Cancer nanomedicine is defined as the application of nanotechnology and nanomaterials for the formulation of cancer therapeutics that can overcome the impediments and restrictions of traditional chemotherapeutics. Multidrug resistance (MDR) in cancer cells can be defined as a decrease or abrogation in the efficacy of anticancer drugs that have different molecular structures and mechanisms of action and is one of the primary causes of therapeutic failure. There have been successes in the development of cancer nanomedicine to overcome MDR; however, relatively few of these formulations have been approved by the United States Food and Drug Administration for the treatment of cancer. This is primarily due to the paucity of knowledge about nanotechnology and the fundamental biology of cancer cells. Here, we discuss the advances, types of nanomedicines, and the challenges regarding the translation of in vitro to in vivo results and their relevance to effective therapies.

Being the fourth most fatal malignancy worldwide, pancreatic cancer is on track to become the second leading cause of cancer-related deaths in the United States by 2030. Gemcitabine is a first-line chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine Elaidate (Gem Elaidate) is a lipophilic derivative which allows hENT1-independent intracellular delivery of gemcitabine and better pharmacokinetics and entrapment in a nanocarrier. Cancer cells and neovasculature are negatively charged compared to healthy cells. Palmitoyl-DL-carnitine chloride (PC) is a Protein kinase C (PKC) inhibitor which also provides a cationic surface charge to nanoliposomes for targeting tumor neovasculature and augmented anticancer potency. The objectives of our study are: (a) to develop and characterize a PKC inhibitor-anchored Gem Elaidate-loaded PEGylated nanoliposome (PGPLs) and (b) to investigate the anticancer activity of Gem Elaidate and PGPLs in 2D and 3D models of pancreatic cancer. The optimized PGPLs resulted in a particle size of 80 ± 2.31 nm, a polydispersity index of 0.15 ± 0.05 and a ζ-potential of +31.6 ± 3.54 mV, with a 93.25% encapsulation efficiency of Gem Elaidate in PGPLs. Our results demonstrate higher cellular uptake, inhibition in migration, as well as angiogenesis potential and significant apoptosis induced by PGPLs in 3D multicellular tumor spheroids of pancreatic cancer cells. Hence, PGPLs could be an effective and novel nanoformulation for the neovasculature-specific delivery of Gemcitabine Elaidate to treat PDAC.

Dostarlimab, a programmed death receptor-1 (PD-1)-blocking IgG4 humanized monoclonal antibody, gained accelerated approval from the US Food and Drug Administration (FDA) in April 2021, and received a full approval in February 2023. Dostarlimab was approved for treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer (EC) that progressed during or after prior treatment who have no other suitable treatment options. Herein, we review the structure-based mechanism of action of dostarlimab and the results of a clinical study (GARNET; NCT02715284) to comprehensively clarify the efficacy and toxicity of the drug. The efficacy and safety of dostarlimab as monotherapy was assessed in a non-randomized, multicenter, open-label, multi-cohort trial that included 209 patients with dMMR recurrent or advanced solid tumors after receiving systemic therapy. Patients received 500 mg of dostarlimab intravenously every three weeks until they were given four doses. Then, patients received 1000 mg dostarlimab intravenously every six weeks until disease progression or unacceptable toxicity. The overall response rate, as determined by shrinkage in tumor size, was 41.6% (95% confidence interval [CI]; 34.9, 48.6), with 34.7 months as the median response duration. In conclusion, dostarlimab is an immunotherapy-based drug that has shown promising results in adult patients with recurrent or advanced dMMR EC. However, its efficacy in other cancer subtypes, the development of resistance to monotherapy, and efficacy and safety in combination with other immunotherapeutic drugs have not yet been studied.