1. BHS035 Drug Delivery
Answer
Introduction
Drug delivery involves formulations, approaches, manufacturing techniques and storage
systems and technologies for efficiently transporting a pharmaceutical substance or
compound to the target to achieve desired therapeutic effects (Wen et al. 2015). Drug
delivery systems are essentially defined as a device or formulation enabling a therapeutic
drug or substance to selectively reach a desired site of action without reaching organs,
tissues or non-target cells.
Paclitaxel is an effective chemotherapeutic drug developed for acting against broad
disorders of cancers like lung, breast or ovarian cancers (Kampan et al. 2015). Paclitaxel is
encapsulated in non-toxic and biodegradable Nano-delivery systems for protecting it
against degradation. The essay will highlight its reformulation properties and present an
evaluation of the complicated delivery system. It would identify challenges pertaining to the
drug delivery of Paclitaxel and discuss a targeted delivery system for overcoming pertinent
issues.
Discussion
Chosen Drug- Paclitaxel
Paclitaxel is known to be a great antineoplastic drug obtained from natural sources in the
last decade. As a pseudoalkaloid with a taxane ring, it was identified after screening over
35000 plant species for assessing antitumor activity by NCI (National Cancer Institute) in
1958 (Mohanlall and Naicker 2020). However, like other anti-cancer related drugs, issues
are faced in the clinical administration of this drug for the cause of its poor solubility.
Therefore, an adjuvant known as Cremophor EL or polyethoxylated castor oil must be
utilized for its administration. Nanoparticles derived from biodegradable polymers lead to
ideal solutions for the adjuvant issues and realizes the need for implementing a targeted
and controlled drug delivery with lower side effects, reducing severely hypersensitive
reactions and better efficacy.
The most widely utilized formulation of Paclitaxel in clinical settings is the drug’s
2. solubilized form, diluted before its administration intravenously. It contains
polyoxyethylated castor oil (Cremophor EL) in a 1:1 v/v mixture with dehydrated ethanol
(Li et al. 2015). In unopened vials, the drug can remain stable for nearly five years at 4°C in
unopened vials. Cremophor EL is also used in formulations of other hydrophobic agents of
cancer like echinomycin, teniposide, and didemnin B. However, the composition of
Cremophor can cause the release of histamine while inducing hypersensitivity and
hypotension. Thus, paclitaxel formulations need to be infused slowly over several hours for
minimizing the frequency or intensity of side effects. Patients should be pre-medicated with
antihistamines and corticosteroids before the infusion of this drug for preventing
anticipated reactions. Commercially available paclitaxel formulations are diluted about 5-20
times in 5% dextrose solutions and normal saline for administering it intravenously (Zhao
et al. 2019). The resultant formulation is diluted in concentrations of 0.3-1.2 mg/ml of the
drug, which is higher than 0.01 mg/ml paclitaxel’s aqueous solubility, posing pertinent risks
of drug precipitation on diluting it.
The insolubility of Paclitaxel in water causes the formulation to proceed in equal parts of
Cremophor EL and ethanol, helping the drug to be dispersed in an aqueous medium. The
precipitation of the drug has been a major hindrance in its long-term stability while
supporting the utilization of inline filters for infusions. The 2’ position in Paclitaxel’s
structure is ideal for inserting functional groups for creating Paclitaxel pro-drugs, as various
derivatives of 2-acyl Paclitaxel would hydrolyze quickly in the blood (Vagvolgyi et al. 2020).
A C-7 prodrug ester of Paclitaxel can be prepared as the C-7 hydroxyl group arrangement
does not influence cytotoxicity. The presence of a stronger electron releasing substituent,
such as an alkoxy group in the ester’s alpha position, facilitates the quickening of hydrolytic
cleavages. Prodrugs exhibit cytotoxic activities compared to Paclitaxel against cancer in
vitro. Paclitaxel prodrugs formulated utilizing PEG is a promising approach as PEG imparts
efficient aqueous solubility. The pursuit of prodrug designing for industrial efforts focuses
on designing water-soluble derivatives and Paclitaxel’s structural analogues. Paclitaxel is
found in 30 mg (5 ml), 300 mg (50 mL) and 100 mg(16.7 mL) multidose vials (Bhat et al.
2016). Every ml of sterile nonpyrogenic solutions contain 6 mg paclitaxel, 2 mg of
anhydrous citric acid, 527 mg of polyoxyl 35 castor oil, and 49.7% (v/v) dehydrated alcohol.
