Nanovectorization of Prostate Cancer Treatment Strategies: A New Approach to Improved Outcomes

Abstract

Prostate cancer (PC) is the most frequent male cancer in the Western world. Progression to Castration Resistant Prostate Cancer (CRPC) is a known consequence of androgen withdrawal therapy, making CRPC an end-stage disease. Combination of cytotoxic drugs and hormonal therapy/or genotherapy is a recognized modality for the treatment of advanced PC. However, this strategy is limited by poor bio-accessibility of the chemotherapy to tumor sites, resulting in an increased rate of collateral toxicity and incidence of multidrug resistance (MDR). Nanovectorization of these strategies has evolved to an effective approach to efficacious therapeutic outcomes. It offers the possibility to consolidate their antitumor activity through enhanced specific and less toxic active or passive targeting mechanisms, as well as enabling diagnostic imaging through theranostics. While studies on nanomedicine are common in other cancer types, only a few have focused on prostate cancer. This review provides an in-depth knowledge of the principles of nanotherapeutics and nanotheranostics, and how the application of this rapidly evolving technology can clinically impact CRPC treatment. With particular reference to respective nanovectors, we draw clinical and preclinical evidence, demonstrating the potentials and prospects of homing nanovectorization into CRPC treatment strategies.

Keywords: CRPC; Non-AR therapeutic targets; nanotheranostics; nanotherapies; prostate cancer.

Figure 1

Schematic illustration showing the nanoparticles classified according to their chemical composition (created with Biorender).

Figure 2

EPR effect. Nanovectors equipped with hydrophilic and flexible polymers escape opsonization and are able to diffuse selectively through the tumor vascular endothelium (orange color) but not through the endothelium of healthy tissue (blue color). Created with Biorender; Adapted from [68], Collège de France, 2013.

Figure 3

A graphical representation of the number of published articles relating to prostate cancer and nanoparticles drug delivery between 2011 and 2021.

Figure 4

Schematization of a liposome used as nanovector. Liposomes generally consist of a lipid bilayer (phospholipids and cholesterol). The drug is encapsulated in the hydrophobic central region. The outer surface of the vector may contain polyethylene glycol (PEG) and ligands, created with Biorender [94].

Figure 5

Showing the reverse and direct micellar structures. Micelle nanovectors consist of direct micelles with the anti-cancer agent positioned either on the surface for hydrophilic drugs (e.g., antisense oligonucleotide for example) or inside for hydrophobic drugs (e.g., chemotherapeutic agents). (Created with Biorender).

Figure 6

Schematic representation of the targeting of anti-cancer agents through defective tumor microvasculature using the system of delivery of echogenic particles. The microbubbles formed by the fusion nanobubbles become echogenic once inside the tumor. Created with Biorender; Adapted from [138], MDPI, 2020.

Figure 7

(a) Lipid-conjugated Antisense Oligonucleotide (LASO) structure; (b) Auto assembly—micelle formation of LASO in aqueous media; with a particle size of 11 nm. Adapted from [141], Elsevier, 2017.

Figure 8

(a) Representation of the structure of a dendrimer; (b) Different stages of the divergent synthesis of a dendrimer created with Biorender; Adapted from [143], Drug Discovery Today, 2001.

Figure 9

Tetrafunctional synthesis of polyamidoamine (PAMAM). Comprehensive Michael addition of amine groups with methyl acrylate, followed by amidation of the ester resulting from ethylenediamine. Adapted and modified from [143], Drug Discovery Today, 2001.

Figure 10

Schematic drawing of nanoparticles used for multimodal imaging and therapy (created with Biorender).

Figure 11

Synthesis of the nanoparticle PLGA-b-PEG-COOH: Docetaxel is encapsulated using the nanoprecipitation method. The nanoparticle is then covalently conjugated to aptamer (Apt) A10. Created with Biorender; modified from [167], Springer Science & Business Media; 2013.

Figure 12

Schematic structure of NK911. A polymeric micelle composed of a copolymer block of PEG and polyaspartic acid (about 30 units). The polyethylene glycol is located at the outer level of the shell of the micelle. NK911 has a very hydrophobic heart, which allows it to capture a sufficient amount of doxorubicin, created with Biorender; adapted and modified from [170], Br J Cancer, 2004.

Figure 13

Structure and anti-cancer effect of the AmDM vector used with a siRNA targeting Hsp27. The AmDm vector is an amphiphilic dendrimer (in violet the hydrophobic alkyl chain, in green the dendrimer part of PANAM hydrophilic). Hsp27 protein is significantly under-translated and tumor proliferation reduced with treatment [173], Pharm Res. 2014.