Cancer is the second-leading cause of mortality in the world. It has been defined as excessive cell proliferation and a lack of cell death that, except for haematological malignancies, form an aberrant cell mass or tumour. New blood vessels help the initial tumour grow, and over time, it develops the capability to metastasize and spread to other regions of the body, ultimately resulting in death. Environmental or hereditary influences harm or mutate the DNA (genetic material) of the cells, leading to cancer. Currently, anti-cancer medications (chemotherapy, hormones, and biological treatments) constitute the medical therapy of choice for metastatic malignancies, whereas surgery and radiation are the mainstays for local and non-metastatic tumours [1]. According to estimates from the International Agency for Research on Cancer (IARC), there will be almost 19.3 million new cases and over 10 million deaths worldwide due to cancer in 2020. Although chemotherapy is a promising treatment strategy for decreasing the impact of cancer, its efficacy in humans is constrained by concurrent multi-drug resistance (MDR) and P-glycoprotein (P-gp) overexpression [2].

The ability to manage the tumour cells innate or acquired resistance to chemotherapeutic drugs is crucial for the outcome of cancer therapy. Due to the MDR phenomenon, which can be defined as the capacity of cells to either acquire resistance or be intrinsically resistant to a variety of structurally distinct particles that do not possess an identical mechanism of action, resistance to a single drug often results in drug-resistant incidents. This multifactorial phenotype is associated with ineffective cancer therapy and a poor prognosis for patients with cancer [3], [4]. All phyla of life include ABC transporters. ABC proteins are primarily used as efflux pumps in eukaryotes, but they also function as ATP-dependent importers as well as exporters in bacterial cells [5]. According to their similarity and domain organisation, the 48 genes and 1 pseudogene that encode ABC transporters in humans are divided into seven families, ranging from ABCA to ABCG, 12 of which have an association with drug efflux and consequent MDR [6]. ABC transporters mediate the physiological efflux of peptides, lipids, sterols, and toxins. The ABC transporter most closely connected with resistance to cancer treatment is P-gp [5]. A rate-limiting step in determining therapeutic effectiveness and safety is determining P-glycoprotein (ABCB1) affinity in living organisms. Due to their significant role in the absorption of drugs, their distribution, metabolism, and excretion, screens for P-gp-mediated movement in vivo and in vitro are now a necessary step in the procedure for developing drugs [7]. This leads to the development of numerous anti-cancer drugs, and other P-gp substrates' bioavailability has been significantly improved with the help of nanocarriers.

P-gp inhibitors are given site-specific activity by being encapsulated in nanocarrier technology, which also avoids toxicity. In this method, the therapeutic drugs may be combined with P-gp inhibitors or excipients for pharmaceuticals that are present inside the carrier system. Therefore, the major objectives of each of these processes are to improve therapeutic agent efficacy, increase drug bioavailability, and increase drug absorption by target organs [8]. Although these compounds do not exhibit toxicity in normal cells, they can have unique impacts on the overexpression of the pump. It is uncertain how these drugs will affect the physiological activity of P-gp. In this situation, focusing on a particular attack on the P-gp, among which the cancerous cell could express a wide course of action, the mechanism that regulates four natural compounds that belong to different classes, such as polyphenols, hydrocarbons, and terpenoids, is presented in particular. A pentacyclic triterpenoid is in lupenol; curcumin is a polyphenol; phytol is an acyclic hydrogenated diterpene alcohol; and heptacosane contains 27 carbon atoms of straight-chain alkane. Each one of those substances has the ability to target P-gp by preventing its transcriptional expression and also serves as a substrate inhibitor for a similar protein [9]. The multi-specific drug transporter P-gp is essential for active drug efflux. The permeability of many orally delivered therapeutic medication compounds with P-gp substrates is decreased as a consequence of the presence of P-gp throughout the GIT. Overexpression of P-gp on the surfaces of the cells of numerous organs act by preventing the entrance of hazardous chemicals and facilitating drug removal through a variety of excretory routes, including bile, urine, etc [10].

P-gp substrates are typically amphipathic molecules having molecular weights ranging between 200 and 1900 Da; the majority of them are aromatic compounds that are either neutral or basic. Additionally, because P-gp has a wide range of substrate specificity, cells could exhibit cross-resistance to several medicines, resulting in MDR. P-gp transports several anticancer medications, rendering the tumours resistant, and is only overexpressed in various types of tumours. P-gp substrates can be given in combination with small-molecule P-gp inhibitors to increase the bioavailability of orally administered medicines. Nanocarriers have been examined in a number of prior studies for P-gp-mediated tumour drug resistance. It is capable of combining with P-gp inhibitors and their effect on constituent parts, having the capacity to avoid P-gp elimination through various methods attributable to the characteristics and formulation of each [1].

According to a recent study, pharmacological molecules with high lipophilicity, more H-bond donors and acceptors, and a tertiary nitrogen atom were more likely to interact with P-gp than those with lower amounts of these characteristics. According to a number of studies, by interfering with the P-gp efflux route, one can circumvent it. Zhang et al. created a hydrophobic (water-repellent) HIF-1 (Hypoxia-inducible factor-1) inhibitor (YC-1) through the incorporation of an anticancer medicine called irinotecan (IRI) with a self-assembled nanoparticle. This led to a significant down-regulation of HIF-1 and an increase in IRI's anticancer efficacy. In recent years, several researchers have discovered that nitric oxide-releasing nanoparticles such as S-nitrosothiol (SNO) and N-diazeniumdiolates (NONOates) and metal oxide nanomaterials, including copper oxide and zinc oxide, also show characteristics that inhibit ABC efflux transporters. Nitric oxide (NO) plays a key role in lowering ATP levels, which prevents the activation of the efflux pump [2].

Due to their capacity for enhanced cytotoxicity against malignant cells, polymeric prodrugs play a crucial role in chemotherapy. Numerous prodrugs, including polyglutamate conjugates, N-(2-hydroxypropyl) methacrylamide (HPMA)-copolymer conjugates, albumin-binding PEG conjugates, and doxorubicin, have been discovered as highly effective inhibitors of P-glycoprotein, and these prodrugs protect drugs against immune-related reactions along with degrading enzymes, enhance blood plasma duration of action, and decrease the elimination by the kidneys of drugs [10]. There are several synthetic anticancer medications available in the market, as described in Table 1, which work on different mechanisms. The marketed formulations are discussed in Table 1 based on the ascending order of the year of approval. Additionally, a few herbal anticancer formulations are also prevalent in the market, as discussed in Table 2.

The broad overview of nanomaterials-based drug delivery platforms and active targeting are discussed in Fig. 1.