Phytochemical-Based Nanomedicine for Targeting Tumor Microenvironment and Inhibiting Cancer Chemoresistance: Recent Advances and Pharmacological Insights

Abstract

Cancer remains the leading cause of death and rapidly evolving disease worldwide. The understanding of disease pathophysiology has improved through advanced research investigation, and several therapeutic strategies are being used for better cancer treatment. However, the increase in cancer relapse and metastatic-related deaths indicate that available therapies and clinically approved chemotherapy drugs are not sufficient to combat cancer. Further, the constant crosstalk between tumor cells and the tumor microenvironment (TME) is crucial for the development, progression, metastasis, and therapeutic response to tumors. In this regard, phytochemicals with multimodal targeting abilities can be used as an alternative to current cancer therapy by inhibiting cancer survival pathways or modulating TME. However, due to their poor pharmacokinetics and low bioavailability, the success of phytochemicals in clinical trials is limited. Therefore, developing phytochemical-based nanomedicine or phytonanomedicine can improve the pharmacokinetic profile of these phytochemicals. Herein, the molecular characteristics and pharmacological insights of the proposed phytonanomedicine in cancer therapy targeting tumor tissue and altering the characteristics of cancer stem cells, chemoresistance, TME, and cancer immunity are well discussed. Further, we have highlighted the clinical perspective and challenges of phytonanomedicine in filling the gap in potential cancer therapeutics using various nanoplatforms. Overall, we have discussed how clinical success and pharmacological insights could make it more beneficial to boost the concept of nanomedicine in the academic and pharmaceutical fields to counter cancer metastases and drug resistance.

Nanocarriers for natural polyphenol senotherapeutics

“…Current preclinical studies predominantly focus on exploring the therapeutic potential of targeting senescence‐related pathways in cancer, with ongoing investigations aiming to understand the efficacy and safety of therapies in modulating the SASP. Phytochemicals, including alkaloids and polyphenols, have demonstrated the ability to promote apoptosis, thereby suppressing tumor growth and cell proliferation (Sa et al., 2023 ).…”

“…A plethora of formulations has been employed to improve the bioavailability and relatively poor pharmacokinetics of “free‐form” phytochemicals (Sa et al., 2023 ). The lack of target selectivity is often described as a hurdle or setback in the classic “one drug, one target” approach to drug discovery, and indeed, there have been increasing calls to investigate drugs that have multiple targets (Casas et al., 2019 ; Talevi, 2015 ), which would be beneficial in pathologies involving a multiplicity of pathways such as senescence.…”