Cyclodextrins are molecule complexing agents used to increase the stability and solubility of
poorly soluble drugs. Various β? and γ?cyclodextrins such as hydroxypropyl, hydroxyethyl,
and dimethyl enhances the solubility of Paclitaxel by 2*10^3 fold, without altering
cytostatic properties of the drug in-vitro (Raza et al. 2021). The quantity of the solubilized
drug improves with CyD concentration; however, precipitation can be noticed in some
stoichiometries. Therefore, health practitioners should be educated concerning the usage of
accurate non-PVC administration sets and containers for inducing convenience in delivering
Paclitaxel. Studies determine amphoterin B, hydroxyzine, mitoxantrone, chlorpromazine,
and methylprednisolone sodium succinate to be incompatible with infusions of Paclitaxel.
Paclitaxel has the ability of microtubule stabilization and has been associated with
3. platinum-based therapy for the provision of standard care in cancer management. It is a
cytoskeletal drug targeting ‘tubulin’. Cells treated with Paclitaxel usually have deformities in
mitotic spindle assemblies, cell division and chromosome segregation. The drug's
mechanism of action suggests that unlike other drugs that target tubulin like colchicine,
which inhibits the assembly of microtubules, Paclitaxel helps stabilise the microtubule
polymer while protecting it from disassembling (Kampan et al. 2015). Chromosomes
remain unable to achieve a spindle configuration in the metaphase. The progression of
mitosis is blocked, and activation of the mitotic checkpoint for a prolonged duration triggers
reversion to the G0 phase of the cell cycle without undergoing cell division or apoptosis.
Paclitaxel’s ability to hinder spindle function is attributed to suppressing the dynamics of
microtubules. However, it occurs at concentrations lower than what is required to block
mitosis. Paclitaxel suppresses the detachment of microtubules from centrosomes at high
therapeutic concentrations, a process activated in mitosis. Paclitaxel effectively binds to
‘beta-tubulin’ sub-unis in microtubules. Unlike vinca alkaloids, which cause microtubule
depolymerization, Paclitaxel acts during the mitotic stage of cellular division. Paclitaxel also
activates multiple pathways of signal transduction, which is linked with proapoptotic
signalling (Lee et al. 2015). The associated pathways with Paclitaxel are TLR-4 dependent
pathway, the c-Jun N-terminal kinase pathway, P38 mitogen-activated protein kinase,
nuclear factor-kappa, and transcription factor activator pathway. Induction of pro-
inflammatory proteins and cytokines would lead to immune-modulatory effects at low-
dosage concentrations and higher doses, inducing cell death. At concentrations of less than
9 nM, Paclitaxel activates Raf-1, responsible for controlling apoptosis (Ozfiliz et al. 2015). At
more than 9 nM, there is an absence of the involvement of Raf-1 kinase, but apoptosis is
induced for the impact of p53 and p21. With similar concentrations but over 24-hour
exposure, a mitotic arrest can be caused irreversibly. Weekly paclitaxel administration
exhibits inhibitory angiogenic activity.
Extracting Paclitaxel from its plant origin, Taxus brevifolia kills many plants for yielding a
few grams of the drug (Zhu and Chen 2019). Consequently, a practical synthetic procedure
of paclitaxel production requires the development of challenges due to the structural
complexities. The current production of Paclitaxel industrially occurs through a technology
of paclitaxel fermentation, where Paclitaxel can be extracted efficiently from cultured cell
lines of Taxus, which can be purified using chromatography. Paclitaxel has a diterpenoid
structure around complex, bulky, and fused taxane rings while containing multiple
hydrophobic substituents, making it a greatly lipophilic compound with aqueous solubility
lesser than 0.01 mg/ml. In addition, the compound does not contain functional groups that
are potentially ionizable, leading to its increase in solubility with altering pH. Among
various non-aqueous solvents, the solubility has been traced to be nearly 46 mM for
ethanol, nearly 20 mM in acetonitrile or methylene chloride, and about 14 mM for
isopropanol. It also shows solubility in tertiary-butanol, methanol and dimethyl sulfoxide.
To decrease toxic effects linked to conventional formulations of Paclitaxel discussed before
while minimizing precipitation risks of Paclitaxel on dilution, a nanoparticle formulation for
4. Paclitaxel has been introduced called Abraxane (Zhao et al. 2015). Particle formation
technology involves a proprietary process binding unmodified albumin to the molecule of
Paclitaxel for producing conjugate masses less than 130 nm size. On infusion, the
nanoparticles dissociate rapidly to yield an albumin-bound drug aggregate. Paclitaxel-
albumin molecules bind to albumin receptors (gp60) on endothelial cells. It helps in the
transportation of Paclitaxel via caveolae formation into extravascular spaces.
