. The essential requirements of nanomaterials for clinical entry are biocompatibility, biodegradability, and controlled drug release rates. Bilirubin nanoparticles (BRNPs) with such requirements fulfilled have been previously demonstrated as a multi-stimuli responsive drug delivery carrier, antioxidant and immune modulator in both anti-cancer therapy and anti-inflammatory therapy for diseases such as asthma, inflammatory bowel disease, ischemic reperfusion injury and islet transplantation. Thus, BRNPs have been adopted as the delivery carriers of ligand-drug conjugates for the development of next generation promising nanomedicines, already proved its efficient therapeutic efficacy and anti-cancer drug delivery carrier by previous research. BRNP-assisted delivery of SMDCs enhanced drug accumulation in the tumor microenvironment (TME) via the enhanced permeation and retention (EPR) effect and simultaneously displayed ROS-sensitive release of ligand-drug conjugates in response to TME characteristics, high level of reactive oxygen species (ROS). Based on intrinsic bilirubin antioxidant characteristics, hydrophobic bilirubin changed into hydrophilic biliverdin. As a model system of ligand-drug conjugates, small molecule ligand (ACUPA) that selectively targets the prostate specific membrane antigen (PSMA) was covalently conjugated to SN-38 using a hydrophilic oligoethyleneglycol (OEG) linker with intracellular cleavable ester linkage. The respective ligand-drug conjugates was protected into nanoparticles, loading percentage about ~ 10 w/w %, freely released the conjugates in the tumor microenvironment, active targeting to tumor uptake of SN-38 drug released in the cytosol, demonstrating strong anti-tumor synergistic efficacy in vivo PSMA overexpressed tumor xenograft model.
In conclusion, to prove universal application and overcome the limit of clinical entry of nanoparticles, other model system further developed and remained on-going verification of deep tumor tissue penetration of SMDCs. Combination with various small molecule ligand, anti-cancer drug and novel nanomedicine could contribute to the progress of clinical fields by increasing the efficiency of cancer treatment and minimizing the side effects by passive and active cancer targeting synergistic combination systems.