An alternate pathway for transport has been considered for binding the nanoparticles with
SPARC or “secreted acidic protein rich in cysteine” (Noorani et al. 2015). However, Sparc
remains overexpressed in various solid tumours, including prostate and bladder cancers, so
the nab-paclitaxel causes a 33% rise in intra-tumoral concentrations and a 50% high
paclitaxel dose delivered in comparison to Paclitaxel infusion, occurring conventionally.
Moreover, as the nab-paclitaxel is solvent-free, there is a shorter infusion time than
Paclitaxel mixed with Cremophor EL.
Among alternative systems of experimental delivery of Paclitaxel, the nanoparticles from
various bio-adhesive materials and biodegradable polymers have been promisingly
considered. Nanotechnology helps improve the bioavailability of poorly soluble drugs while
enhancing the overall system of drug delivery. Nanoparticles can permeate through tissues
without adding to their potential of drug targeting. Therefore, the drug delivery should
occur efficiently to the targeted tissue without clogging the capillaries to protect the drug’s
stability and bioactivity. On incorporating Paclitaxel into nanoparticles, drug action has had
a demonstrable enhancement for the notable changes in pharmacokinetics and tissue
distribution. Nanoparticles can also evade quick clearance through the reticuloendothelial
system and accumulate preferentially in solid tumours by escaping prevalent angiogenic
vasculatures that permeate through the neoplasm (Kianfar 2021). The delivery of drugs in
nanoparticle carriers lead to an extension of drug retention in tumours, causes prolonged
survival of test subjects, and diminution in the growth of tumours.
Furthermore, the phenotype of multidrug resistance mediated by p-glycoproteins of tumour
cells can be overcome by utilizing nanoparticle delivery of the drug. It is significant as the
acquired resistance for Paclitaxel can be reported. Additional advantages of nanoparticles
are levied due to their enhanced stability mode, for biological fluids or during storage.
Preparation of Paclitaxel nanoparticles utilizing the method of interfacial deposition can be
observed. An organic PLGA solution in acetone with Paclitaxel can be added to an aqueous
poloxamer 188 solutions. It is observed at room temperature through constant stirring
using magnetic fields, followed by harvesting and washing the nanoparticles using
ultracentrifugation. In vitro studies examine the conduction of measuring residual paclitaxel
amount at particular time points after having the PLGA-nanoparticles consisting of
Paclitaxel diluted in PBS solution and incubated in horizontal shakers at 37°C (Madani et al.
2018). The particles exhibit biphasic patterns for releasing Paclitaxel, along with a fast
release on the first day and constant slower release later.
5. Liposomes are lipoid vesicles offering flexible platforms for encapsulating hydrophilic and
lipophilic drugs. Lipophilic drugs attain a lipid bilayer while hydrophilic drugs remain
located in the vesicle cavity. When drugs are encapsulated in liposomes, a change in
pharmacodynamics and pharmacokinetic properties results in a reduction of toxicity and an
increase in drug potency. The preparation and characteristic sterile stabilization of
Paclitaxel- liposomes are compared to conventional liposomes loaded with Paclitaxel due to
its circulation in blood for extended periods. PEGylated liposomes are prepared using
Paclitaxel with cholesterol and phospholipids in the molar ratio of 1:30 (Mol drug: Mol
lipid). Incorporating more than 20% cholesterol decreases formulations' physical stability
and incorporation efficiency (Lee 2020). The spleen and liver distribution of PEGylated
liposomes consisting of Paclitaxel have been evaluated after Paclitaxel extraction from the
tissues using “t-butyl methyl ether”. These formulations have been assessed to be well-
tolerated in mice when administered via intraperitoneal and intravenous bolus doses. The
maximum dose that can be tolerated has been deduced to be within 200 mg/kg in the case
of liposomal Paclitaxel and 30 mg/kg by Intravenous administration, or50 mg/kg for free
Paclitaxel via Intra-peritonial routes.
Conclusion
The maintenance of a proper procedure to administer drugs or pharmaceutical components
correctly for humans and animals is of paramount importance to derive positive outcomes.
The product needs to be stable and adequate delivery maintenance under different
physiological variables. After a broad field of research on novel conventional approaches for
delivering Paclitaxel, the acknowledgement of controlled, steady and effective therapeutic
delivery has been examined. Cremophor EL can enhance the solubility and dispersion of
Paclitaxel in an aqueous medium. Nanoparticles have been considered for aiding Paclitaxel
delivery approaches by utilizing a formulated compound called Abraxane. Environmental-
friendly processes can produce naturally derived pharmaceutical ingredients from plant
cells. Paclitaxel administration as 1-hour infusions through weekly and 3-week treatment
regimens can actively treat various tumours and carcinomas, inducing unknown primary
sites.
References
Bhat, M.A., Varshneya, C., Bhardwaj, P. and Patil, R.J., 2016. Paclitaxel-Development,
properties, toxicity/safety evaluation and the scope of improvement. IOSR Journal of
Biotechnology and Biochemistry, 2(4), pp.40-48.
Kampan, N.C., Madondo, M.T., McNally, O.M., Quinn, M. and Plebanski, M., 2015. Paclitaxel
and its evolving role in the management of ovarian cancer. BioMed research
international, 2015.
Kianfar, E., 2021. Protein nanoparticles in drug delivery: animal protein, plant proteins and
6. protein cages, albumin nanoparticles. Journal of Nanobiotechnology, 19(1), pp.1-32.
Lee, J.H., Kim, C., Sethi, G. and Ahn, K.S., 2015. Brassinin inhibits STAT3 signaling pathway
through modulation of PIAS-3 and SOCS-3 expression and sensitizes human lung cancer
xenograft in nude mice to paclitaxel. Oncotarget, 6(8), p.6386.
Lee, M.K., 2020. Liposomes for enhanced bioavailability of water-insoluble drugs: in vivo
evidence and recent approaches. Pharmaceutics, 12(3), p.264.
Li, Y., Chen, N., Palmisano, M. and Zhou, S., 2015. Pharmacologic sensitivity of paclitaxel to
its delivery vehicles drives distinct clinical outcomes of paclitaxel formulations. Molecular
pharmaceutics, 12(4), pp.1308-1317.
Madani, F., Esnaashari, S.S., Mujokoro, B., Dorkoosh, F., Khosravani, M. and Adabi, M., 2018.
Investigation of effective parameters on size of paclitaxel loaded PLGA
nanoparticles. Advanced pharmaceutical bulletin, 8(1), p.77.
Mohanlall, V. and Naicker, L., 2020. A brief review of secondary plant metabolites as
anticancer agents. COJ Rev & Res, Vol. 2, Issue 4.
Noorani, L., Stenzel, M., Liang, R., Pourgholami, M.H. and Morris, D.L., 2015. Albumin
nanoparticles increase the anticancer efficacy of albendazole in ovarian cancer xenograft
model. Journal of nanobiotechnology, 13(1), pp.1-12.
Ozfiliz, P., Kizilboga, T., Demir, S., Alkurt, G., Palavan?Unsal, N., Arisan, E.D. and
Dinler?Doganay, G., 2015. Bag?1 promotes cell survival through c?Myc?mediated ODC
upregulation that is not preferred under apoptotic stimuli in MCF?7 cells. Cell Biochemistry
and Function, 33(5), pp.293-307.
Raza, A., Miles, J.A., Sime, F.B., Ross, B.P., Roberts, J.A., Popat, A., Kumeria, T. and Falconer,
J.R., 2021. PLGA encapsulated γ-cyclodextrin-meropenem inclusion complex formulation for
oral delivery. International Journal of Pharmaceutics, 597, p.120280.
Vágvölgyi, M., Bélteky, P., Bogdán, D., Nové, M., Spengler, G., Latif, A.D., Zupkó, I., Gáti, T.,
Tóth, G., Kónya, Z. and Hunyadi, A., 2020. Squalenoylated Nanoparticle Pro-Drugs of
Adjuvant Antitumor 11α-Hydroxyecdysteroid 2, 3-Acetonides Act as Cytoprotective Agents
Against Doxorubicin and Paclitaxel. Frontiers in pharmacology, p.1368.
Wen, H., Jung, H. and Li, X., 2015. Drug delivery approaches in addressing clinical
pharmacology-related issues: opportunities and challenges. The AAPS journal, 17(6),
pp.1327-1340.
Zhao, L., Bi, D., Qi, X., Guo, Y., Yue, F., Wang, X. and Han, M., 2019. Polydopamine-based
7. surface modification of paclitaxel nanoparticles for osteosarcoma targeted
therapy. Nanotechnology, 30(25), p.255101.
Zhao, M., Lei, C., Yang, Y., Bu, X., Ma, H., Gong, H., Liu, J., Fang, X., Hu, Z. and Fang, Q., 2015.
Abraxane, the nanoparticle formulation of paclitaxel can induce drug resistance by up-
regulation of P-gp. PloS one, 10(7), p.e0131429.
Zhu, L. and Chen, L., 2019. Progress in research on paclitaxel and tumor
immunotherapy. Cellular & molecular biology letters, 24(1), pp.1-11.
